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Journal articles on the topic 'ONCOGENESE'
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1
HULSTAERT E, CHEVOLET I, KRUSE V, and BROCHEZ L. "Virale oncogenese van het merkelcelcarcinoom." Tijdschrift voor Geneeskunde, no. 9 (2016): 557–62. http://dx.doi.org/10.47671/tvg.72.09.2002109.
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Der, C. J. "Cellular oncogenes and human carcinogenesis." Clinical Chemistry 33, no. 5 (May 1, 1987): 641–46. http://dx.doi.org/10.1093/clinchem/33.5.641.
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Abstract Experimental studies over the past decade have identified 30 or so cellular genes as potential oncogenes. The genetic events that lead to cellular oncogene activation may result in the excessive or inappropriate expression of the gene, or the expression of an aberrant gene product. Although the involvement of these putative cellular oncogenes in human oncogenesis has not been proven, the accumulation of considerable experimental evidence strongly implicates some role of these genes in the malignant process. The inactivation of certain genetic loci (suppressor genes) may also contribute to tumor progression.
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Scarzello, Anthony, Jim Stauffer, Tim Back, Jeff Subleski, Jonathan Weiss, John Ortaldo, and Robert Wiltrout. "Immunological characterization of oncogene-driven models of hepatocellular carcinoma. (100.19)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 100.19. http://dx.doi.org/10.4049/jimmunol.184.supp.100.19.
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Abstract Constitutively active AKT, MET, and beta-catenin (CAT) are initiating oncogenes that efficiently induce hepatic primary tumors when co-delivered; but not as single agents. Using a qPCR assay, we have begun to detail the early events of oncogene integration and to correlate the amount of integrated oncogene with developing tumor size. Furthermore, we found that the serum from mice injected with MET/CAT have elevated levels of alpha fetoprotein, a biomarker which has been similarly observed in advanced cases of HCC. Correlating the influx of infiltrating leukocytes and serum biomarker levels with the quantity of integrated oncogenes is critical to characterize their relative contributions to tumor progression. The profile of liver leukocytes in both MET/CAT and AKT/CAT murine models display phenotypes similar to those in HCC patients. By day 14, increased frequency and numbers of Tregs, MDSCs, as well as an up-regulation of PD-1 on CD4+ and CD8+ T cells was observed. The oncogene-driven tumor models described in this study exhibit many of the molecular and cellular events underlying HCC progression in humans. This molecularly defined approach to hepatocellular oncogenesis should enable us to characterize the contributions of inflammation in a primary tumor model with a defined oncogene signaling pathway.
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Cooper, H. L., N. Feuerstein, M. Noda, and R. H. Bassin. "Suppression of tropomyosin synthesis, a common biochemical feature of oncogenesis by structurally diverse retroviral oncogenes." Molecular and Cellular Biology 5, no. 5 (May 1985): 972–83. http://dx.doi.org/10.1128/mcb.5.5.972-983.1985.
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To identify proteins whose production may be altered as a common event in the expression of structurally diverse oncogenes, we compared two-dimensional electropherograms of newly synthesized proteins from NIH/3T3 cell lines transformed by a variety of retroviral oncogenes, from cellular revertant lines, and from a line (433.3) which expresses the v-ras oncogene in response to corticosteroids. Most alterations in the synthesis of specific proteins detected by this approach appeared to be the result of selection during prolonged cultivation and were probably unrelated to the transformation process. However, we detected seven proteins whose synthesis was strongly suppressed in cell lines transformed by each of the six retroviral oncogenes we studied and whose production was fully or partially restored in two cellular revertant lines. Suppression of two of these proteins was also correlated with the initial appearance of morphological alteration during corticosteroid-induced oncogene expression in 433.3 cells. These proteins (p37/4.78 and p41/4.75) were identified as tropomyosins, a group of at least five cytoskeletal proteins. Transformation by the papovaviruses simian virus 40 and polyomavirus caused no suppression of synthesis of these tropomyosins. This indicates that suppression of tropomyosin synthesis is not a nonspecific response by cells to being forced to grow with the transformed phenotype but is specifically associated with oncogenesis by diverse retroviral oncogenes. The results are consistent with the hypothesis that the different biochemical processes initiated by expression of structurally diverse retroviral oncogenes may converge on a limited number of common targets, one of which is the mechanism which regulates the synthesis of tropomyosins.
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Cooper, H. L., N. Feuerstein, M. Noda, and R. H. Bassin. "Suppression of tropomyosin synthesis, a common biochemical feature of oncogenesis by structurally diverse retroviral oncogenes." Molecular and Cellular Biology 5, no. 5 (May 1985): 972–83. http://dx.doi.org/10.1128/mcb.5.5.972.
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To identify proteins whose production may be altered as a common event in the expression of structurally diverse oncogenes, we compared two-dimensional electropherograms of newly synthesized proteins from NIH/3T3 cell lines transformed by a variety of retroviral oncogenes, from cellular revertant lines, and from a line (433.3) which expresses the v-ras oncogene in response to corticosteroids. Most alterations in the synthesis of specific proteins detected by this approach appeared to be the result of selection during prolonged cultivation and were probably unrelated to the transformation process. However, we detected seven proteins whose synthesis was strongly suppressed in cell lines transformed by each of the six retroviral oncogenes we studied and whose production was fully or partially restored in two cellular revertant lines. Suppression of two of these proteins was also correlated with the initial appearance of morphological alteration during corticosteroid-induced oncogene expression in 433.3 cells. These proteins (p37/4.78 and p41/4.75) were identified as tropomyosins, a group of at least five cytoskeletal proteins. Transformation by the papovaviruses simian virus 40 and polyomavirus caused no suppression of synthesis of these tropomyosins. This indicates that suppression of tropomyosin synthesis is not a nonspecific response by cells to being forced to grow with the transformed phenotype but is specifically associated with oncogenesis by diverse retroviral oncogenes. The results are consistent with the hypothesis that the different biochemical processes initiated by expression of structurally diverse retroviral oncogenes may converge on a limited number of common targets, one of which is the mechanism which regulates the synthesis of tropomyosins.
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Moore, Patrick S. "KSHV-encoded oncogenes and oncogenesis." Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology 14, no. 4 (April 1997): A14. http://dx.doi.org/10.1097/00042560-199704010-00033.
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Ito, Reina E., Chitose Oneyama, and Kazuhiro Aoki. "Oncogenic mutation or overexpression of oncogenic KRAS or BRAF is not sufficient to confer oncogene addiction." PLOS ONE 16, no. 4 (April 1, 2021): e0249388. http://dx.doi.org/10.1371/journal.pone.0249388.
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Oncogene addiction is a cellular property by which cancer cells become highly dependent on the expression of oncogenes for their survival. Oncogene addiction can be exploited to design molecularly targeted drugs that kill only cancer cells by inhibiting the specific oncogenes. Genes and cell lines exhibiting oncogene addiction, as well as the mechanisms by which cell death is induced when addicted oncogenes are suppressed, have been extensively studied. However, it is still not fully understood how oncogene addiction is acquired in cancer cells. Here, we take a synthetic biology approach to investigate whether oncogenic mutation or oncogene expression suffices to confer the property of oncogene addiction to cancer cells. We employed human mammary epithelium-derived MCF-10A cells expressing the oncogenic KRAS or BRAF. MCF-10A cells harboring an oncogenic mutation in a single-allele of KRAS or BRAF showed weak transformation activity, but no characteristics of oncogene addiction. MCF-10A cells overexpressing oncogenic KRAS demonstrated the transformation activity, but MCF-10A cells overexpressing oncogenic BRAF did not. Neither cell line exhibited any oncogene addiction properties. These results indicate that the introduction of oncogenic mutation or the overexpression of oncogenes is not sufficient for cells to acquire oncogene addiction, and that oncogene addiction is not associated with transformation activity.
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Semina, Ekaterina V., Karina D. Rysenkova, Konstantin E. Troyanovskiy, Anna A. Shmakova, and Kseniya A. Rubina. "MicroRNAs in Cancer: From Gene Expression Regulation to the Metastatic Niche Reprogramming." Biochemistry (Moscow) 86, no. 7 (June 7, 2021): 785–99. http://dx.doi.org/10.1134/s0006297921070014.
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Abstract By 2003, the Human Genome project had been completed; however, it turned out that 97% of genome sequences did not encode proteins. The explanation came later when it was found the untranslated DNA contain sequences for short microRNAs (miRNAs) and long noncoding RNAs that did not produce any mRNAs or tRNAs, but instead were involved in the regulation of gene expression. Initially identified in the cytoplasm, miRNAs have been found in all cell compartments, where their functions are not limited to the degradation of target mRNAs. miRNAs that are secreted into the extracellular space as components of exosomes or as complexes with proteins, participate in morphogenesis, regeneration, oncogenesis, metastasis, and chemoresistance of tumor cells. miRNAs play a dual role in oncogenesis: on one hand, they act as oncogene suppressors; on the other hand, they function as oncogenes themselves and inactivate oncosuppressors, stimulate tumor neoangiogenesis, and mediate immunosuppressive processes in the tumors, The review presents current concepts of the miRNA biogenesis and their functions in the cytoplasm and nucleus with special focus on the noncanonical mechanisms of gene regulation by miRNAs and involvement of miRNAs in oncogenesis, as well as the authors’ opinion on the role of miRNAs in metastasis and formation of the premetastatic niche.
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Nowell, Peter C., and Carlo M. Croce. "Chromosomal approaches to oncogenes and oncogenesis 1." FASEB Journal 2, no. 15 (December 1988): 3054–60. http://dx.doi.org/10.1096/fasebj.2.15.3056765.
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Land, H., A. C. Chen, J. P. Morgenstern, L. F. Parada, and R. A. Weinberg. "Behavior of myc and ras oncogenes in transformation of rat embryo fibroblasts." Molecular and Cellular Biology 6, no. 6 (June 1986): 1917–25. http://dx.doi.org/10.1128/mcb.6.6.1917-1925.1986.
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The requirements for transformation of rat embryo fibroblasts (REFs) by transfected ras and myc oncogenes were explored. Under conditions of dense monolayer culture, neither oncogene was able to transform REFs on its own. However, the introduction of a ras oncogene together with a selectable neomycin resistance marker into REFs allowed killing of the normal nontransfected cells and the outgrowth of colonies of ras transformants, 10% of which survived crisis and became tumorigenic. These cells expressed greater than 10-fold-higher levels of ras p21 than tumorigenic cells cotransfected with ras and myc oncogenes. The myc oncogene similarly was unable to induce tumorigenic conversion of REFs unless especially refractile colonies of oncogene-bearing cells, produced by use of a cotransfected selectable marker, were picked and subcultured. Tumorigenic conversion of REFs by single transfected oncogenes appears to require special culture conditions and high levels of gene expression.
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Land, H., A. C. Chen, J. P. Morgenstern, L. F. Parada, and R. A. Weinberg. "Behavior of myc and ras oncogenes in transformation of rat embryo fibroblasts." Molecular and Cellular Biology 6, no. 6 (June 1986): 1917–25. http://dx.doi.org/10.1128/mcb.6.6.1917.
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The requirements for transformation of rat embryo fibroblasts (REFs) by transfected ras and myc oncogenes were explored. Under conditions of dense monolayer culture, neither oncogene was able to transform REFs on its own. However, the introduction of a ras oncogene together with a selectable neomycin resistance marker into REFs allowed killing of the normal nontransfected cells and the outgrowth of colonies of ras transformants, 10% of which survived crisis and became tumorigenic. These cells expressed greater than 10-fold-higher levels of ras p21 than tumorigenic cells cotransfected with ras and myc oncogenes. The myc oncogene similarly was unable to induce tumorigenic conversion of REFs unless especially refractile colonies of oncogene-bearing cells, produced by use of a cotransfected selectable marker, were picked and subcultured. Tumorigenic conversion of REFs by single transfected oncogenes appears to require special culture conditions and high levels of gene expression.
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Alema, S., F. Tato, and D. Boettiger. "myc and src oncogenes have complementary effects on cell proliferation and expression of specific extracellular matrix components in definitive chondroblasts." Molecular and Cellular Biology 5, no. 3 (March 1985): 538–44. http://dx.doi.org/10.1128/mcb.5.3.538-544.1985.
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The effects of the avian viral oncogenes src and myc were compared for their ability to alter the differentiated phenotype and the proliferative capacity of definitive chondroblasts. As previously demonstrated, viruses carrying the src oncogene suppressed the synthesis of the chondroblast-specific products, type II collagen and cartilage-specific sulfated proteoglycan. In contrast, infection with MC29 and HB1 viruses, which carry the myc oncogene, did not suppress the synthesis of these normal differentiated cell products, but the infected cells exhibited an increased proliferative potential. The MH2 virus, which carries both the myc and mil oncogenes, both induced the suppression of these chondroblast-specific products and increased cell proliferation. The implications of these results for cooperation between oncogenes and the multi-oncogene models for neoplastic transformation are discussed.
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Alema, S., F. Tato, and D. Boettiger. "myc and src oncogenes have complementary effects on cell proliferation and expression of specific extracellular matrix components in definitive chondroblasts." Molecular and Cellular Biology 5, no. 3 (March 1985): 538–44. http://dx.doi.org/10.1128/mcb.5.3.538.
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The effects of the avian viral oncogenes src and myc were compared for their ability to alter the differentiated phenotype and the proliferative capacity of definitive chondroblasts. As previously demonstrated, viruses carrying the src oncogene suppressed the synthesis of the chondroblast-specific products, type II collagen and cartilage-specific sulfated proteoglycan. In contrast, infection with MC29 and HB1 viruses, which carry the myc oncogene, did not suppress the synthesis of these normal differentiated cell products, but the infected cells exhibited an increased proliferative potential. The MH2 virus, which carries both the myc and mil oncogenes, both induced the suppression of these chondroblast-specific products and increased cell proliferation. The implications of these results for cooperation between oncogenes and the multi-oncogene models for neoplastic transformation are discussed.
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Cline, M. J., H. Battifora, and J. Yokota. "Proto-oncogene abnormalities in human breast cancer: correlations with anatomic features and clinical course of disease." Journal of Clinical Oncology 5, no. 7 (July 1987): 999–1006. http://dx.doi.org/10.1200/jco.1987.5.7.999.
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DNAs from fifty-three primary breast cancers were hybridized with 16 different proto-oncogene or oncogene probes. Abnormalities of one or more of five proto-oncogenes were found in fifty-eight percent of tumors at the time of mastectomy. Amplification of c-myc and c-erbB-2, and allelic deletions of c-ras-Ha and c-myb were the most common abnormalities. The presence of altered proto-oncogenes correlated with clinical stage of the cancers. Fifteen of 43 evaluable tumors of stages I to III recurred, and four of five evaluable stage IV tumors progressed within 16 to 24 months of surgery. All but one of the cancers that recurred or progressed had detectably altered proto-oncogenes (P less than .001). Analysis of proto-oncogenes may have prognostic value in breast cancer.
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Alqahtani, Tariq, Vishnu Kumarasamy, Sahar Saleh Alghamdi, Rasha Saad Suliman, Khalid Bin Saleh, Mohammed A. Alrashed, Mohammed Aldhaeefi, and Daekyu Sun. "Adefovir Dipivoxil as a Therapeutic Candidate for Medullary Thyroid Carcinoma: Targeting RET and STAT3 Proto-Oncogenes." Cancers 15, no. 7 (April 5, 2023): 2163. http://dx.doi.org/10.3390/cancers15072163.
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Aberrant gene expression is often linked to the progression of various cancers, making the targeting of oncogene transcriptional activation a potential strategy to control tumor growth and development. The RET proto-oncogene’s gain-of-function mutation is a major cause of medullary thyroid carcinoma (MTC), which is part of multiple endocrine neoplasia type 2 (MEN2) syndrome. In this study, we used a cell-based bioluminescence reporter system driven by the RET promoter to screen for small molecules that potentially suppress the RET gene transcription. We identified adefovir dipivoxil as a transcriptional inhibitor of the RET gene, which suppressed endogenous RET protein expression in MTC TT cells. Adefovir dipivoxil also interfered with STAT3 phosphorylation and showed high affinity to bind to STAT3. Additionally, it inhibited RET-dependent TT cell proliferation and increased apoptosis. These results demonstrate the potential of cell-based screening assays in identifying transcriptional inhibitors for other oncogenes.
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Yousefi, Maryam, Gábor Boross, Carly Weiss, Christopher W. Murray, Jess D. Hebert, Hongchen Cai, Emily L. Ashkin, et al. "Combinatorial Inactivation of Tumor Suppressors Efficiently Initiates Lung Adenocarcinoma with Therapeutic Vulnerabilities." Cancer Research 82, no. 8 (February 22, 2022): 1589–602. http://dx.doi.org/10.1158/0008-5472.can-22-0059.
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Abstract Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Many oncogenes and tumor suppressor genes are altered in this cancer type, and the discovery of oncogene mutations has led to the development of targeted therapies that have improved clinical outcomes. However, a large fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we perform iterative in vivo functional screens using quantitative autochthonous mouse model systems to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Generation of hundreds of diverse combinations of tumor suppressor alterations demonstrates that inactivation of suppressors of the RAS and PI3K pathways drives the development of oncogene-negative lung adenocarcinoma. Human genomic data and histology identified RAS/MAPK and PI3K pathway activation as a common feature of an event in oncogene-negative human lung adenocarcinomas. These Onc-negativeRAS/PI3K tumors and related cell lines are vulnerable to pharmacologic inhibition of these signaling axes. These results transform our understanding of this prevalent yet understudied subtype of lung adenocarcinoma. Significance: To address the large fraction of lung adenocarcinomas lacking mutations in proto-oncogenes for which targeted therapies are unavailable, this work uncovers driver pathways of oncogene-negative lung adenocarcinomas and demonstrates their therapeutic vulnerabilities.
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Moore, P. S., and Y. Chang. "Kaposi's Sarcoma-Associated Herpesvirus-Encoded Oncogenes and Oncogenesis." JNCI Monographs 1998, no. 23 (April 1, 1998): 65–71. http://dx.doi.org/10.1093/oxfordjournals.jncimonographs.a024176.
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Deng, Davy, Frank Dubois, Alexander Crane, Ashot Harutyunyan, Rameen Beroukhim, and Pratiti Bandopadhayay. "EPCO-21. CORE REGULATORY CIRCUIT TRANSCRIPTION FACTORS DRIVE EXPRESSION FROM HIGH LEVEL AMPLICONS IN PEDIATRIC HIGH-GRADE GLIOMAS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi6. http://dx.doi.org/10.1093/neuonc/noab196.020.
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Abstract BACKGROUND Pediatric High-Grade Gliomas (pHGGs) show recurrent high-level amplifications around the oncogenes MET, MYCN and EGFR. However what drives expression of the oncogenes from these amplicons remains unclear. We aim to discover enhancers on these amplicons that are responsible for oncogene expressions and the core regulatory transcription factors (TFs) they bind. METHOD Using RNA-seq from 12 pHGG cell lines, we identified groups of high and low-expressing pHGG lines for MET, MYCN and EGFR. We then compared the H3K27Ac ChIP-seq between the two groups using diffbind. This allowed us to identify statistically significant peaks that are differentially activated in the oncogene-high v.s. oncogene-low expressing groups. Additionally, we overlapped the positions of these candidate oncogene enhancers with the regions that are recurrently incorporated into high-level amplicons based on published whole genome sequencing data. Using a previously defined set of core regulatory TFs we determined which TF binds the amplified oncogene enhancers and could be driving oncogenic expressions of MET, MYCN and EGFR in pHGGs. RESULTS We identify 3 cell lines for both the high- and low-expressing groups for each oncogene. Cell lines with high expression of the oncogene showed distinct enhancers with significant enrichment in H3K27Ac compared to the cell lines with low expression for each oncogene. Of all enhancers with enrichment high oncogene expression groups those with binding sites for known pHGG core regulatory circuit TF were preferentially incorporated into the high-level amplicons of the oncogene. We also identified core TFs that bind enhancers for MYCN, EGFR and MET as well as core TFs that are unique to a single oncogene. CONCLUSION We identified candidate core transcription factor that drives expression of multiple oncogenes in pHGG. These could serve as a potential novel therapeutic target for pHGGs with addiction to MYCN or RTK signaling.
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Coulier, F., R. Kumar, M. Ernst, R. Klein, D. Martin-Zanca, and M. Barbacid. "Human trk oncogenes activated by point mutation, in-frame deletion, and duplication of the tyrosine kinase domain." Molecular and Cellular Biology 10, no. 8 (August 1990): 4202–10. http://dx.doi.org/10.1128/mcb.10.8.4202-4210.1990.
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Malignant activation of the human trk proto-oncogene, a member of the tyrosine protein kinase receptor family, has been implicated in the development of certain human cancers, including colon and thyroid papillary carcinomas. trk oncogenes have also been identified in cultured cells transfected with various DNAs. In this study, we report the characterization of three in vitro-generated trk oncogenes, trk2, trk4, and trk5 (R. Oskam, F. Coulier, M. Ernst, D. Martin-Zanca, and M. Barbacid, Proc. Natl. Acad. Sci. USA 85:2964-2968, 1988), in an effort to understand the spectrum of mutational events that can activate the human trk gene. Nucleotide sequence analysis of cDNA clones of trk2 and trk4 revealed that these oncogenes were generated by a head-to-tail arrangement of two trk tyrosine protein kinase domains connected by a purine-rich region. These oncogenes code for cytoplasmic molecules of 67,000 (p67trk2) and 69,000 (p69trk4) daltons. In contrast, the product of the trk5 oncogene, gp95trk5, is a cell surface glycoprotein of 95,000 daltons. This oncogene was generated by a 153-base-pair in-frame deletion within sequences coding for the extracellular domain of the trk receptor. This activating deletion encompasses a triplet coding for one of the nine cysteine residues that the trk receptor shares with the product of the highly related trkB tyrosine protein kinase gene. Introduction of a single point mutation (TGT----AGT) in this codon resulted in a novel trk oncogene whose product, gp140S345, differs from the nontransforming trk proto-oncogene receptor in a single amino acid residue, Ser-345 instead of Cys-345. These results illustrate that multiple molecular mechanisms, including point mutation, internal deletion, and kinase domain duplication, can result in the malignant activation of the human trk proto-oncogene.
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Coulier, F., R. Kumar, M. Ernst, R. Klein, D. Martin-Zanca, and M. Barbacid. "Human trk oncogenes activated by point mutation, in-frame deletion, and duplication of the tyrosine kinase domain." Molecular and Cellular Biology 10, no. 8 (August 1990): 4202–10. http://dx.doi.org/10.1128/mcb.10.8.4202.
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Malignant activation of the human trk proto-oncogene, a member of the tyrosine protein kinase receptor family, has been implicated in the development of certain human cancers, including colon and thyroid papillary carcinomas. trk oncogenes have also been identified in cultured cells transfected with various DNAs. In this study, we report the characterization of three in vitro-generated trk oncogenes, trk2, trk4, and trk5 (R. Oskam, F. Coulier, M. Ernst, D. Martin-Zanca, and M. Barbacid, Proc. Natl. Acad. Sci. USA 85:2964-2968, 1988), in an effort to understand the spectrum of mutational events that can activate the human trk gene. Nucleotide sequence analysis of cDNA clones of trk2 and trk4 revealed that these oncogenes were generated by a head-to-tail arrangement of two trk tyrosine protein kinase domains connected by a purine-rich region. These oncogenes code for cytoplasmic molecules of 67,000 (p67trk2) and 69,000 (p69trk4) daltons. In contrast, the product of the trk5 oncogene, gp95trk5, is a cell surface glycoprotein of 95,000 daltons. This oncogene was generated by a 153-base-pair in-frame deletion within sequences coding for the extracellular domain of the trk receptor. This activating deletion encompasses a triplet coding for one of the nine cysteine residues that the trk receptor shares with the product of the highly related trkB tyrosine protein kinase gene. Introduction of a single point mutation (TGT----AGT) in this codon resulted in a novel trk oncogene whose product, gp140S345, differs from the nontransforming trk proto-oncogene receptor in a single amino acid residue, Ser-345 instead of Cys-345. These results illustrate that multiple molecular mechanisms, including point mutation, internal deletion, and kinase domain duplication, can result in the malignant activation of the human trk proto-oncogene.
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Martín-Lorenzo, Alberto, Inés Gonzalez-Herrero, Guillermo Rodríguez-Hernández, Idoia García-Ramírez, Carolina Vicente-Dueñas, and Isidro Sánchez-García. "Early epigenetic cancer decisions." Biological Chemistry 395, no. 11 (November 1, 2014): 1315–20. http://dx.doi.org/10.1515/hsz-2014-0185.
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Abstract A cancer dogma states that inactivation of oncogene(s) can cause cancer remission, implying that oncogenes are the Achilles’ heel of cancers. This current model of cancer has kept oncogenes firmly in focus as therapeutic targets and is in agreement with the fact that in human cancers all cancerous cells, with independence of the cellular heterogeneity existing within the tumour, carry the same oncogenic genetic lesions. However, recent studies of the interactions between an oncogene and its target cell have shown that oncogenes contribute to cancer development via developmental reprogramming of the epigenome within the target cell. These results provide the first evidence that carcinogenesis can be initiated by epigenetic stem cell reprogramming, and uncover a new role for oncogenes in the origin of cancer. Here we analyse these evidences and discuss how this vision offers new avenues for developing novel anti-cancer interventions.
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Fan, Alice C., Debabrita Deb-Basu, Melissa Horoschak, Amy Shirer, David Voehringer, Roger O’Neill, and Dean W. Felsher. "Nano-Fluidic Detection of Oncoprotein Signaling in Preclinical and Patient Lymphoma Samples." Blood 108, no. 11 (November 16, 2006): 2527. http://dx.doi.org/10.1182/blood.v108.11.2527.2527.
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Abstract Inactivation of oncogenes can be an effective cancer therapy. Determining precise levels of oncogene expression is important in the development of drugs to target oncogenes. We have developed a novel automated nano-fluidic Western-blot-like technology to detect and quantify oncogene expression in small numbers of mouse and human hematopoietic tumor cells. To detect different levels of oncogene expression, we generated transgenic mice in which the MYC or BCL2 oncogenes are regulated conditionally via the Tetracycline Regulatory System (Tet-system). Using lymphoma- derived cell lines from these mice, we titrated the level of oncogene expression by adding different concentrations of doxycycline in vitro. We were able to distinguish among different levels of oncogene expression in cell lysates, with high sensitivity in as few as 400 cells by nano-fluidic detection. Next, lymphoma derived cell lines were injected subcutaneously into syngeneic mice. Upon tumor development, MYC or BCL2 oncogenes were inactivated in vivo. Both MYC and BCL2 levels decreased in serial fine needle aspirations (FNAs) of tumor nodules upon parallel analysis with nano-fluidic detection and Western blot. Finally, we used nano-fluidic detection to determine levels of MYC, BCL2, AKT and ERK in lymph node samples from patients with follicular, transformed DLBC, Burkitt’s, and mantle cell lymphomas. BCL2 was overexpressed in mantle cell and follicular lymphoma patients, confirmed by Western analysis, whereas MYC was found to be overexpressed in Burkitt’s lymphoma. These results demonstrate that nano-fluidic detection technology may be used both as a preclinical tool for the assessment of changes in oncoprotein signaling and as a clinical diagnostic modality on microscopic clinical specimens.
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Romeo, Maria Anele, Maria Saveria Gilardini Montani, Andrea Arena, Rossella Benedetti, Gabriella D’Orazi, and Mara Cirone. "c-Myc Sustains Pancreatic Cancer Cell Survival and mutp53 Stability through the Mevalonate Pathway." Biomedicines 10, no. 10 (October 5, 2022): 2489. http://dx.doi.org/10.3390/biomedicines10102489.
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It has been shown that wild-type (wt)p53 inhibits oncogene c-Myc while mutant (mut)p53 may transactivate it, with an opposite behavior that frequently occurs in the crosstalk of wt or mutp53 with molecules/pathways promoting carcinogenesis. Even if it has been reported that mutp53 sustains c-Myc, whether c-Myc could in turn influence mutp53 expression remains to be investigated. In this study, we found that pharmacological or genetic inhibition of c-Myc downregulated mutp53, impaired cell survival and increased DNA damage in pancreatic cancer cells. At the molecular level, we observed that c-Myc inhibition reduced the expression of mevalonate kinase (MVK), a molecule belonging to the mevalonate pathway that—according to previous findings—can control mutp53 stability, and thus contributes to cancer cell survival. In conclusion, this study unveils another criminal alliance between oncogenes, such as c-Myc and mutp53, that plays a key role in oncogenesis.
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Scheerger and Zempleni. "Expression of Oncogenes Depends on Biotin in Human Small Cell Lung Cancer Cells NCI-H69." International Journal for Vitamin and Nutrition Research 73, no. 6 (December 1, 2003): 461–67. http://dx.doi.org/10.1024/0300-9831.73.6.461.
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Oncogenes play important roles in cell proliferation and biotin status correlates with gene expression and proliferation rates in human cells. In this study we determined whether biotin supply affects biotin homeostasis, expression of oncogenes, and proliferation rates in NCI-H69 small cell lung cancer cells. NCI-H69 cells were cultured in media containing deficient (0.025 nmol/L), physiologic (0.25 nmol/L), or pharmacologic (10 nmol/L) concentrations of biotin for 3 weeks. Biotin concentrations in culture media correlated negatively with biotin transport rates, suggesting that cells responded to marginal biotin supply with increased expression of biotin transporters. Increased biotin uptake was not sufficient to prevent depletion of intracellular biotin in cells cultured in biotin-deficient medium, as judged by decreased activity of biotin-dependent propionyl-CoA carboxylase and decreased biotinylation of histones. The expression of oncogenes N-myc, c-myb, N-ras, and raf correlated with biotin supply in media: oncogene expression increased by up to 20% in cells cultured in pharmacologic medium compared to physiologic controls; oncogene expression decreased by up to 47% in cells cultured in deficient medium. This observation is consistent with a role for biotin in oncogene-dependent metabolic pathways. Cellular uptake of thymidine (marker for proliferation) was not affected by biotin supply, suggesting that effects of biotin-dependent expression of oncogenes on the growth of tumor cells are quantitatively minor. The clinical significance of effects of biotin supply on expression of oncogenes remains to be elaborated.
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Byun, Eunyoung, Joo Weon Lim, Jung Mogg Kim, and Hyeyoung Kim. "α-Lipoic Acid InhibitsHelicobacter pylori-Induced Oncogene Expression and Hyperproliferation by Suppressing the Activation of NADPH Oxidase in Gastric Epithelial Cells." Mediators of Inflammation 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/380830.
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Hyperproliferation and oncogene expression are observed in the mucosa ofHelicobacter pylori- (H. pylori-)infected patients with gastritis or adenocarcinoma. Expression of oncogenes such asβ-catenin and c-myc is related to oxidative stress.α-Lipoic acid (α-LA), a naturally occurring thiol compound, acts as an antioxidant and has an anticancer effect. The aim of this study is to investigate the effect ofα-LA onH. pylori-induced hyperproliferation and oncogene expression in gastric epithelial AGS cells by determining cell proliferation (viable cell numbers, thymidine incorporation), levels of reactive oxygen species (ROS), NADPH oxidase activation (enzyme activity, subcellular levels of NADPH oxidase subunits), activation of redox-sensitive transcription factors (NF-κB, AP-1), expression of oncogenes (β-catenin, c-myc), and nuclear localization ofβ-catenin. Furthermore, we examined whether NADPH oxidase mediates oncogene expression and hyperproliferation inH. pylori-infected AGS cells using treatment of diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase. As a result,α-LA inhibited the activation of NADPH oxidase and, thus, reduced ROS production, resulting in inhibition on activation of NF-κB and AP-1, induction of oncogenes, nuclear translocation ofβ-catenin, and hyperproliferation inH. pylori-infected AGS cells. DPI inhibitedH. pylori-induced activation of NF-κB and AP-1, oncogene expression and hyperproliferation by reducing ROS levels in AGS cells. In conclusion, we propose that inhibiting NADPH oxidase byα-LA could prevent oncogene expression and hyperproliferation occurring inH. pylori-infected gastric epithelial cells.
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Winter, E., and M. Perucho. "Oncogene amplification during tumorigenesis of established rat fibroblasts reversibly transformed by activated human ras oncogenes." Molecular and Cellular Biology 6, no. 7 (July 1986): 2562–70. http://dx.doi.org/10.1128/mcb.6.7.2562-2570.1986.
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Normal rat fibroblasts of the established cell line Rat 4 were cotransformed with activated human ras oncogenes and with a cloned chicken thymidine kinase (tk) gene. Linkage between tk and ras genes allowed the isolation of oncogene deletion revertants and of cell clones showing varying degrees of malignant phenotype. Southern and Northern experiments in concert with tumorigenicity assays show that the malignant transformation of these cells by mutant ras oncogenes is a gradual but reversible process that depends on the relative abundance of oncogene sequences and their corresponding transcripts. We also show that moderate amplification of a c-K-ras oncogene in these cells results in a clear increase in their tumorigenicity and that the mutant gene present in low copy numbers in cultured cells undergoes amplification in the corresponding in vivo induced tumors.
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Winter, E., and M. Perucho. "Oncogene amplification during tumorigenesis of established rat fibroblasts reversibly transformed by activated human ras oncogenes." Molecular and Cellular Biology 6, no. 7 (July 1986): 2562–70. http://dx.doi.org/10.1128/mcb.6.7.2562.
Full textAbstract:
Normal rat fibroblasts of the established cell line Rat 4 were cotransformed with activated human ras oncogenes and with a cloned chicken thymidine kinase (tk) gene. Linkage between tk and ras genes allowed the isolation of oncogene deletion revertants and of cell clones showing varying degrees of malignant phenotype. Southern and Northern experiments in concert with tumorigenicity assays show that the malignant transformation of these cells by mutant ras oncogenes is a gradual but reversible process that depends on the relative abundance of oncogene sequences and their corresponding transcripts. We also show that moderate amplification of a c-K-ras oncogene in these cells results in a clear increase in their tumorigenicity and that the mutant gene present in low copy numbers in cultured cells undergoes amplification in the corresponding in vivo induced tumors.
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Brown, Geoffrey. "Oncogenes, Proto-Oncogenes, and Lineage Restriction of Cancer Stem Cells." International Journal of Molecular Sciences 22, no. 18 (September 7, 2021): 9667. http://dx.doi.org/10.3390/ijms22189667.
Full textAbstract:
In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes are viewed as deregulating cell proliferation or suppressing apoptosis in driving cancer. The cancer stem cell theory states that most, if not all, cancers are a hierarchy of cells that arises from a transformed tissue-specific stem cell. These normal counterparts generate various cell types of a tissue, which adds a new dimension to how oncogenes might lead to the anarchic behavior of cancer cells. It is that stem cells, such as hematopoietic stem cells, replenish mature cell types to meet the demands of an organism. Some oncogenes appear to deregulate this homeostatic process by restricting leukemia stem cells to a single cell lineage. This review examines whether cancer is a legacy of stem cells that lose their inherent versatility, the extent that proto-oncogenes play a role in cell lineage determination, and the role that epigenetic events play in regulating cell fate and tumorigenesis.
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Ronco, PM, D. Prie, R. Piedagnel, and B. Lelongt. "Oncogene-Transformed Renal Cell Lines: Physiological and Oncogenetic Studies." Physiology 9, no. 5 (October 1, 1994): 208–14. http://dx.doi.org/10.1152/physiologyonline.1994.9.5.208.
Full textAbstract:
Use of inducible oncogenes has recently boosted interest in immortalized cell lines derived by transfection of primary cultures or from transgenic mice. When the oncogene is functional, cells exhibit a transformed phenotype, whereas upon oncogene inactivation, they can differentiate up to the level of the parental cells.
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Nisa, Nabilatun, Sri Puji Astuti Wahyuningsih, Win Darmanto, Putut Rakhmad Purnama, Firli Rahmah Primula Dewi, Tipuk Soegiarti, and Deya Karsari. "Effect of the Ethanol Extract of Red Okra Pods (Abelmoschus esculentus (L.) Moench) to Inhibit Cervical Cancer Cells Growth through Cell Cycle-Associated Oncogenes." Scientifica 2022 (April 26, 2022): 1–7. http://dx.doi.org/10.1155/2022/1094771.
Full textAbstract:
This study aims to evaluate the potency of ethanol extract of red okra pods (EEROP) in inhibiting growth of cervical cancer cells through repression of the cell cycle-associated oncogenes. The EEROP treatment was given to HeLa cells cultured with RPMI medium and incubated at 37°C with 5% CO2. The MTT method was used to measure HeLa cell growth and IC50 values. The mRNA levels of the three cell cycle-associated oncogenes (MYC, TYMS, and MDM2) were evaluated by qRT-PCR to determine the effect of EEROP treatment on the cell cycle. The lowest percentage of viable cells at 24, 48, and 72 hours after EEROP treatment was in the dose of 1000 μg/mL with a growth percentage of 71.60% at 24 hours, 55.61% at 48 hours, and 46.97% at 72 hours. The IC50 values were 2845, 1153, and 776.8 μg/mL for 24, 48, and 72 hours, respectively. The three oncogenes at a dose of 1000 μg/mL significantly decreased the lowest mRNA levels compared to other doses with MYC oncogene that experienced the greatest decrease. The mRNA level of dose 1000 μg/mL EEROP at the MYC oncogene was 0.014-fold changes, at the TYMS oncogene was 0.097-fold changes, and at the MDM2 oncogene was 0.028-fold changes. The EEROP has been shown to decrease the expression of three cell cycle-associated oncogenes. This is also supported by the growth of HeLa cells that did not increase throughout 24, 48, and 72 hours. However, further research is needed on the main active components in red okra that function as anticancer, so that in the future, okra can not only stop cancer cell growth but also induce cancer cell death.
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Kelekar, A., and M. D. Cole. "Immortalization by c-myc, H-ras, and Ela oncogenes induces differential cellular gene expression and growth factor responses." Molecular and Cellular Biology 7, no. 11 (November 1987): 3899–907. http://dx.doi.org/10.1128/mcb.7.11.3899-3907.1987.
Full textAbstract:
Early-passage rat kidney cells were immortalized or rescued from senescence with three different oncogenes: viral promoter-driven c-myc, H-ras (Val-12), and adenovirus type 5 E1a. The normal c-myc and H-ras (Gly-12) were unable to immortalize cells under similar conditions. Quantitation of RNA in the ras-immortalized lines demonstrated that the H-ras oncogene was expressed at a level equivalent to that of the normal H-ras gene in established human or rat cell lines. Cell lines immortalized by different oncogenes were found to have distinct growth responses to individual growth factors in a short-term assay. E1a-immortalized cells were largely independent of serum growth factors, whereas c-myc-immortalized cells responded to serum better than to epidermal growth factor and insulin. H-ras-immortalized cells responded significantly to insulin alone and gave a maximal response to epidermal growth factor and insulin. Several cellular genes associated with platelet-derived growth factor stimulation, including c-myc, were expressed at high levels in the H-ras-immortalized cells, and c-myc expression was deregulated, suggesting that the H-ras oncogene has provided a "competence" function. H-ras-immortalized cells could not be morphologically transformed by secondary transfection with a long terminal repeat-c-myc oncogene, but secondary transfection of the same cells with H-ras (Val-12) produced morphologically transformed colonies that had 20- to 40-fold higher levels of H-ras oncogene expression. Thus, transformation in this system is dependent on high levels of H-ras oncogene expression rather than on the presence of activated H-ras and c-myc oncogenes in the same cell.
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Kelekar, A., and M. D. Cole. "Immortalization by c-myc, H-ras, and Ela oncogenes induces differential cellular gene expression and growth factor responses." Molecular and Cellular Biology 7, no. 11 (November 1987): 3899–907. http://dx.doi.org/10.1128/mcb.7.11.3899.
Full textAbstract:
Early-passage rat kidney cells were immortalized or rescued from senescence with three different oncogenes: viral promoter-driven c-myc, H-ras (Val-12), and adenovirus type 5 E1a. The normal c-myc and H-ras (Gly-12) were unable to immortalize cells under similar conditions. Quantitation of RNA in the ras-immortalized lines demonstrated that the H-ras oncogene was expressed at a level equivalent to that of the normal H-ras gene in established human or rat cell lines. Cell lines immortalized by different oncogenes were found to have distinct growth responses to individual growth factors in a short-term assay. E1a-immortalized cells were largely independent of serum growth factors, whereas c-myc-immortalized cells responded to serum better than to epidermal growth factor and insulin. H-ras-immortalized cells responded significantly to insulin alone and gave a maximal response to epidermal growth factor and insulin. Several cellular genes associated with platelet-derived growth factor stimulation, including c-myc, were expressed at high levels in the H-ras-immortalized cells, and c-myc expression was deregulated, suggesting that the H-ras oncogene has provided a "competence" function. H-ras-immortalized cells could not be morphologically transformed by secondary transfection with a long terminal repeat-c-myc oncogene, but secondary transfection of the same cells with H-ras (Val-12) produced morphologically transformed colonies that had 20- to 40-fold higher levels of H-ras oncogene expression. Thus, transformation in this system is dependent on high levels of H-ras oncogene expression rather than on the presence of activated H-ras and c-myc oncogenes in the same cell.
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Lanza, L. A., D. J. Wilson, B. Ikejiri, J. A. Roth, and E. A. Grimm. "Human oncogene-transfected tumor cells display differential susceptibility to lysis by lymphokine-activated killer cells (LAK) and natural killer cells." Journal of Immunology 137, no. 8 (October 15, 1986): 2716–20. http://dx.doi.org/10.4049/jimmunol.137.8.2716.
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Abstract NIH 3T3 tertiary transfectants containing the N-ras or c-Ha-ras oncogenes derived from human tumors were tested for susceptibility to lymphokine-activated killer (LAK) cell and natural killer (NK) cell lysis. N-ras tertiary transfectants contained a human acute lymphocytic leukemia-derived N-ras oncogene. C-Ha-ras transfectants contained either the position 61-activated form of the oncogene (45.342, 45.322, and 45.3B2) or the position 12-activated form (144-162). In 4 hr 51Cr release assays, seven of seven in vivo grown human oncogene transfected NIH 3T3 fibroblasts were lysed by murine LAK effectors, whereas six of seven were lysed by human LAK effectors. There was no difference in susceptibility to lysis between cells transfected with the N-ras oncogene, the position 61 activated c-Ha-ras oncogene, or the position 12 activated c-Ha-ras oncogene. Cultured NIH 3T3 fibroblasts, as well as in vitro and in vivo grown NIH 3T3 tertiary transfectants were resistant to lysis by murine NK effectors and were relatively resistant (4/6 were not lysed) to lysis by human NK effectors. We conclude that human oncogene-transfected tumors are susceptible to lysis by both murine and human LAK cells while being relatively resistant to lysis by murine and human NK cells. Different oncogenes or the same oncogene activated by different point mutations do not specifically determine susceptibility to lysis by LAK or NK. Also the presence of an activated oncogene does not appear to be sufficient for inducing susceptibility to these cytotoxic lymphocyte populations.
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Alarid, E. T., J. J. Windle, D. B. Whyte, and P. L. Mellon. "Immortalization of pituitary cells at discrete stages of development by directed oncogenesis in transgenic mice." Development 122, no. 10 (October 1, 1996): 3319–29. http://dx.doi.org/10.1242/dev.122.10.3319.
Full textAbstract:
Targeted expression of oncogenes in transgenic mice can immortalize specific cell types to serve as valuable cultured model systems. Utilizing promoter regions from a set of genes expressed at specific stages of differentiation in a given cell lineage, we demonstrate that targeted oncogenesis can produce cell lines representing sequential stages of development, in essence allowing both spatial and temporal immortalization. Our strategy was based on our production of a committed but immature pituitary gonadotrope cell line by directing expression of the oncogene SV40 T antigen using a gonadotrope-specific region of the human glycoprotein hormone alpha-subunit gene in transgenic mice. These cells synthesize alpha-subunit and gonadotropin-releasing hormone (GnRH) receptor, yet are not fully differentiated in that they do not synthesize the beta-subunits of luteinizing hormone (LH) or follicle-stimulating hormone (FSH). This observation lead to the hypothesis that targeting oncogenesis with promoters that are activated earlier or later in development might immortalize cells that were more primitive or more differentiated, respectively. To test this hypothesis, we used an LHbeta promoter to immortalize a cell that represents a subsequent stage of gonadotrope differentiation (expression of alpha-subunit, GnRH receptor, and LH beta-subunit but not FSH beta-subunit). Conversely, targeting oncogenesis with a longer fragment of the human alpha-subunit gene (which is activated earlier in development) resulted in the immortalization of a progenitor cell that is more primitive, expressing only the alpha-subunit gene. Interestingly, this transgene also immortalized cells of the thyrotrope lineage that express both alpha- and beta-subunits of thyroid-stimulating hormone and the transcription factor GHF-1 (Pit-1). Thus, targeted tumorigenesis immortalizes mammalian cells at specific stages of differentiation and allows the production of a series of cultured cell lines representing sequential stages of differentiation in a given cell lineage.
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Leung, Kevin K., Gary M. Wilson, Lisa L. Kirkemo, Nicholas M. Riley, Joshua J. Coon, and James A. Wells. "Broad and thematic remodeling of the surfaceome and glycoproteome on isogenic cells transformed with driving proliferative oncogenes." Proceedings of the National Academy of Sciences 117, no. 14 (March 23, 2020): 7764–75. http://dx.doi.org/10.1073/pnas.1917947117.
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The cell surface proteome, the surfaceome, is the interface for engaging the extracellular space in normal and cancer cells. Here we apply quantitative proteomics ofN-linked glycoproteins to reveal how a collection of some 700 surface proteins is dramatically remodeled in an isogenic breast epithelial cell line stably expressing any of six of the most prominent proliferative oncogenes, including the receptor tyrosine kinases, EGFR and HER2, and downstream signaling partners such as KRAS, BRAF, MEK, and AKT. We find that each oncogene has somewhat different surfaceomes, but the functions of these proteins are harmonized by common biological themes including up-regulation of nutrient transporters, down-regulation of adhesion molecules and tumor suppressing phosphatases, and alteration in immune modulators. Addition of a potent MEK inhibitor that blocks MAPK signaling brings each oncogene-induced surfaceome back to a common state reflecting the strong dependence of the oncogene on the MAPK pathway to propagate signaling. Cell surface protein capture is mediated by covalent tagging of surface glycans, yet current methods do not afford sequencing of intact glycopeptides. Thus, we complement the surfaceome data with whole cell glycoproteomics enabled by a recently developed technique called activated ion electron transfer dissociation (AI-ETD). We found massive oncogene-induced changes to the glycoproteome and differential increases in complex hybrid glycans, especially for KRAS and HER2 oncogenes. Overall, these studies provide a broad systems-level view of how specific driver oncogenes remodel the surfaceome and the glycoproteome in a cell autologous fashion, and suggest possible surface targets, and combinations thereof, for drug and biomarker discovery.
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Rey, Federica, Letizia Messa, Cecilia Pandini, Rossella Launi, Bianca Barzaghini, Giancarlo Micheletto, Manuela Teresa Raimondi, et al. "Transcriptome Analysis of Subcutaneous Adipose Tissue from Severely Obese Patients Highlights Deregulation Profiles in Coding and Non-Coding Oncogenes." International Journal of Molecular Sciences 22, no. 4 (February 17, 2021): 1989. http://dx.doi.org/10.3390/ijms22041989.
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Obesity is a major risk factor for a large number of secondary diseases, including cancer. Specific insights into the role of gender differences and secondary comorbidities, such as type 2 diabetes (T2D) and cancer risk, are yet to be fully identified. The aim of this study is thus to find a correlation between the transcriptional deregulation present in the subcutaneous adipose tissue of obese patients and the oncogenic signature present in multiple cancers, in the presence of T2D, and considering gender differences. The subcutaneous adipose tissue (SAT) of five healthy, normal-weight women, five obese women, five obese women with T2D and five obese men were subjected to RNA-sequencing, leading to the identification of deregulated coding and non-coding RNAs, classified for their oncogenic score. A panel of DE RNAs was validated via Real-Time PCR and oncogene expression levels correlated the oncogenes with anthropometrical parameters, highlighting significant trends. For each analyzed condition, we identified the deregulated pathways associated with cancer, the prediction of possible prognosis for different cancer types and the lncRNAs involved in oncogenic networks and tissues. Our results provided a comprehensive characterization of oncogenesis correlation in SAT, providing specific insights into the possible molecular targets implicated in this process. Indeed, the identification of deregulated oncogenes also in SAT highlights hypothetical targets implicated in the increased oncogenic risk in highly obese subjects. These results could shed light on new molecular targets to be specifically modulated in obesity and highlight which cancers should receive the most attention in terms of better prevention in obesity-affected patients.
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Chernov, A. N. "The impact of the nerve growth factor on the number of MYCC, MYCN oncogene copies in human medulloblastoma cells." Malignant tumours 9, no. 1 (April 10, 2019): 22–28. http://dx.doi.org/10.18027/2224-5057-2019-9-1-22-28.
Full textAbstract:
Introduction: The search for new molecular targets for chemotherapy of malignancies, particularly pediatric brain tumors, is a relevant issue of modern oncology. MYC expression and amplification is often observed in brain tumors, which is an unfavorable prognostic factor. Many oncogenic processes are regulated by some growth factors including the nerve growth factor (NGF).Purpose: To study the changes in the number of MYCCand MYCN‑gene copies in MB cells exposed to the NGF.Material and methods: The impact of the NGF on the number of MYCC‑, MYCN oncogene copies in the primary human medulloblastoma cell culture was assessed using the method of fluorescence in situ hybridization.Results: Exposure to the NGF was shown to decrease the number of MB cells containing 6, 8 copies of MYCN oncogenes and 3, 8 copies of MYCC oncogene. The NGF was also shown to increase the number of tumor cells that contain a double set of copies of both oncogenes. There was a statistically significant (p<0.0001) negative correlation (r=–0.65) between the average number of MYCC oncogene copies and the NGF cytotoxicity index.Conclusion: The increased number of oncogene copies reduces the susceptibility of MB cells to the growth factor.
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Slebos, RJ, and S. Rodenhuis. "The molecular genetics of human lung cancer." European Respiratory Journal 2, no. 5 (May 1, 1989): 461–69. http://dx.doi.org/10.1183/09031936.93.02050461.
Full textAbstract:
With the development of molecular biological techniques the search for genetic alterations in cancer cells has resulted in the beginning of a molecular description of cellular transformation. Most of these genetic changes occur in genes which have a role in the control of cellular growth and development, the proto oncogenes. In the last decade, it has become clear that the myc and ras oncogene families are important in the carcinogenesis of human lung cancers. The myc oncogenes are usually found to be altered in small cell lung cancer (SCLC), and these alterations appear to correlate with rapid growth and progression. Mutations in the Kras gene are specific for adenocarcinoma, a subclass of non small cell lung cancer (NSCLC). Kras gene mutations are closely associated with tobacco smoking, since all were found in adenocarcinomas from patients with a history of smoking. The erbB oncogene, which encodes the epidermal growth factor receptor, is often highly expressed in epidermoid carcinomas. The roles for other oncogenes, such as raf or myb, as well as those of "suppressor" genes remain to be investigated, but may be of paramount importance. The study of alterations in proto oncogenes may aid in the (sub)classification and diagnosis of lung cancer, and may yield useful prognostic information in the near future.
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Needleman, SW, MH Kraus, SK Srivastava, PH Levine, and SA Aaronson. "High frequency of N-ras activation in acute myelogenous leukemia." Blood 67, no. 3 (March 1, 1986): 753–57. http://dx.doi.org/10.1182/blood.v67.3.753.753.
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Abstract Using the NIH/3T3 cell transfection assay, activated cellular oncogenes have been detected in around 10% to 20% of human tumors. From a series of DNA preparations from tissues infiltrated with acute myelogenous leukemia (AML), 50% (3/6) caused transformation of NIH/3T3 cells. Thus AML appears to be the human tumor with the highest frequency of oncogenes detected by DNA transfection. In each case the oncogene involved was N-ras, a member of the ras gene family. Biologic and clinical parameters of AML patients with and without N-ras oncogenes in their tumors are discussed.
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Needleman, SW, MH Kraus, SK Srivastava, PH Levine, and SA Aaronson. "High frequency of N-ras activation in acute myelogenous leukemia." Blood 67, no. 3 (March 1, 1986): 753–57. http://dx.doi.org/10.1182/blood.v67.3.753.bloodjournal673753.
Full textAbstract:
Using the NIH/3T3 cell transfection assay, activated cellular oncogenes have been detected in around 10% to 20% of human tumors. From a series of DNA preparations from tissues infiltrated with acute myelogenous leukemia (AML), 50% (3/6) caused transformation of NIH/3T3 cells. Thus AML appears to be the human tumor with the highest frequency of oncogenes detected by DNA transfection. In each case the oncogene involved was N-ras, a member of the ras gene family. Biologic and clinical parameters of AML patients with and without N-ras oncogenes in their tumors are discussed.
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Baltanas, Fernando C., and Eugenio Santos. "Advances in Molecular Research of Oncogenes." International Journal of Molecular Sciences 24, no. 8 (April 13, 2023): 7222. http://dx.doi.org/10.3390/ijms24087222.
Full textAbstract:
The isolation of the first human oncogene (HRAS), a critical breakthrough in cancer research, has occurred over forty years ago, and the identification of new pathogenic oncogenes has continuously grown since [...]
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Karlina, I. S., E. S. Gorozhanina, and I. V. Ulasov. "THE PROSPECT OF USING ONCOGENES’ INHA, DLL4 AND MMP2 ROLE IN DIAGNOSIS AND TREATMENT OF ONCOLOGICAL DISEASE." Russian Journal of Biotherapy 20, no. 1 (April 8, 2021): 8–15. http://dx.doi.org/10.17650/1726-9784-2021-20-1-8-15.
Full textAbstract:
A large role in the development of malignant tumors is played by a genetic predisposition. Risk factors for cancer include the presence of mutations in oncogenes‑genes that cause the development of tumors. They were first found in the genome of viruses, and their analogs, called proto‑oncogenes, were found in humans. The study of the work of oncogenes is a promising direction in the development of new methods for the diagnosis and treatment of oncological diseases. The discovery and research of oncogenes of all classes are necessary not only to understand the mechanisms of neoplasm development but also to develop new methods of cancer treatment. Oncogenes are responsible for the synthesis of growth factors, and also control the course of the cell cycle. With an excess or violation of the functions of gene products, the processes of cell growth and division are disrupted, which leads to cell degeneration, their uncontrolled division, and, as a result, to the formation of a tumor. Based on the above, we can say that by studying the mechanisms of oncogenes at the molecular level, the functions of their products, and their influence on the vital processes of cells and the whole organism, it is possible to develop ways to treat cancer by inhibiting or correcting the work of a particular oncogene or its product. The process of oncogene activation is multifaceted and can be caused by the persistence of oncogenic viruses, the integration of retroviruses into the cell genome, the presence of point mutations or deletions in genomic DNA, chromosome translocation, or protein‑protein interaction. That is why the total number of oncogenes and possible ways of their activation at different stages of tumor progression are not fully known. In this regard, we decided in this review to analyze the available information about the relatively new and poorly studied oncogenes INHA, DLL4, and MMP2, which control important functions, including metastasis and tumor growth.
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Cao, Yajun, Bobin Ning, Ye Tian, Tingwei Lan, Yunxiang Chu, Fangli Ren, Yinyin Wang, et al. "CREPT Disarms the Inhibitory Activity of HDAC1 on Oncogene Expression to Promote Tumorigenesis." Cancers 14, no. 19 (September 30, 2022): 4797. http://dx.doi.org/10.3390/cancers14194797.
Full textAbstract:
Histone deacetylases 1 (HDAC1), an enzyme that functions to remove acetyl molecules from ε-NH3 groups of lysine in histones, eliminates the histone acetylation at the promoter regions of tumor suppressor genes to block their expression during tumorigenesis. However, it remains unclear why HDAC1 fails to impair oncogene expression. Here we report that HDAC1 is unable to occupy at the promoters of oncogenes but maintains its occupancy with the tumor suppressors due to its interaction with CREPT (cell cycle-related and expression-elevated protein in tumor, also named RPRD1B), an oncoprotein highly expressed in tumors. We observed that CREPT competed with HDAC1 for binding to oncogene (such as CCND1, CLDN1, VEGFA, PPARD and BMP4) promoters but not the tumor suppressor gene (such as p21 and p27) promoters by a chromatin immunoprecipitation (ChIP) qPCR experiment. Using immunoprecipitation experiments, we deciphered that CREPT specifically occupied at the oncogene promoter via TCF4, a transcription factor activated by Wnt signaling. In addition, we performed a real-time quantitative PCR (qRT-PCR) analysis on cells that stably over-expressed CREPT and/or HDAC1, and we propose that HDAC1 inhibits CREPT to activate oncogene expression under Wnt signaling activation. Our findings revealed that HDAC1 functions differentially on tumor suppressors and oncogenes due to its interaction with the oncoprotein CREPT.
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Izzotti, Alberto, Gabriela Coronel Vargas, Alessandra Pulliero, Simona Coco, Irene Vanni, Cristina Colarossi, Giuseppina Blanco, et al. "Relationship between the miRNA Profiles and Oncogene Mutations in Non-Smoker Lung Cancer. Relevance for Lung Cancer Personalized Screenings and Treatments." Journal of Personalized Medicine 11, no. 3 (March 5, 2021): 182. http://dx.doi.org/10.3390/jpm11030182.
Full textAbstract:
Oncogene mutations may be drivers of the carcinogenesis process. MicroRNA (miRNA) alterations may be adaptive or pathogenic and can have consequences only when mutation in the controlled oncogenes occurs. The aim of this research was to analyze the interplay between miRNA expression and oncogene mutation. A total of 2549 miRNAs were analyzed in cancer tissue—in surrounding normal lung tissue collected from 64 non-smoking patients and in blood plasma. Mutations in 92 hotspots of 22 oncogenes were tested in the lung cancer tissue. MicroRNA alterations were related to the mutations occurring in cancer patients. Conversely, the frequency of mutation occurrence was variable and spanned from the k-ras and p53 mutation detected in 30% of patients to 20% of patients in which no mutation was detected. The prediction of survival at a 3-year follow up did not occur for mutation analysis but was, conversely, well evident for miRNA analysis highlighting a pattern of miRNA distinguishing between survivors and death in patients 3 years before this clinical onset. A signature of six lung cancer specific miRNAs occurring both in the lungs and blood was identified. The obtained results provide evidence that the analysis of both miRNA and oncogene mutations was more informative than the oncogene mutation analysis currently performed in clinical practice.
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Magnusson, Magnus K., Kristin E. Meade, Ryotaro Nakamura, John Barrett, and Cynthia E. Dunbar. "Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor β receptor fusion oncogene." Blood 100, no. 3 (August 1, 2002): 1088–91. http://dx.doi.org/10.1182/blood-2002-01-0165.
Full textAbstract:
Abstract Platelet-derived growth factor β receptor (PDGFβR) fusion genes have been shown to be critical transforming oncogenes in a subset of patients with chronic myelomonocytic leukemia (CMML). The sensitivity of dysregulated tyrosine kinase oncogenes to the tyrosine kinase inhibitor STI571 (imatinib mesylate) makes it a potentially attractive treatment option in this subset of patients. We have recently cloned a novel member of the PDGFβR fusion oncogene family, rabaptin-5-PDGFβR. A patient with CMML carrying the rabaptin-5-PDGFβR fusion gene underwent allogeneic stem cell transplantation (SCT) and was monitored closely with a sensitive reverse transcriptase–polymerase chain assay to detect the novel fusion gene transcript. After achieving a molecular remission at 5 months after transplantation, 15 months after SCT the patient showed persistent and progressive evidence of molecular relapse. After demonstrating in vitro that cells transformed with this specific fusion oncogene are efficiently killed by STI571, the patient was started on STI571. The patient responded rapidly and entered molecular remission after 6 weeks of therapy, and he continues to be in remission 6 months later. These results suggest that STI571 may be an effective targeted therapy in patients with CMML related to PDGFβR fusion oncogenes.
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Starble, Rebecca M., Eric G. Sun, Tyler B. Jensen, Rana Gbyli, Ning Sun, and Andrew Z. Xiao. "Abstract B016: A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): B016. http://dx.doi.org/10.1158/1538-7445.cancepi22-b016.
Full textAbstract:
Abstract Lung cancer is the leading cause of cancer-related death worldwide and affects over 2 million people each year. In lung adenocarcinoma (LUAD), somatic activating mutations of epidermal growth factor receptor (EGFR) occur in approximately 15% of patients. The first-line therapy for patients with EGFR-mutant LUAD is administration of osimertinib, an EGFR tyrosine kinase inhibitor (TKI). While many patients’ tumors initially respond to osimertinib treatment, resistance inevitably develops in most cases, which is a major challenge that hinders treatment efficacy. One common mechanism of resistance to osimertinib is the amplification of oncogenes, such as MET, HER2, and RET. Despite the high prevalence of oncogene amplifications in resistant tumors, the mechanisms that control oncogene amplification and transcription are poorly understood. Recent work has shown that oncogenes are frequently amplified on extrachromosomal DNA (ecDNA), which are circularized and highly amplified DNA sequences that are present in at least 14% of human cancers. Additional studies have implicated ecDNA amplification in the acquisition of resistance to TKIs, yet the mechanisms through which ecDNA is regulated are largely unknown. In the present study, we have identified a novel epigenetic factor that promotes the acquisition of TKI resistance through the organization and transcription of oncogene amplicons, some of which occur on ecDNA. To determine whether this factor binds to DNA, we used and found that it is enriched at the promoters of amplified oncogenes. Further, we performed protein immunoprecipitation followed by mass spectrometry and identified multiple candidate interacting factors, such as histone readers and components of the cohesin machinery. Depletion of this epigenetic factor prevents the acquisition of TKI resistance and leads to reduced transcription of oncogene amplicons. Thus, we propose a novel mechanism that promotes the acquisition of TKI resistance via the spatial organization and transcription of oncogene amplicons. Citation Format: Rebecca M. Starble, Eric G. Sun, Tyler B. Jensen, Rana Gbyli, Ning Sun, Andrew Z. Xiao. A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B016.
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Sawey, M. J., A. T. Hood, F. J. Burns, and S. J. Garte. "Activation of c-myc and c-K-ras oncogenes in primary rat tumors induced by ionizing radiation." Molecular and Cellular Biology 7, no. 2 (February 1987): 932–35. http://dx.doi.org/10.1128/mcb.7.2.932-935.1987.
Full textAbstract:
An activated K-ras oncogene was detected by transfection in NIH 3T3 cells and by Southern blot analysis in 6 of 12 rat skin tumors induced by ionizing radiation. The DNA from 10 of the 12 tumors also showed c-myc gene amplification and restriction polymorphisms. Evidence for tissue specificity was observed in patterns of oncogene activation, with each of three clear cell carcinomas exhibiting activation of both c-myc and K-ras oncogenes.
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Sawey, M. J., A. T. Hood, F. J. Burns, and S. J. Garte. "Activation of c-myc and c-K-ras oncogenes in primary rat tumors induced by ionizing radiation." Molecular and Cellular Biology 7, no. 2 (February 1987): 932–35. http://dx.doi.org/10.1128/mcb.7.2.932.
Full textAbstract:
An activated K-ras oncogene was detected by transfection in NIH 3T3 cells and by Southern blot analysis in 6 of 12 rat skin tumors induced by ionizing radiation. The DNA from 10 of the 12 tumors also showed c-myc gene amplification and restriction polymorphisms. Evidence for tissue specificity was observed in patterns of oncogene activation, with each of three clear cell carcinomas exhibiting activation of both c-myc and K-ras oncogenes.
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Zhao, Ran, Bin Hu, Lei Chen, and Bo Zhou. "Identification of Latent Oncogenes with a Network Embedding Method and Random Forest." BioMed Research International 2020 (September 23, 2020): 1–11. http://dx.doi.org/10.1155/2020/5160396.
Full textAbstract:
Oncogene is a special type of genes, which can promote the tumor initiation. Good study on oncogenes is helpful for understanding the cause of cancers. Experimental techniques in early time are quite popular in detecting oncogenes. However, their defects become more and more evident in recent years, such as high cost and long time. The newly proposed computational methods provide an alternative way to study oncogenes, which can provide useful clues for further investigations on candidate genes. Considering the limitations of some previous computational methods, such as lack of learning procedures and terming genes as individual subjects, a novel computational method was proposed in this study. The method adopted the features derived from multiple protein networks, viewing proteins in a system level. A classic machine learning algorithm, random forest, was applied on these features to capture the essential characteristic of oncogenes, thereby building the prediction model. All genes except validated oncogenes were ranked with a measurement yielded by the prediction model. Top genes were quite different from potential oncogenes discovered by previous methods, and they can be confirmed to become novel oncogenes. It was indicated that the newly identified genes can be essential supplements for previous results.
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Vinas-Castells, Rosa, Alja Kozulic-Pirher, Tomás Aparicio, Sandra Casas Recasens, Mark P. Roberto, Rachel Sue, Francisco Martinez, Nuria López-Bigas, Jean Gautier, and David Dominguez-Sola. "Abstract 1517: Molecular architecture of replication stress response to oncogene deregulation." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1517. http://dx.doi.org/10.1158/1538-7445.am2022-1517.
Full textAbstract:
Abstract Oncogene deregulation triggers replication stress, which can be detected in precancerous lesions and is a source of subsequent genomic instability in cancer. Studies on the mechanisms underlying DNA replication stress caused by frequently deregulated oncogenes, like MYC or RAS, can identify novel mechanisms of oncogenesis and point to actionable pathways with potential for anticancer therapy. To understand the molecular mechanisms underlying this cellular response, we used high-content microscopy to monitor the dynamic behavior of >60 GFP-tagged proteins linked to replication stress or DNA damage in primary human cells. Iterations of this screen identified a proteomic signature specific to MYC- and RAS-driven replication stress that was significantly different from responses activated by other sources of replication stress (i.e. DNA damaging drugs). These findings indicated that the replication stress response to oncogenes is somewhat unique. MYC-dependent replication stress responses typically activated the INO80 chromatin-remodeling complex — a highly conserved complex necessary for maintenance of genome stability in yeast. Core components of the INO80 complex assembled onto chromatin at MYC-bound sites and were quantitatively enriched at active replication forks. These molecular events were independent of transcription, and their disruption by pharmacological or genetic means specifically altered replication dynamics and cellular growth in cells overexpressing MYC. Notably, we identified recurrent somatic mutations in several genes encoding for INO80 complex components across multiple cancer types, with an abundance of nonsense and splice-site mutations consistent with loss of function. Most of these mutant variants behaved as hypomorphs when tested in cell-based assays: they were insensitive to MYC deregulation and failed to rescue cell proliferation in knock-out cells with MYC overexpression. Computational predictions also suggested that many of these mutations had been selected as potential cancer drivers. Consistent with this notion, we found that in vivo, INO80 complex mutations shortened tumor latency in a mouse model of MYC-dependent lymphomagenesis. Collectively, these findings indicate that the replication stress response to oncogene deregulation is unique in its molecular architecture, and modification of this response by partial loss-of-function mutations in cancer facilitates tumor progression. Citation Format: Rosa Vinas-Castells, Alja Kozulic-Pirher, Tomás Aparicio, Sandra Casas Recasens, Mark P. Roberto, Rachel Sue, Francisco Martinez, Nuria López-Bigas, Jean Gautier, David Dominguez-Sola. Molecular architecture of replication stress response to oncogene deregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1517.