Journal articles: 'Tumour suppressor gene pten'

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B??ni, R., A. O. Vortmeyer, G. Burg, G. Hofbauer, and Z. Zhuang. "The PTEN tumour suppressor gene and malignant melanoma." Melanoma Research 8, no. 4 (August 1998): 300–302. http://dx.doi.org/10.1097/00008390-199808000-00002.

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Kaufmann, J., G. Pronk, K. Giese, and A. Klippel. "Identification of novel effectors of invasive cell growth downstream of phosphoinositide 3-kinase." Biochemical Society Transactions 32, no. 2 (April 1, 2004): 355–59. http://dx.doi.org/10.1042/bst0320355.

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Conventional approaches to identifying cancer targets are complicated by the chromosomal instability of tumour cells, and typically result in a large number of differentially expressed candidate genes with uncertain disease relevance. Here we present a novel approach which aims to elucidate the molecular changes that are induced after loss of tumour suppressor function. Using gene silencing tools, we mimic the loss of tumour suppressor function to identify key regulators of tumour initiation and progression. Loss of function of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) correlates with increased invasive cell growth due to the resulting chronic activation of the PI 3-kinase (phosphoinositide 3-kinase) pathway. Induced activation of PI 3-kinase either by inhibiting PTEN expression or by using p110*, a constitutively active PI 3-kinase, increased signalling and the invasive growth potential of cells. Using this unbiased approach we have identified novel downstream effectors of PI 3-kinase/PTEN signalling that mediate the behaviour of cells with a hyperactive PI 3-kinase pathway. These molecules represent candidate targets for therapeutic intervention in patients with PTEN-deficient tumours.

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Pereiro, Patricia, Antonio Figueras, and Beatriz Novoa. "Zebrafish pten Genes Play Relevant but Distinct Roles in Antiviral Immunity." Vaccines 8, no. 2 (April 26, 2020): 199. http://dx.doi.org/10.3390/vaccines8020199.

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The PTEN (phosphatase and TENsin homolog on chromosome 10) gene encodes a bifunctional phosphatase that acts as a tumor suppressor. However, PTEN has been implicated in different immune processes, including autophagy, inflammation, regulation of natural killer (NK) cell cytolytic activity and type I interferon responses. Unlike mammals, zebrafish possess two pten genes (ptena and ptenb). This study explores the involvement of both zebrafish pten genes in antiviral defense. Although ptena−/− and ptenb−/− larvae were more susceptible to Spring viremia of carp virus (SVCV), the viral replication rate was lower in the mutant larvae than in the wild-type larvae. We observed that both mutant lines showed alterations in the transcription of numerous genes, including those related to the type I interferon (IFN) system, cytolytic activity, autophagy and inflammation, and some of these genes were regulated in opposite ways depending on which pten gene was mutated. Even though the lower replication rate of SVCV could be associated with impaired autophagy in the mutant lines, the higher mortality observed in the ptena−/− and ptenb−/− larvae does not seem to be associated with an uncontrolled inflammatory response.

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Marino, Silvia, Paul Krimpenfort, Carly Leung, Hetty A. G. M. van der Korput, Jan Trapman, Isabelle Camenisch, Anton Berns, and Sebastian Brandner. "PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum." Development 129, no. 14 (July 15, 2002): 3513–22. http://dx.doi.org/10.1242/dev.129.14.3513.

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PTEN is a tumour suppressor gene involved in cell cycle control, apoptosis and mediation of adhesion and migration signalling. Germline mutations of PTEN in humans are associated with familial tumour syndromes, among them Cowden disease. Glioblastomas, highly malignant glial tumours of the central nervous system frequently show loss of PTEN. Recent reports have outlined some aspects of PTEN function in central nervous system development. Using a conditional gene disruption approach, we inactivated Pten in mice early during embryogenesis locally in a region specific fashion and later during postnatal development in a cell-specific manner, to study the role of PTEN in differentiation, migration and neoplastic transformation. We show that PTEN is required for the realisation of normal cerebellar architecture, for regulation of cell and organ size, and for proper neuronal and glial migration. However, PTEN is not required for cell differentiation and lack of PTEN is not sufficient to induce neoplastic transformation of neuronal or glial cells

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Islam, Mohammad Ariful, Yingjie Xu, Harshal Zope, Wuji Cao, Morteza Mahmoudi, Robert Langer, Philip W. Kantoff, Jinjun Shi, Bruce R. Zetter, and Omid C. Farokhzad. "Restoration of tumor suppression in vivo by systemic delivery of chemically-modified PTEN mRNA nanoparticles." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11582. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11582.

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11582 Background: The onset and maintenance of cancer frequently involves gain of oncogenic function along with loss of tumor suppression. PTEN is a well-characterized tumor suppressor gene that is lost or mutated in many human cancers including ~50% of metastatic castration-resistant prostate cancer (mCRPC). Reintroduction of functional PTEN for mCRPC treatment has proven difficult. Methods: PTEN mRNA was synthesized by in vitro transcription method and modified with ARCA capping and enzymatic polyadenylation, and then substituted with Pseudo-UTP, 5’-Methyl-CTP. A robust self-assembly approach was employed to prepare PTEN mRNA nanoparticles (NPs) using cationic lipid-like compound G0-C14 and PLGA polymer coated with lipid-PEG shell. PTEN expression in tumors and PI3K-AKT pathway were confirmed by IHC and western blot, respectively. Apoptosis was checked by flow cytometry and Tunel assays. In vivo toxicity was studied by hematologic and histologic tests, and immune response. Results: We successfully restored PTEN mRNA to PTEN-null prostate cancer (PCa) cells via systemic delivery of mRNA NPs. These mRNA NPs are stable in serum, demonstrate minimal toxicity, and provide highly effective transfection in PCa cells (substantially higher HA-PTEN expression than plasmid PTEN transfection) and PCa xenograft tumors, leading to ~85% inhibition of tumor cell growth in vitro and in vivo. We also confirm mRNA NP-mediated systemic restoration of PTEN function in PTEN-null PCa and delineate its tumor suppression through inhibition of the PI3K-AKT pathway and enhancement of apoptosis. Conclusions: The work provides proof of principle for the systemic reintroduction of mRNA-based tumor suppressor genes to tumors in vivo. Because PTEN loss is frequent in late-stage PCa, this approach may have feasibility in this patient population. Considering the strong potential of mRNA therapy and the lack of systemic studies of in vivo mRNA transfection of tumors, this study sheds light on the useful application of NP-mediated mRNA delivery for validating tumor suppressors (e.g., PTEN) as a therapeutic target in cancer treatment where loss of a tumor suppressor contributes to the underlying genetic mechanism of cancer.

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Persad, Sujata, Armelle A.Troussard, Timothy R. McPhee, David J. Mulholland, and Shoukat Dedhar. "Tumor Suppressor Pten Inhibits Nuclear Accumulation of β-Catenin and T Cell/Lymphoid Enhancer Factor 1–Mediated Transcriptional Activation." Journal of Cell Biology 153, no. 6 (June 4, 2001): 1161–74. http://dx.doi.org/10.1083/jcb.153.6.1161.

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β-Catenin is a protein that plays a role in intercellular adhesion as well as in the regulation of gene expression. The latter role of β-catenin is associated with its oncogenic properties due to the loss of expression or inactivation of the tumor suppressor adenomatous polyposis coli (APC) or mutations in β-catenin itself. We now demonstrate that another tumor suppressor, PTEN, is also involved in the regulation of nuclear β-catenin accumulation and T cell factor (TCF) transcriptional activation in an APC-independent manner. We show that nuclear β-catenin expression is constitutively elevated in PTEN null cells and this elevated expression is reduced upon reexpression of PTEN. TCF promoter/luciferase reporter assays and gel mobility shift analysis demonstrate that PTEN also suppresses TCF transcriptional activity. Furthermore, the constitutively elevated expression of cyclin D1, a β-catenin/TCF–regulated gene, is also suppressed upon reexpression of PTEN. Mechanistically, PTEN increases the phosphorylation of β-catenin and enhances its rate of degradation. We define a pathway that involves mainly integrin-linked kinase and glycogen synthase kinase 3 in the PTEN-dependent regulation of β-catenin stability, nuclear β-catenin expression, and transcriptional activity. Our data indicate that β-catenin/TCF–mediated gene transcription is regulated by PTEN, and this may represent a key mechanism by which PTEN suppresses tumor progression.

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Ibnat, Nabilah, Rowshan Ara Islam, and Ezharul Hoque Chowdhury. "Inhibition of Breast Tumour Growth with Intravenously Administered PRKCA siRNA- and PTEN Tumour Suppressor Gene-Loaded Carbonate Apatite Nanoparticles." Applied Sciences 11, no. 17 (September 2, 2021): 8133. http://dx.doi.org/10.3390/app11178133.

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Gene therapy aims to silence an oncogene through RNA interference, or replace an abnormal tumour suppressor via gene augmentation. In this study, we intended RNA interference for PRKCA oncogene and gene augmentation for PTEN tumour suppressor with a view to reduce tumour growth in a mouse model of breast cancer. Inorganic carbonate apatite nanoparticles (CA NPs) were utilized to deliver the synthetic siRNA and the purified gene-carrying plasmid DNA both in vitro and in vivo. Effects of PRKCA siRNA- and PTEN plasmid-loaded NPs on viability of MCF-7, MDA-MB-231 and 4T1 breast cancer cells were assessed by MTT assay. The cell viability data in MCF-7 cell line demonstrated that combined delivery of PRKCA specific siRNA and PTEN plasmid with CA NPs had an additive effect to significantly decrease cellular growth compared to individual treatments. In addition, we observed a similar pattern of cumulative influence for combined treatment in triple negative MDA-MB-231 breast cancer cell line. Upon treatment with PRKCA siRNA+PTEN plasmid-loaded NPs, a remarkable decrease in the phosphorylated form of AKT protein of PI3K/AKT pathway was observed in Western blot, indicative of diminished proliferative signal. Moreover, in vivo study in MCF-7 xenograft breast cancer mouse model demonstrated that the rate of growth and final tumour volume were reduced significantly in the mouse group that received intravenous treatment of PRKCA siRNA+NPs, and PTEN plasmid+NPs. Our findings demonstrated that PRKCA siRNA and PTEN plasmid loaded into CA NPs attenuated breast tumour growth, suggesting their therapeutic potential in the treatment of breast cancer.

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de Sousa, Sílvia Ferreira, Marina Gonçalves Diniz, Josiane Alves França, Thaís dos Santos Fontes Pereira, Rennan Garcias Moreira, Jean Nunes dos Santos, Ricardo Santiago Gomez, and Carolina Cavalieri Gomes. "Cancer genes mutation profiling in calcifying epithelial odontogenic tumour." Journal of Clinical Pathology 71, no. 3 (November 10, 2017): 279–83. http://dx.doi.org/10.1136/jclinpath-2017-204813.

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AimsTo identify calcifying epithelial odontogenic tumour (CEOT) mutations in oncogenes and tumour suppressor genes.MethodsA panel of 50 genes commonly mutated in cancer was sequenced in CEOT by next-generation sequencing. Sanger sequencing was used to cover the region of the frameshift deletion identified in one sample.ResultsMissense single nucleotide variants (SNVs) with minor allele frequency (MAF) <1% were detected in PTEN, MET and JAK3. A frameshift deletion in CDKN2A occurred in association with a missense mutation in the same gene region, suggesting a second hit in the inactivation of this gene. APC, KDR, KIT, PIK3CA and TP53 missense SNVs were identified; however, these are common SNVs, showing MAF >1%.ConclusionCEOT harbours mutations in the tumour suppressor PTEN and CDKN2A and in the oncogenes JAK3 and MET. As these mutations occurred in only one case each, they are probably not driver mutations for these tumours.

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Hlobilkova, Alice, Jana Knillova, Jiri Bartek, Jiri Lukas, and Zdenek Kolar. "THE MECHANISM OF ACTION OF THE TUMOUR SUPPRESSOR GENE PTEN." Biomedical Papers 147, no. 1 (November 1, 2003): 19–25. http://dx.doi.org/10.5507/bp.2003.003.

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Inoue, Kazushi, Elizabeth A. Fry, and Pankaj Taneja. "Recent Progress in Mouse Models for Tumor Suppressor Genes and its Implications in Human Cancer." Clinical Medicine Insights: Oncology 7 (January 2013): CMO.S10358. http://dx.doi.org/10.4137/cmo.s10358.

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Gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes (TSG) lead to cancer. In most human cancers, these mutations occur in somatic tissues. However, hereditary forms of cancer exist for which individuals are heterozygous for a germline mutation in a TSG locus at birth. The second allele is frequently inactivated by gene deletion, point mutation, or promoter methylation in classical TSGs that meet Knudson's two-hit hypothesis. Conversely, the second allele remains as wild-type, even in tumors in which the gene is haplo-insufficient for tumor suppression. This article highlights the importance of PTEN, APC, and other tumor suppressors for counteracting aberrant PI3K, β-catenin, and other oncogenic signaling pathways. We discuss the use of gene-engineered mouse models (GEMM) of human cancer focusing on Pten and Apc knockout mice that recapitulate key genetic events involved in initiation and progression of human neoplasia. Finally, the therapeutic potential of targeting these tumor suppressor and oncogene signaling networks is discussed.

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Suzuki, A., T. Sasaki, T. W. Mak, and T. Nakano. "Functional analysis of the tumour suppressor gene PTEN in murine B cells and keratinocytes." Biochemical Society Transactions 32, no. 2 (April 1, 2004): 362–65. http://dx.doi.org/10.1042/bst0320362.

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To investigate the roles of the PTEN (phosphatase and tensin homologue deleted from chromosome 10)/PI3K (phosphoinositide 3-kinase) signalling pathway in vivo, we have generated a series of mutant mice with null or tissue-specific gene-targeted deletions of Pten. Here we present our investigations of Pten function in B cells and keratinocytes in mice. Mice with a B cell-specific mutation of Pten showed increased serum autoantibodies and elevated numbers of B1a cells. Among conventional B (B2) cells in mutant spleens, numbers of marginal zone B cells were significantly increased, while those of follicular B cells were reciprocally decreased. Immunoglobulin class switch recombination was defective and associated with impaired induction of activation-induced cytidine deaminase. Mice with a keratinocyte-specific mutation of Pten exhibited epidermal hyperplasia, hyperkeratosis and accelerated skin morphogenesis. Within 3 weeks of birth, 90% of these animals died of malnutrition, possibly caused by hyperkeratosis of the oesophageal epithelia. Surviving mutant mice developed spontaneous skin tumours within 8.5 months of birth, and chemical treatment accelerated the onset of tumours. Our data show that PTEN is an important regulator in B cells and keratinocytes.

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Zhang, Xiaoqun Catherine, Antonella Piccini, Michael P. Myers, Linda Van Aelst, and Nicholas K. Tonks. "Functional analysis of the protein phosphatase activity of PTEN." Biochemical Journal 444, no. 3 (May 29, 2012): 457–64. http://dx.doi.org/10.1042/bj20120098.

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In vitro, the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) displays intrinsic phosphatase activity towards both protein and lipid substrates. In vivo, the lipid phosphatase activity of PTEN, through which it dephosphorylates the 3 position in the inositol sugar of phosphatidylinositol derivatives, is important for its tumour suppressor function; however, the significance of its protein phosphatase activity remains unclear. Using two-photon laser-scanning microscopy and biolistic gene delivery of GFP (green fluorescent protein)-tagged constructs into organotypic hippocampal slice cultures, we have developed an assay of PTEN function in living tissue. Using this bioassay, we have demonstrated that overexpression of wild-type PTEN led to a decrease in spine density in neurons. Furthermore, it was the protein phosphatase activity, but not the lipid phosphatase activity, of PTEN that was essential for this effect. The ability of PTEN to decrease neuronal spine density depended upon the phosphorylation status of serine and threonine residues in its C-terminal segment and the integrity of the C-terminal PDZ-binding motif. The present study reveals a new aspect of the function of this important tumour suppressor and suggest that, in addition to dephosphorylating the 3 position in phosphatidylinositol phospholipids, the critical protein substrate of PTEN may be PTEN itself.

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Romano, Corrado, and Carmelo Schepis. "PTEN Gene: A Model for Genetic Diseases in Dermatology." Scientific World Journal 2012 (2012): 1–8. http://dx.doi.org/10.1100/2012/252457.

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PTEN gene is considered one of the most mutated tumor suppressor genes in human cancer, and it’s likely to become the first one in the near future. Since 1997, its involvement in tumor suppression has smoothly increased, up to the current importance. Germline mutations of PTEN cause the PTEN hamartoma tumor syndrome (PHTS), which include the past-called Cowden, Bannayan-Riley-Ruvalcaba, Proteus, Proteus-like, and Lhermitte-Duclos syndromes. Somatic mutations of PTEN have been observed in glioblastoma, prostate cancer, and brest cancer cell lines, quoting only the first tissues where the involvement has been proven. The negative regulation of cell interactions with the extracellular matrix could be the way PTEN phosphatase acts as a tumor suppressor. PTEN gene plays an essential role in human development. A recent model sees PTEN function as a stepwise gradation, which can be impaired not only by heterozygous mutations and homozygous losses, but also by other molecular mechanisms, such as transcriptional regression, epigenetic silencing, regulation by microRNAs, posttranslational modification, and aberrant localization. The involvement of PTEN function in melanoma and multistage skin carcinogenesis, with its implication in cancer treatment, and the role of front office in diagnosing PHTS are the main reasons why the dermatologist should know about PTEN.

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Stefano, Sioletic, and Scambia Giovanni. "The PTEN Tumor Suppressor Gene in Soft Tissue Sarcoma." Cancers 11, no. 8 (August 14, 2019): 1169. http://dx.doi.org/10.3390/cancers11081169.

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Soft tissue sarcoma (STS) is a rare malignancy of mesenchymal origin classified into more than 50 different subtypes with distinct clinical and pathologic features. Despite the poor prognosis in the majority of patients, only modest improvements in treatment strategies have been achieved, largely due to the rarity and heterogeneity of these tumors. Therefore, the discovery of new prognostic and predictive biomarkers, together with new therapeutic targets, is of enormous interest. Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor that commonly loses its function via mutation, deletion, transcriptional silencing, or protein instability, and is frequently downregulated in distinct sarcoma subtypes. The loss of PTEN function has consequent alterations in important pathways implicated in cell proliferation, survival, migration, and genomic stability. PTEN can also interact with other tumor suppressors and oncogenic signaling pathways that have important implications for the pathogenesis in certain STSs. The aim of the present review is to summarize the biological significance of PTEN in STS and its potential role in the development of new therapeutic strategies.

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Peng, Cong, Yaoyu Chen, Zhongfa Yang, Haojian Zhang, Lori Osterby, Alan G. Rosmarin, and Shaoguang Li. "PTEN is a tumor suppressor in CML stem cells and BCR-ABL–induced leukemias in mice." Blood 115, no. 3 (January 21, 2010): 626–35. http://dx.doi.org/10.1182/blood-2009-06-228130.

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Abstract The tumor suppressor gene phosphatase and tensin homolog (PTEN) is inactivated in many human cancers. However, it is unknown whether PTEN functions as a tumor suppressor in human Philadelphia chromosome–positive leukemia that includes chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL) and is induced by the BCR-ABL oncogene. By using our mouse model of BCR-ABL–induced leukemias, we show that Pten is down-regulated by BCR-ABL in leukemia stem cells in CML and that PTEN deletion causes acceleration of CML development. In addition, overexpression of PTEN delays the development of CML and B-ALL and prolongs survival of leukemia mice. PTEN suppresses leukemia stem cells and induces cell-cycle arrest of leukemia cells. Moreover, PTEN suppresses B-ALL development through regulating its downstream gene Akt1. These results demonstrate a critical role of PTEN in BCR-ABL–induced leukemias and suggest a potential strategy for the treatment of Philadelphia chromosome–positive leukemia.

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Chen, Muhan, Dawid G. Nowak, Navneet Narula, Brian Robinson, Kaitlin Watrud, Alexandra Ambrico, Tali M. Herzka, et al. "The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein." Journal of Cell Biology 216, no. 3 (February 13, 2017): 641–56. http://dx.doi.org/10.1083/jcb.201604025.

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Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.

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Levine, R. A., T. Forest, and C. Smith. "Tumor Suppressor PTEN is Mutated in Canine Osteosarcoma Cell Lines and Tumors." Veterinary Pathology 39, no. 3 (May 2002): 372–78. http://dx.doi.org/10.1354/vp.39-3-372.

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Canine osteosarcoma (OS) cell lines contain mutations that directly or indirectly inactivate the tumor suppressor genes p53 and retinoblastoma. Another important tumor suppressor, PTEN, is mutated in many human cancers. To determine whether inactivation of PTEN plays a role in the pathogenesis of canine OS, we studied its expression in canine OS cell lines and tumors. Four of five canine OS cell lines (CO2, CO3, CO5, and CO7) constitutively express high levels of the phosphorylated form of Akt, an indirect indicator of aberrant PTEN expression. PTEN protein is essentially absent from three of these cell lines (CO2, CO5, and CO7), whereas CO3 contains a potentially inactivating amino acid substitution in PTEN at codon 340. Genomic hybridization experiments indicate that CO2, CO5, and CO7 contain large deletions within the PTEN gene. Ten of 15 OS tumors exhibit variable or negative PTEN staining. Evaluation of a PTEN-negative staining tumor by Southern blotting indicates that the PTEN gene is deleted in this tumor. These results indicate that PTEN is mutated or downregulated in a high percentage of canine OS cell lines and tumors and likely plays an important role in the pathogenesis of the disease.

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Ramaswamy, Shivapriya, and William R. Sellers. "PTEN: A Prostate Cancer Tumor-Suppressor Gene." Prostate Journal 2, no. 2 (April 2000): 55–61. http://dx.doi.org/10.1046/j.1525-1411.2000.22001.x.

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Suzuki, A., K. Hamada, T. Sasaki, T. W. Mak, and T. Nakano. "Role of PTEN/PI3K pathway in endothelial cells." Biochemical Society Transactions 35, no. 2 (March 20, 2007): 172–76. http://dx.doi.org/10.1042/bst0350172.

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PTEN (phosphatase and tensin homologue deleted on chromosome 10) is an important tumour-suppressor gene that encodes a 3-phosphatase. The major substrate of PTEN is PIP3 (phosphatidylinositol 3,4,5-trisphosphate) generated by the action of PI3Ks (phosphoinositide 3-kinases). Hereditary mutation of PTEN causes tumour-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of PTEN in mice. Heterozygous mutation of PTEN in endothelial cells enhances postnatal neovascularization, including tumour angiogenesis necessary for tumour growth. This observation suggests that Cowden disease patients are not only at risk for additional tumorigenic mutations due to complete loss of PTEN function, but may also experience accelerated growth of incipient tumours due to enhanced angiogenesis. Homozygous mutation of Pten in murine endothelial cells impairs cardiovascular morphogenesis and is embryonic lethal due to endothelial cell hyperproliferation and impaired vascular remodelling. Additional homozygous mutation of p85α, the regulatory subunit of class IA PI3Ks, or p110γ, the catalytic subunit of the sole class IB PI3K, led to a partial rescue of all phenotypes in our PTEN-deficient mice. Thus inhibition of the PI3K pathway, including the targeting of PI3Kγ, may be an attractive therapeutic strategy for the treatment of various malignancies.

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Li, Hui-Fang, Adam Keeton, Michele Vitolo, Clinton Maddox, Lynn Rasmussen, Judith Hobrath, E. Lucille White, et al. "A High-Throughput Screen with Isogenic PTEN+/+ and PTEN−/− Cells Identifies CID1340132 as a Novel Compound That Induces Apoptosis in PTEN and PIK3CA Mutant Human Cancer Cells." Journal of Biomolecular Screening 16, no. 4 (February 18, 2011): 383–93. http://dx.doi.org/10.1177/1087057110397357.

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The PTEN tumor suppressor gene is one of the most commonly mutated genes in human cancer. Because inactivation of PTEN is a somatic event, PTEN mutations represent an important genetic difference between cancer cells and normal cells and therefore a potential anticancer drug target. However, it remains a substantial challenge to identify compounds that target loss-of-function events such as mutations of tumor suppressors. In an effort to identify small molecules that preferentially kill cells with mutations of PTEN, the authors developed and implemented a high-throughput, paired cell-based screen composed of parental HCT116 cells and their PTEN gene-targeted derivatives. From 138 758 compounds tested, two hits were identified, and one, N′-[(1-benzyl-1H-indol-3-yl)methylene]benzenesulfonohydrazide (CID1340132), was further studied using a variety of cell-based models, including HCT116, MCF10A, and HEC1A cells with targeted deletion of either their PTEN or PIK3CA genes. Preferential killing of PTEN and PIK3CA mutant cells was accompanied by DNA damage, inhibition of DNA synthesis, and apoptosis. Taken together, these data validate a cell-based screening approach for identifying lead compounds that target cells with specific tumor suppressor gene mutations and describe a novel compound with preferential killing activity toward PTEN and PIK3CA mutant cells.

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Ahn, Younghee, Chae Young Hwang, Seung-Rock Lee, Ki-Sun Kwon, and Cheolju Lee. "The tumour suppressor PTEN mediates a negative regulation of the E3 ubiquitin-protein ligase Nedd4." Biochemical Journal 412, no. 2 (May 14, 2008): 331–38. http://dx.doi.org/10.1042/bj20071403.

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The tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10; a phosphatidylinositol 3-phosphatase) is a multifunctional protein deregulated in many types of cancer. It is suggested that a number of proteins that relate with PTEN functionally or physically have not yet been found. In order to search for PTEN-interacting proteins that might be crucial in the regulation of PTEN, we exploited a proteomics-based approach. PTEN-expressing NIH 3T3 cell lysates were used in affinity chromatography and then analysed by LC–ESI–MS/MS (liquid chromatography–electrospray ionization–tandem MS). A total of 93 proteins were identified. Among the proteins identified, we concentrated on the E3 ubiquitin-protein ligase Nedd4 (neural-precursor-cell-expressed, developmentally down-regulated gene 4), and performed subsequent validation experiments using HeLa cells. Nedd4 inhibited PTEN-induced apoptotic cell death and, conversely, the Nedd4 level was down-regulated by PTEN. The down-regulation effect was diminished by a mutation (C124S) in the catalytic site of PTEN. Nedd4 expression was also decreased by a PI3K (phosphoinositide 3-kinase) inhibitor, LY294002, suggesting that the regulation is dependent on the phosphatase-kinase activity of the PTEN-PI3K/Akt pathway. Semi-quantitative real-time PCR analysis revealed that Nedd4 was transcriptionally regulated by PTEN. Thus our results have important implications regarding the roles of PTEN upon the E3 ubquitin ligase Nedd4 as a negative feedback regulator as well as a substrate.

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Gray, IC, LMD Stewart, SMA Phillips, JA Hamilton, NE Gray, GJ Watson, NK Spurr, and D. Snary. "Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN." British Journal of Cancer 78, no. 10 (November 1998): 1296–300. http://dx.doi.org/10.1038/bjc.1998.674.

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Ali, I. U. "Gatekeeper for Endometrium: the PTEN Tumor Suppressor Gene." Journal of the National Cancer Institute 92, no. 11 (June 7, 2000): 861–63. http://dx.doi.org/10.1093/jnci/92.11.861.

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Mazloumi Gavgani, Fatemeh, Victoria Smith Arnesen, Rhîan Jacobsen, Camilla Krakstad, Erling Hoivik, and Aurélia Lewis. "Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer." International Journal of Molecular Sciences 19, no. 12 (December 7, 2018): 3931. http://dx.doi.org/10.3390/ijms19123931.

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The phosphoinositide 3-kinase (PI3K) signalling pathway is highly dysregulated in cancer, leading to elevated PI3K signalling and altered cellular processes that contribute to tumour development. The pathway is normally orchestrated by class I PI3K enzymes and negatively regulated by the phosphatase and tensin homologue, PTEN. Endometrial carcinomas harbour frequent alterations in components of the pathway, including changes in gene copy number and mutations, in particular in the oncogene PIK3CA, the gene encoding the PI3K catalytic subunit p110α, and the tumour suppressor PTEN. PIK3CB, encoding the other ubiquitously expressed class I isoform p110β, is less frequently altered but the few mutations identified to date are oncogenic. This isoform has received more research interest in recent years, particularly since PTEN-deficient tumours were found to be reliant on p110β activity to sustain transformation. In this review, we describe the current understanding of the common and distinct biochemical properties of the p110α and p110β isoforms, summarise their mutations and highlight how they are targeted in clinical trials in endometrial cancer.

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Downes, C. P., S. Walker, G. McConnachie, Y. Lindsay, I. H. Batty, and N. R. Leslie. "Acute regulation of the tumour suppressor phosphatase, PTEN, by anionic lipids and reactive oxygen species." Biochemical Society Transactions 32, no. 2 (April 1, 2004): 338–42. http://dx.doi.org/10.1042/bst0320338.

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PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a member of the protein tyrosine phosphatase family that is structurally adapted to facilitate the metabolism of 3-phosphoinositide lipid second messengers, especially PtdIns(3,4,5)P3. Cellular PTEN activity is restrained by the retention of C-terminally phosphorylated enzyme in the cytosol. Dephosphorylation by as yet undefined phosphatases initiates an electrostatic switch which targets PTEN specifically to the plasma membrane, where it binds through multiple positively charged residues in both the C2 and N-terminal domains and is susceptible to feedback regulation through proteolytic degradation. PTEN also forms signalling complexes with PDZ domain-containing adaptors, such as the MAGUK (membrane-associated guanylate kinase) proteins, interactions which appear to be necessary for metabolism of localized pools of PtdIns(3,4,5)P3 involved in regulating actin cytoskeleton dynamics. TPIP [TPTE (transmembrane phosphatase with tensin homology) and PTEN homologous inositol lipid phosphatase] is a novel gene product which exists in multiply spliced forms. TPIPα has PtdIns(3,4,5)P3 3-phosphatase activity and is localized to the endoplasmic reticulum, via two transmembrane spanning regions, where it may metabolize PtdIns(3,4,5)P3 that appears to be unaffected by expressed PTEN. PTEN can be acutely regulated by oxidative stress and by endogenously produced reactive oxygen species. This mechanism provides a novel means to stimulate phosphoinositide 3-kinase-dependent signalling pathways, which may be important in circumstances where PtdIns(3,4,5)P3 and oxidants are produced concurrently.

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Nero, Camilla, Francesca Ciccarone, Antonella Pietragalla, and Giovanni Scambia. "PTEN and Gynecological Cancers." Cancers 11, no. 10 (September 28, 2019): 1458. http://dx.doi.org/10.3390/cancers11101458.

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PTEN is a tumour suppressor gene, and its loss of function is frequently observed in both heritable and sporadic cancers. It is involved in a great variety of biological processes, including maintenance of genomic stability, cell survival, migration, proliferation and metabolism. A better understanding of PTEN activity and regulation has therefore emerged as a subject of primary interest in cancer research. Gynaecological cancers are variously interested by PTEN deregulation and many perspective in terms of additional prognostic information and new therapeutic approaches can be explored. Here, we present the most significant findings on PTEN in gynaecological cancers (ovarian, endometrial, cervical, vulvar and uterine cancer) focusing on PTEN alterations incidence, biological role and clinical implications.

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Ferraro, Bernadette, Gerold Bepler, Swati Sharma, Alan Cantor, and Eric B. Haura. "EGR1 Predicts PTEN and Survival in Patients With Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 23, no. 9 (March 20, 2005): 1921–26. http://dx.doi.org/10.1200/jco.2005.08.127.

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Purpose The zinc finger transcription factor early growth response gene 1 (EGR1) is underexpressed in non–small-cell lung cancer (NSCLC) compared with normal lung. EGR1 expression has been linked to tumor suppression as a result of cell cycle arrest and apoptosis through regulation of tumor suppressor pathways including PTEN. For these reasons, we hypothesized that reduced levels of EGR1 would correlate with inferior outcome in patients with NSCLC. Patients and Methods Patients who underwent surgical resection for NSCLC had RNA extracted from tumor tissue and EGR1 gene expression was quantified by real-time quantitative polymerase chain reaction. The levels of EGR1 expression were examined in relationship to patient characteristics, histology, tumor stage, PTEN expression, and overall and disease-free survival. Results EGR1 expression strongly correlated with PTEN expression (P < .0001). No correlation of EGR1 with histology or stage was detected. Patients with high levels of EGR1 had better overall and disease-free survival compared with patients with low levels of EGR1 (P = .040 and P = .096, respectively). In a stratified log-rank test, low EGR1 expression was predictive of poor survival independent of tumor stage. Conclusion EGR1 gene expression predicts PTEN levels and survival after surgical resection of NSCLC. Consistent with its known tumor suppressor properties, lower levels of EGR1 are associated with poor outcome. Identification of patients with low EGR1 therefore may identify patients at high risk for disease recurrence and may also identify patients who have tumors resistant to therapy secondary to loss of pathways such as PTEN.

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S, Sithara, Sheela Varghese, and Sankar S. "PHOSPHOTENSIN TUMOUR SUPPRESSOR GENE (PTEN) EXPRESSION PATTERNS IN ENDOMETRIAL HYPERPLASIAS AND ENDOMETRIOID CARCINOMA." Journal of Evolution of Medical and Dental Sciences 8, no. 7 (February 18, 2019): 403–6. http://dx.doi.org/10.14260/jemds/2019/89.

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Aggerholm, Anni, Kirsten Grønbaek, Per Guldberg, and Peter Hokland. "Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders." European Journal of Haematology 65, no. 2 (August 2000): 109–13. http://dx.doi.org/10.1034/j.1600-0609.2000.90181.x.

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Lima, E. M., J. J. Araújo, M. L. Harada, P. P. Assumpção, R. R. Burbano, and C. Casartelli. "Molecular study of the tumour suppressor gene PTEN in gastric adenocarcinoma in Brazil." Clinical and Experimental Medicine 5, no. 3 (October 2005): 129–32. http://dx.doi.org/10.1007/s10238-005-0077-0.

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Luongo, Francesca, Francesca Colonna, Federica Calapà, Sara Vitale, Micol E. Fiori, and Ruggero De Maria. "PTEN Tumor-Suppressor: The Dam of Stemness in Cancer." Cancers 11, no. 8 (July 30, 2019): 1076. http://dx.doi.org/10.3390/cancers11081076.

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PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.

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Nan, B., T. Snabboon, E. Unni, Yuan X-J, YE Whang, and M. Marcelli. "The PTEN tumor suppressor is a negative modulator of androgen receptor transcriptional activity." Journal of Molecular Endocrinology 31, no. 1 (August 1, 2003): 169–83. http://dx.doi.org/10.1677/jme.0.0310169.

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To investigate whether the tumor suppressor gene PTEN affects the activity of the androgen receptor (AR), we monitored the expression of the apoptotic gene HA-Bax (inserted in an adenovirus where it is driven by the AR-responsive promoter ARR(2)PB) in the presence or absence of dihydrotestosterone, in PTEN (+) or (-) prostate cancer cell lines, infected with an adenovirus containing wild-type PTEN (Av-CMV-PTEN) or a control LacZ-expressing construct. Our results showed that AR transcriptional activity was antagonized by PTEN expression. This antagonism was not cell line dependent, as it was observed in both LNCaP and LAPC-4 cells, or promoter dependent, as it was observed for a reporter gene (HA-Bax) driven by an exogenous androgen-responsive promoter (the ARR(2)PB promoter), and for a native gene (prostate-specific antigen; PSA) driven by an endogenous AR-responsive promoter. Additional experiments performed with viruses containing constitutively active (Adeno-myrAkt) or dominant negative (Adeno-dnAkt) forms of Akt demonstrated that Akt, a protein kinase whose activation is known to be inhibited by PTEN, mediated the observed antagonism between PTEN and AR transcriptional activity. Recently, two putative Akt phosphorylation sites have been identified in the AR sequence. Site-directed mutagenesis was utilized to convert these two serine into alanine residues. The resulting construct, named CMV-AR S213A&S791A was transfected in AR (-) and PTEN (-) PC-3 cells in the presence or absence of Av-CMV-PTEN and of two reporter plasmids (GRE(2)E1b-Luc and PSA P/E-luc) containing the luciferase gene driven by well-characterized androgen responsive promoters. These experiments demonstrated that, similarly to the wild-type molecule, AR S213A&S791A was transcriptionally inhibited by PTEN, suggesting that Akt does not have an effect on AR transcription by direct phosphorylation, but probably by affecting the availability of a downstream molecule whose main mechanism of action is that of modulating AR transcription. The data presented here suggest that loss of PTEN function may facilitate activation of AR signaling and progression to androgen independence in prostate cancer.

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Yamada, Kenneth M., and Masaru Araki. "Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis." Journal of Cell Science 114, no. 13 (July 1, 2001): 2375–82. http://dx.doi.org/10.1242/jcs.114.13.2375.

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PTEN (also known as MMAC-1 or TEP-1) is one of the most frequently mutated tumor suppressors in human cancer. It is also essential for embryonic development. PTEN functions primarily as a lipid phosphatase to regulate crucial signal transduction pathways; a key target is phosphatidylinositol 3,4,5-trisphosphate. In addition, it displays weak tyrosine phosphatase activity, which may downmodulate signaling pathways that involve focal adhesion kinase (FAK) or Shc. Levels of PTEN are regulated in embryos and adult organisms, and gene-targeting studies demonstrate that it has a crucial role in normal development. Functions for PTEN have been identified in the regulation of many normal cell processes, including growth, adhesion, migration, invasion and apoptosis. PTEN appears to play particularly important roles in regulating anoikis (apoptosis of cells after loss of contact with extracellular matrix) and cell migration. Gene targeting and transient expression studies have provided insight into the specific signaling pathways that regulate these processes. Characterization of the diverse signaling networks modulated by PTEN, as well as the regulation of PTEN concentration, enzymatic activity, and coordination with other phosphatases, should provide intriguing new insight into the biology of normal and malignant cells.

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de la Rosa, Jorge, Julia Weber, Roland Rad, Allan Bradley, and Juan Cadiñanos. "Disentangling PTEN-cooperating tumor suppressor gene networks in cancer." Molecular & Cellular Oncology 4, no. 4 (May 4, 2017): e1325550. http://dx.doi.org/10.1080/23723556.2017.1325550.

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Ebbesen, Saya H., Maurizio Scaltriti, Carl U. Bialucha, Natasha Morse, Edward R. Kastenhuber, Hannah Y. Wen, Lukas E. Dow, José Baselga, and Scott W. Lowe. "Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas." Proceedings of the National Academy of Sciences 113, no. 11 (February 29, 2016): 3030–35. http://dx.doi.org/10.1073/pnas.1523693113.

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Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracycline-regulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.

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Stefanska, Barbara, Patrick Salamé, Andrzej Bednarek, and Krystyna Fabianowska-Majewska. "Comparative effects of retinoic acid, vitamin D and resveratrol alone and in combination with adenosine analogues on methylation and expression of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells." British Journal of Nutrition 107, no. 6 (August 1, 2011): 781–90. http://dx.doi.org/10.1017/s0007114511003631.

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Aberrations in DNA methylation patterns have been reported to be involved in driving changes in the expression of numerous genes during carcinogenesis and have become promising targets for chemopreventive action of natural compounds. In the present study, we investigated the effects of all-trans retinoic acid (ATRA), vitamin D3 and resveratrol alone and in combination with adenosine analogues, 2-chloro-2′-deoxyadenosine (2CdA) and 9-β-d-arabinosyl-2-fluoroadenine (F-ara-A), on the methylation and expression of phosphatase and tensin homologue (PTEN) tumour suppressor gene in MCF-7 and MDA-MB-231 breast cancer cells. The present results showed that in non-invasive MCF-7 cells, ATRA, vitamin D3 and resveratrol possess high efficacy in the reduction of PTEN promoter methylation. It was associated with PTEN induction as well as DNA methyltransferase down-regulation and p21 up-regulation after treatments with vitamin D3 and resveratrol, suggesting a complex regulation of the DNA methylation machinery. Vitamin D3 and resveratrol improved the inhibitory effects of 2CdA and F-ara-A on PTEN methylation in MCF-7 cells; however, only the combined action of vitamin D3 and 2CdA boosted the induction of PTEN expression, suggesting a cooperation of these compounds in additional processes driving changes in PTEN expression. In contrast, in highly invasive MDA-MB-231 cells, only vitamin D3 reduced PTEN methylation and induced its expression without notable effects in combined treatments. The present results suggest that natural compounds can find application in epigenetic anticancer therapy aimed at inhibition of promoter methylation of tumour suppressor genes and induction of their expression at early stages of carcinogenesis.

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de la Haba-Rodriguez, Juan, Cano M, Rangal Y, Morales Cristina, Fuentes E, Montero M, Porras I, Chia B, Rodriguez A, and Enrique Aranda. "PTEN-deficient breast cancer in neoadjuvant treatment." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1125. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1125.

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1125 Background: Loss of function mutations in the tumour suppressor gene PTEN or lack of PTEN expression have both been observed in a wide range of human tumours. PTEN encodes a phosphatase, whose activity antagonizes PI3 kinase signal pathway by dephosphorylation the plasma membrane lipid, phosphoinositide-3,4,5-trisphosphate (PIP3). Loss of PTEN phosphatase activity is thought to foster tumorigenesis, at least in part, by causing downstream constitutive activation of AKT. In addition to this role, PTEN has been suggested to have a nuclear function in maintaining genomic stability[2]. Our proposal is to identify those tumours without expression of PTEN, their characteristics and response to treatment. Methods: We have studied PTEN expression by immunohistochemistry in tumours samples from 86 patients treated with neoadjuvant treatment. Normal breast epithelium or vascular endothelium were used as positive control. PTEN was evaluated by inmunoreactive stain score, taking into account staining intensity and percentage of positive cells, PTEN deficiency (PTEN -) has been stablished by a IRS=0[1]. We analyzed the PTEN localization (nuclear vs citoplasmatic). Results: In our serie, 38 (44.2%) of the tumours samples were PTEN deficient. Taking into account as reference PTEN + tumours, we have found that PTEN deficient tumours are more frequently; ductal carcinoma (94.2% vs 81.8%), G3 (72% vs 48.7%), ER negative (47% vs 30.4%), Triple negative (24.2% vs 15%) and higher Ki67 expression (>20%) in the 100% of PTEN deficient tumours. The pathological rate response was PTEN -:18.4% vs PTEN +:19.1% p:ns, and the recurrence rate was higher in PTEN- (26,3% vs 8,3%) p:0.025. Conclusions: The PTEN deficient breast tumours is associated to more histological aggressive profile, and we have not found relations with the pathological rate response to neoadjuvant treatment.

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Freihoff, D., A. Kempe, B. Beste, B. Wappenschmidt, E. Kreyer, Y. Hayashi, A. Meindl, et al. "Exclusion of a major role for the PTEN tumour-suppressor gene in breast carcinomas." British Journal of Cancer 79, no. 5-6 (January 29, 1999): 754–58. http://dx.doi.org/10.1038/sj.bjc.6690121.

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Hyun, Teresa, Alan Yam, Salvatore Pece, Xiaozhen Xie, Jie Zhang, Toru Miki, J. Silvio Gutkind, and Weiqun Li. "Loss of PTEN expression leading to high Akt activation in human multiple myelomas." Blood 96, no. 10 (November 15, 2000): 3560–68. http://dx.doi.org/10.1182/blood.v96.10.3560.

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Abstract Mouse plasma cell tumor (PCT) and human multiple myeloma (MM) are terminal B-cell malignancies sharing many similarities. Our recent work demonstrated that activation of the insulin-like growth factor receptor (IGF-IR)/insulin receptor substrate (IRS)/phosphatidylinositol 3′ kinase (PI 3′K) pathway was evident in the tumor lines derived from both species. Although PI 3′K activity was higher in mouse tumor lines than that in human tumors, activation of Akt serine/threonine kinase was markedly lower in mouse lines. This discrepancy prompted us to test the status of PTEN tumor suppressor gene, as it has been shown to be a negative regulator of PI 3′K activity. Although all the mouse lines expressed intact PTEN, 2 of the 4 human lines (Δ47 and OPM2) possessing the highest Akt activity lost PTEN expression. Sequencing analysis demonstrated that the PTEN gene contains a deletion spacing from exon 3 to exon 5 or 6 in the Δ47 line and from exon 3 to 7 in the OPM2 line. Restoration of PTEN expression suppressed IGF-I–induced Akt activity, suggesting that loss of PTEN is responsible for uncontrolled Akt activity in these 2 lines. Despite the expression of PTEN with the concomitant low Akt activity in all mouse PCT lines, their p70S6K activities were generally higher than those in 3 human MM lines, arguing for specific negative regulation of Akt, but not p70S6K by PTEN. These results suggest that p70S6K and Akt may be differentially used by the plasma cell tumors derived from mice and humans, respectively.

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Hyun, Teresa, Alan Yam, Salvatore Pece, Xiaozhen Xie, Jie Zhang, Toru Miki, J. Silvio Gutkind, and Weiqun Li. "Loss of PTEN expression leading to high Akt activation in human multiple myelomas." Blood 96, no. 10 (November 15, 2000): 3560–68. http://dx.doi.org/10.1182/blood.v96.10.3560.h8003560_3560_3568.

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Mouse plasma cell tumor (PCT) and human multiple myeloma (MM) are terminal B-cell malignancies sharing many similarities. Our recent work demonstrated that activation of the insulin-like growth factor receptor (IGF-IR)/insulin receptor substrate (IRS)/phosphatidylinositol 3′ kinase (PI 3′K) pathway was evident in the tumor lines derived from both species. Although PI 3′K activity was higher in mouse tumor lines than that in human tumors, activation of Akt serine/threonine kinase was markedly lower in mouse lines. This discrepancy prompted us to test the status of PTEN tumor suppressor gene, as it has been shown to be a negative regulator of PI 3′K activity. Although all the mouse lines expressed intact PTEN, 2 of the 4 human lines (Δ47 and OPM2) possessing the highest Akt activity lost PTEN expression. Sequencing analysis demonstrated that the PTEN gene contains a deletion spacing from exon 3 to exon 5 or 6 in the Δ47 line and from exon 3 to 7 in the OPM2 line. Restoration of PTEN expression suppressed IGF-I–induced Akt activity, suggesting that loss of PTEN is responsible for uncontrolled Akt activity in these 2 lines. Despite the expression of PTEN with the concomitant low Akt activity in all mouse PCT lines, their p70S6K activities were generally higher than those in 3 human MM lines, arguing for specific negative regulation of Akt, but not p70S6K by PTEN. These results suggest that p70S6K and Akt may be differentially used by the plasma cell tumors derived from mice and humans, respectively.

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Lee, Yu-Ru, Ming Chen, Jonathan D. Lee, Jinfang Zhang, Shu-Yu Lin, Tian-Min Fu, Hao Chen, et al. "Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway." Science 364, no. 6441 (May 16, 2019): eaau0159. http://dx.doi.org/10.1126/science.aau0159.

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Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain–containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. WWP1 appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.

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Liu, Juinn-Lin, Xiaoyang Sheng, Zsuzsanna K. Hortobagyi, Zhenyu Mao, Gary E. Gallick, and W. K. Alfred Yung. "Nuclear PTEN-Mediated Growth Suppression Is Independent of Akt Down-Regulation." Molecular and Cellular Biology 25, no. 14 (July 2005): 6211–24. http://dx.doi.org/10.1128/mcb.25.14.6211-6224.2005.

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ABSTRACT The tumor suppressor gene PTEN is a phosphoinositide phosphatase that is inactivated by deletion and/or mutation in diverse human tumors. Wild-type PTEN is expressed both in the cytoplasm and nucleus in normal cells, with a preferential nuclear localization in differentiated or resting cells. To elucidate the relationship between PTEN′s subcellular localization and its biologic activities, we constructed different PTEN mutants that targeted PTEN protein into different subcellular compartments. Our data show that the subcellular localization patterns of a PTEN (ΔPDZB) mutant versus a G129R phosphatase mutant were indistinguishable from those of wild-type PTEN. In contrast, the Myr-PTEN mutant demonstrated an enhanced association with the cell membrane. We found that nuclear PTEN alone is capable of suppressing anchorage-independent growth and facilitating G1 arrest in U251MG cells without inhibiting Akt activity. Nuclear compartment-specific PTEN-induced growth suppression is dependent on possessing a functional lipid phosphatase domain. In addition, the down-regulation of p70S6K could be mediated, at least in part, through activation of AMP-activated protein kinase in an Akt-independent fashion. Introduction of a constitutively active mutant of Akt, Akt-DD, only partially rescues nuclear PTEN-mediated growth suppression. Our collective results provide the first direct evidence that PTEN can contribute to G1 growth arrest through an Akt-independent signaling pathway.

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Lai, Dulcie, Stacy Visser-Grieve, and Xiaolong Yang. "Tumour suppressor genes in chemotherapeutic drug response." Bioscience Reports 32, no. 4 (April 23, 2012): 361–74. http://dx.doi.org/10.1042/bsr20110125.

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Since cancer is one of the leading causes of death worldwide, there is an urgent need to find better treatments. Currently, the use of chemotherapeutics remains the predominant option for cancer therapy. However, one of the major obstacles for successful cancer therapy using these chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. Therefore identification of genes involved in chemotherapeutic response is critical for predicting tumour response and treating drug-resistant cancer patients. A group of genes commonly lost or inactivated are tumour suppressor genes, which can promote the initiation and progression of cancer through regulation of various biological processes such as cell proliferation, cell death and cell migration/invasion. Recently, mounting evidence suggests that these tumour suppressor genes also play a very important role in the response of cancers to a variety of chemotherapeutic drugs. In the present review, we will provide a comprehensive overview on how major tumour suppressor genes [Rb (retinoblastoma), p53 family, cyclin-dependent kinase inhibitors, BRCA1 (breast-cancer susceptibility gene 1), PTEN (phosphatase and tensin homologue deleted on chromosome 10), Hippo pathway, etc.] are involved in chemotherapeutic drug response and discuss their applications in predicting the clinical outcome of chemotherapy for cancer patients. We also propose that tumour suppressor genes are critical chemotherapeutic targets for the successful treatment of drug-resistant cancer patients in future applications.

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Fata, Jimmie E., Shawon Debnath, Edmund C. Jenkins, and Marcia V. Fournier. "Nongenomic Mechanisms of PTEN Regulation." International Journal of Cell Biology 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/379685.

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A large amount of data supports the view that PTEN is a bona fide tumor suppressor gene. However, recent evidence suggests that derailment of cellular localization and expression levels of functional nonmutated PTEN is a determining force in inducing abnormal cellular and tissue outcomes. As the cellular mechanisms that regulate normal PTEN enzymatic activity resolve, it is evident that deregulation of these mechanisms can alter cellular processes and tissue architecture and ultimately lead to oncogenic transformation. Here we discuss PTEN ubiquitination, PTEN complex formation with components of the adherens junction, PTEN nuclear localization, and microRNA regulation of PTEN as essential regulatory mechanisms that determine PTEN function independent of gene mutations and epigenetic events.

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Maxwell, Risinger, Shaw, Alvarez, Barrett, Futreal, and Berchuck. "Mutations in the PTEN tumor suppressor gene in cervical carcinomas." International Journal of Gynecological Cancer 8, no. 6 (November 1998): 489–93. http://dx.doi.org/10.1046/j.1525-1438.1998.98102.x.

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Vasudevan, Krishna Murthi, Sushma Gurumurthy, and Vivek M. Rangnekar. "Suppression of PTEN Expression by NF-κB Prevents Apoptosis." Molecular and Cellular Biology 24, no. 3 (February 1, 2004): 1007–21. http://dx.doi.org/10.1128/mcb.24.3.1007-1021.2004.

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ABSTRACT NF-κB is a heterodimeric transcription activator consisting of the DNA binding subunit p50 and the transactivation subunit p65/RelA. NF-κB prevents cell death caused by tumor necrosis factor (TNF) and other genotoxic insults by directly inducing antiapoptotic target genes. We report here that the tumor suppressor PTEN, which functions as a negative regulator of phosphatidylinositol (PI)-3 kinase/Akt-mediated cell survival pathway, is down regulated by p65 but not by p50. Moreover, a subset of human lung or thyroid cancer cells expressing high levels of endogenous p65 showed decreased expression of PTEN that could be rescued by specific inhibition of the NF-κB pathway with IκB overexpression as well as with small interfering RNA directed against p65. Importantly, TNF, a potent inducer of NF-κB activity, suppressed PTEN gene expression in IKKβ+/+ cells but not in IKKβ−/− cells, which are deficient in the NF-κB activation pathway. These findings indicated that NF-κB activation was necessary and sufficient for inhibition of PTEN expression. The promoter, RNA, and protein levels of PTEN are down-regulated by NF-κB. The mechanism underlying suppression of PTEN expression by NF-κB was independent of p65 DNA binding or transcription function and involved sequestration of limiting pools of transcriptional coactivators CBP/p300 by p65. Restoration of PTEN expression inhibited NF-κB transcriptional activity and augmented TNF-induced apoptosis, indicating a negative regulatory loop involving PTEN and NF-κB. PTEN is, thus, a novel target whose suppression is critical for antiapoptosis by NF-κB.

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Muñoz, Jorge, María del Mar Inda, Paula Lázcoz, Idoya Zazpe, Xing Fan, Jorge Alfaro, Teresa Tuñón, Juan A. Rey, and Javier S. Castresana. "Promoter Methylation of RASSF1A Associates to Adult Secondary Glioblastomas and Pediatric Glioblastomas." ISRN Neurology 2012 (January 9, 2012): 1–10. http://dx.doi.org/10.5402/2012/576578.

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While allelic losses and mutations of tumor suppressor genes implicated in the etiology of astrocytoma have been widely assessed, the role of epigenetics is still a matter of study. We analyzed the frequency of promoter hypermethylation by methylation-specific PCR (MSP) in five tumor suppressor genes (PTEN, MGMT, RASSF1A, p14ARF, and p16INK4A), in astrocytoma samples and cell lines. RASSF1A was the most frequently hypermethylated gene in all grades of astrocytoma samples, in cell lines, and in adult secondary GBM. It was followed by MGMT. PTEN showed a slight methylation signal in only one GBM and one pilocytic astrocytoma, and in two cell lines; while p14ARF and p16INK4A did not show any evidence of methylation in primary tumors or cell lines. In pediatric GBM, RASSF1A was again the most frequently altered gene, followed by MGMT; PTEN, p14 and p16 showed no alterations. Lack or reduced expression of RASSF1A in cell lines was correlated with the presence of methylation. RASSF1A promoter hypermethylation might be used as a diagnostic marker for secondary GBM and pediatric GBM. Promoter hypermethylation might not be an important inactivation mechanism in other genes like PTEN, p14ARF and p16INK4A, in which other alterations (mutations, homozygous deletions) are prevalent.

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De Vivo, I. "Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers." Journal of Medical Genetics 37, no. 5 (May 1, 2000): 336–41. http://dx.doi.org/10.1136/jmg.37.5.336.

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Yang, Qing, Xiaofeng Qiao, Daguang Li, Bo Chen, Lingmin Zhang, Cuiling Yuan, and Hua Lin. "Expression and association of IL-21, FBXL20 and tumour suppressor gene PTEN in laryngeal cancer." Saudi Journal of Biological Sciences 26, no. 8 (December 2019): 2048–51. http://dx.doi.org/10.1016/j.sjbs.2019.08.013.

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Kulke, M. H., R. D. Odze, K. S. Thakore, G. Thomas, H. Wang, M. Loda, and C. Eng. "Allelic loss of 10q23, the PTEN tumour suppressor gene locus, in Barrett’s oesophagus-associated adenocarcinoma." British Journal of Cancer 84, no. 6 (2001): 748–53. http://dx.doi.org/10.1054/bjoc.2000.1660.

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Journal articles on the topic 'Tumour suppressor gene pten'

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