Journal articles: 'MRNA downregulation'

1

Yeilding, N. M., and W. M. Lee. "Coding elements in exons 2 and 3 target c-myc mRNA downregulation during myogenic differentiation." Molecular and Cellular Biology 17, no. 5 (May 1997): 2698–707. http://dx.doi.org/10.1128/mcb.17.5.2698.

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Downregulation in expression of the c-myc proto-oncogene is an early molecular event in differentiation of murine C2C12 myoblasts into multinucleated myotubes. During differentiation, levels of c-myc mRNA decrease 3- to 10-fold despite a lack of change in its transcription rate. To identify cis-acting elements that target c-myc mRNA for downregulation during myogenesis, we stably transfected C2C12 cells with mutant myc genes or chimeric genes in which various myc sequences were fused to the human beta-globin gene or to the bacterial chloramphenicol acetyltransferase (CAT) gene. Deletion of coding sequences from myc exon 2 or exon 3 abolished downregulation of myc mRNA during myogenic differentiation, while deletion of introns or sequences in the 5' or 3' untranslated regions (UTRs) did not, demonstrating that coding elements in both exons 2 and 3 are necessary for myc mRNA downregulation. Fusion of coding sequences from either myc exon 2 or 3 to beta-globin mRNA conferred downregulation onto the chimeric mRNA, while fusion of myc 3' UTR sequences or coding sequences from CAT or ribosomal protein L32 did not, demonstrating that coding elements in myc exons 2 and 3 specifically confer downregulation. These results present the apparent paradox that coding elements in either myc exon 2 or myc exon 3 are sufficient to confer downregulation onto beta-globin mRNA, but neither element alone was sufficient for myc mRNA downregulation, suggesting that some feature of beta-globin mRNA may potentiate the regulatory properties of myc exons 2 and 3. A similar regulatory function is not shared by all mRNAs because fusion of either myc exon 2 or myc exon 3 to CAT mRNA did not confer downregulation onto the chimeric mRNA, but fusion of the two elements together did. We conclude from these results that two myc regulatory elements, one exon 2 and one in exon 3, are required for myc mRNA downregulation. Finally, using a highly sensitive and specific PCR-based assay for comparing mRNA levels, we demonstrated that the downregulation mediated by myc exons 2 and 3 results in a decrease in cytoplasmic mRNA levels, but not nuclear mRNA levels, indicating that regulation is a postnuclear event.

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Asada, Sachie, Yoshitoshi Kasuya, Takeshi Sakurai, Tomoh Masaki, and Katsutoshi Goto. "Endothelin-1-Induced Downregulation of ETB Receptor mRNA." Journal of Cardiovascular Pharmacology 26 (1995): S272–275. http://dx.doi.org/10.1097/00005344-199526003-00082.

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Asada, Sachie, Yoshitoshi Kasuya, Takeshi Sakurai, Tomoh Masaki, and Katsutoshi Goto. "Endothelin-1-Induced Downregulation of ETB Receptor mRNA." Journal of Cardiovascular Pharmacology 26 (1995): S272–275. http://dx.doi.org/10.1097/00005344-199506263-00082.

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Liu, Jinyao, Ayako Hakucho, and Tatsuya Fujimiya. "Angiotensinase C mRNA and Protein Downregulations Are Involved in Ethanol-Deteriorated Left Ventricular Systolic Dysfunction in Spontaneously Hypertensive Rats." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/409350.

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The influences of angiotensinase C on ethanol-induced left ventricular (LV) systolic function were assessed in spontaneously hypertensive rats (SHRs). SHRs were fed by a liquid diet with or without ethanol for 49 days. The normotensive Wistar Kyoto rats (WKY) were fed by the liquid diet without ethanol and used as control. We evaluated LV systolic function, angiotensinase C mRNA and protein expressions, activation of the renin-angiotensin system (RAS), and the gene expressions of LV collagen (Col) III a1 and matrix metalloproteinases- (MMP-) 9. Compared to the WKY, LV systolic dysfunction (expressed by decreased fractional shortening and ejection fraction) was observed in the SHRs before ethanol treatment and further deteriorated by ethanol treatment. In the ethanol-treated SHRs, the following were observed: downregulations of angiotensinase C mRNA and protein, increased RAS activity with low collagen production as evidenced by angiotensin II and angiotensin type 1 receptor (AT1R) protein upregulation,AT1aR mRNA downregulation, and an MMP-9 mRNA expression upregulation trend with the downregulation of Col III a1 mRNA expression in LV. We conclude that chronic ethanol regimen is sufficient to promote the enhanced RAS activity-induced decrease in the production of cardiac collagen via downregulated angiotensinase C, leading to the further deterioration of LV systolic dysfunction in SHRs.

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Huang, Fu-Chen, Ying-Hsien Huang, Ho-Chang Kuo, and Sung-Chou Li. "Identifying Downregulation of Autophagy Markers in Kawasaki Disease." Children 7, no. 10 (October 4, 2020): 166. http://dx.doi.org/10.3390/children7100166.

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Kawasaki disease (KD) is the most common cause of heart disease acquired in childhood. Even if treated with high-dose intravenous immunoglobulin G (IVIG) at the early stage; children are still at risk of developing coronary artery lesions. Accumulating evidence suggests that autophagy is enhanced in various heart diseases. Evaluating the pathogenic role of autophagy in KD and coronary artery lesions (CAL) may aid in identifying a potential therapeutic target for the treatment or prevention of the disease. Blood samples were obtained from 20 children with KD at the onset of disease and 21 days after IVIG therapy. Twenty children with other causes of febrile disease and 20 healthy children were included as controls. Total RNA was extracted from white blood cells; and autophagy-related gene mRNA expression levels were measured using real-time polymerase chain reaction. The patients with KD had downregulated levels of LC3B mRNA (0.50 ± 0.06 vs. 1.67 ± 0.15; p < 0.001), BECN1 mRNA (0.70 ± 0.08 vs. 1.43 ± 0.23; p < 0.05), and ATG16L1 mRNA (0.28 ± 0.04 vs. 0.96 ± 0.16; p < 0.01) compared to the febrile control group. The values of these parameters all increased significantly 21 days after the IVIG therapy as follows: LC3B mRNA (1.77 ± 0.29 vs. 0.50 ± 0.06; p < 0.001), BECN1 mRNA (1.67 ± 0.36 vs. 0.70 ± 0.08; p < 0.05), and ATG16L1 mRNA (2.96 ± 0.43 vs. 0.28 ± 0.04; p < 0.001), while the level of ATG16L1 mRNA persists low in KD patients with CAL. Our results showed the autophagy-related genes expressions in KD and their change after IVIG administration. This suggests that autophagy may have a protective effect on KD.

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Ichiki, Toshihiro, Kotaro Takeda, and Akira Takeshita. "Reactive Oxygen Species-Mediated Homologous Downregulation of Angiotensin II Type 1 Receptor Mrna by Angiotensin II." Hypertension 36, suppl_1 (October 2000): 688. http://dx.doi.org/10.1161/hyp.36.suppl_1.688-b.

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58 Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of Angiotensin II (Ang II) through type 1 Ang II receptor (AT1-R). However, the role of ROS in the regulation of AT1-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT1-R by Ang II. Ang II (10 -6 mol/L) decreased AT1-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells (VSMC). Ang II dose-dependently (10 -8 -10 -6 ) suppressed AT1-R mRNA at 6 hours of stimulation. Preincubation of VSMC with N-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT1-R mRNA. The effect of NAC was due to stabilization of the AT1-R mRNA that was destabilized by Ang II. Ang II did not affect the promoter activity of AT1-R gene. Diphenylene iodonium (DPI), an inhibitor of NADH/NADPH oxidase failed to inhibit the Ang II-induced AT1-R mRNA downregulation. The Ang II-induced AT1-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as PD98059 whereas DPI did not inhibit it. To confirm the role of ROS in the regulation of AT1-R mRNA expression, VSMC were stimulated with H 2 O 2 . H 2 O 2 suppressed the AT1-R mRNA expression and activated ERK. These results suggest that production of ROS and activation of ERK are critical for downregulation of AT1-R mRNA. The differential effect of NAC and DPI on the downregulation of AT1-R mRNA may suggest the presence of other sources than NADH/NADPH oxidase pathway for ROS in Ang II signaling. Generation of ROS through stimulation of AT1-R not only mediates signaling of Ang II but may play a crucial role in the adaptation process of AT1-R to the sustained stimulation of Ang II.

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Tao, Xianzun, and Guangxia Gao. "Tristetraprolin Recruits Eukaryotic Initiation Factor 4E2 To Repress Translation of AU-Rich Element-Containing mRNAs." Molecular and Cellular Biology 35, no. 22 (September 14, 2015): 3921–32. http://dx.doi.org/10.1128/mcb.00845-15.

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Tristetraprolin (TTP) regulates the expression of AU-rich element-containing mRNAs through promoting the degradation and repressing the translation of target mRNA. While the mechanism for promoting target mRNA degradation has been extensively studied, the mechanism underlying translational repression is not well established. Here, we show that TTP recruits eukaryotic initiation factor 4E2 (eIF4E2) to repress target mRNA translation. TTP interacted with eIF4E2 but not with eIF4E. Overexpression of eIF4E2 enhanced TTP-mediated translational repression, and downregulation of endogenous eIF4E2 or overexpression of a truncation mutant of eIF4E2 impaired TTP-mediated translational repression. Overexpression of an eIF4E2 mutant that lost the cap-binding activity also impaired TTP's activity, suggesting that the cap-binding activity of eIF4E2 is important in TTP-mediated translational repression. We further show that TTP promoted eIF4E2 binding to target mRNA. These results imply that TTP recruits eIF4E2 to compete with eIF4E to repress the translation of target mRNA. This notion is supported by the finding that downregulation of endogenous eIF4E2 increased the production of tumor necrosis factor alpha (TNF-α) protein without affecting the mRNA levels in THP-1 cells. Collectively, these results uncover a novel mechanism by which TTP represses target mRNA translation.

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8

Latham, K. E., and I. R. Konigsberg. "Mitogen stimulation affects contractile protein mRNA abundance and translation in embryonic quail myocytes." Molecular and Cellular Biology 9, no. 8 (August 1989): 3203–11. http://dx.doi.org/10.1128/mcb.9.8.3203.

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In cultures of differentiated, fusion-blocked muscle cells obtained from embryonic Japanese quail (Coturnix coturnix japonica), mitogen stimulation leads to an immediate reduction in the rates of synthesis of skeletal muscle myosin heavy chain (MHC) and alpha-actin. The molecular mechanisms responsible for this downregulation were examined. The cellular abundances of the alpha-actin and MHC mRNAs were affected differently by mitogen stimulation; alpha-actin mRNA abundance declined by an amount which quantitatively accounted for the observed decrease in alpha-actin synthesis, whereas MHC mRNA abundance remained virtually unchanged during the first 6 h following mitogen stimulation, a period during which MHC synthesis declined by more than 70%. MHC mRNA abundance did decline between 6 and 12 h after mitogen stimulation. Downregulation of MHC synthesis therefore involves an initial block in mRNA translation combined with a later loss of MHC mRNA from the cytoplasma, while alpha-actin synthesis is regulated at the level of mRNA abundance. These observations are consistent with the hypothesis that, in addition to transcriptional activation of muscle-specific genes, skeletal muscle differentiation normally involves cell cycle-dependent modulations in cellular factors which control message stability and message translation.

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9

Latham, K. E., and I. R. Konigsberg. "Mitogen stimulation affects contractile protein mRNA abundance and translation in embryonic quail myocytes." Molecular and Cellular Biology 9, no. 8 (August 1989): 3203–11. http://dx.doi.org/10.1128/mcb.9.8.3203-3211.1989.

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In cultures of differentiated, fusion-blocked muscle cells obtained from embryonic Japanese quail (Coturnix coturnix japonica), mitogen stimulation leads to an immediate reduction in the rates of synthesis of skeletal muscle myosin heavy chain (MHC) and alpha-actin. The molecular mechanisms responsible for this downregulation were examined. The cellular abundances of the alpha-actin and MHC mRNAs were affected differently by mitogen stimulation; alpha-actin mRNA abundance declined by an amount which quantitatively accounted for the observed decrease in alpha-actin synthesis, whereas MHC mRNA abundance remained virtually unchanged during the first 6 h following mitogen stimulation, a period during which MHC synthesis declined by more than 70%. MHC mRNA abundance did decline between 6 and 12 h after mitogen stimulation. Downregulation of MHC synthesis therefore involves an initial block in mRNA translation combined with a later loss of MHC mRNA from the cytoplasma, while alpha-actin synthesis is regulated at the level of mRNA abundance. These observations are consistent with the hypothesis that, in addition to transcriptional activation of muscle-specific genes, skeletal muscle differentiation normally involves cell cycle-dependent modulations in cellular factors which control message stability and message translation.

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10

Nanbu, R., P. A. Menoud, and Y. Nagamine. "Multiple instability-regulating sites in the 3' untranslated region of the urokinase-type plasminogen activator mRNA." Molecular and Cellular Biology 14, no. 7 (July 1994): 4920–28. http://dx.doi.org/10.1128/mcb.14.7.4920.

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In LLC-PK1 cells urokinase-type plasminogen activator (uPA) mRNA has a short half-life. It is stabilized by inhibition of protein synthesis and by downregulation of protein kinase C (PKC). In the present study on uPA mRNA metabolism, we focused our attention on the 3' untranslated region (3'UTR) of the uPA mRNA, as this region is long and highly conserved among several mammalian species, including mice and humans. To investigate the possible role of the 3'UTR of uPA mRNA in mRNA metabolism, we inserted this region into the 3'UTR of the rabbit beta-globin gene that is linked to the cytomegalovirus promoter and stably transfected it into LLC-PK1 cells. While the parental globin mRNA was stable, the chimeric mRNA was degraded as rapidly as endogenous uPA mRNA, suggesting that the 3'UTR of uPA mRNA contains most of the information required for its rapid turnover. Further analysis showed that there are at least three independent determinants of instability in the 3'UTR; one is an AU-rich sequence located immediately 3' of the poly(A) addition signal, and one is a sequence containing a stem structure. One determinant seems to require ongoing RNA synthesis for its activity. All chimeric unstable globin mRNAs became stable in the presence of cycloheximide, a protein synthesis inhibitor, suggesting that the stabilization of mRNA by protein synthesis inhibition is not through a specific sequence in the mRNA. In PKC-downregulated cells, globin mRNAs with the complete 3'UTR or the AU-rich sequence were stabilized, suggesting that PKC downregulation stabilizes uPA mRNA through the AU-rich sequence. Here we discuss the significance of multiple, independently acting instability determinants in the regulation of uPA mRNA metabolism.

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11

Nanbu, R., P. A. Menoud, and Y. Nagamine. "Multiple instability-regulating sites in the 3' untranslated region of the urokinase-type plasminogen activator mRNA." Molecular and Cellular Biology 14, no. 7 (July 1994): 4920–28. http://dx.doi.org/10.1128/mcb.14.7.4920-4928.1994.

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In LLC-PK1 cells urokinase-type plasminogen activator (uPA) mRNA has a short half-life. It is stabilized by inhibition of protein synthesis and by downregulation of protein kinase C (PKC). In the present study on uPA mRNA metabolism, we focused our attention on the 3' untranslated region (3'UTR) of the uPA mRNA, as this region is long and highly conserved among several mammalian species, including mice and humans. To investigate the possible role of the 3'UTR of uPA mRNA in mRNA metabolism, we inserted this region into the 3'UTR of the rabbit beta-globin gene that is linked to the cytomegalovirus promoter and stably transfected it into LLC-PK1 cells. While the parental globin mRNA was stable, the chimeric mRNA was degraded as rapidly as endogenous uPA mRNA, suggesting that the 3'UTR of uPA mRNA contains most of the information required for its rapid turnover. Further analysis showed that there are at least three independent determinants of instability in the 3'UTR; one is an AU-rich sequence located immediately 3' of the poly(A) addition signal, and one is a sequence containing a stem structure. One determinant seems to require ongoing RNA synthesis for its activity. All chimeric unstable globin mRNAs became stable in the presence of cycloheximide, a protein synthesis inhibitor, suggesting that the stabilization of mRNA by protein synthesis inhibition is not through a specific sequence in the mRNA. In PKC-downregulated cells, globin mRNAs with the complete 3'UTR or the AU-rich sequence were stabilized, suggesting that PKC downregulation stabilizes uPA mRNA through the AU-rich sequence. Here we discuss the significance of multiple, independently acting instability determinants in the regulation of uPA mRNA metabolism.

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12

Jin, Hua, Mi Ra Suh, Jinju Han, Kyu-Hyeon Yeom, Yoontae Lee, Inha Heo, Minju Ha, Seogang Hyun, and V. Narry Kim. "Human UPF1 Participates in Small RNA-Induced mRNA Downregulation." Molecular and Cellular Biology 29, no. 21 (August 24, 2009): 5789–99. http://dx.doi.org/10.1128/mcb.00653-09.

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ABSTRACT MicroRNAs (miRNAs) are endogenous antisense regulators that trigger endonucleolytic mRNA cleavage, translational repression, and/or mRNA decay. miRNA-mediated gene regulation is important for numerous biological pathways, yet the underlying mechanisms are still under rigorous investigation. Here we identify human UPF1 (hUPF1) as a protein that contributes to RNA silencing. When hUPF1 is knocked down, miRNA targets are upregulated. The depletion of hUPF1 also increases the off-target messages of small interfering RNAs (siRNAs), which are imperfectly complementary to transfected siRNAs. Conversely, when overexpressed, wild-type hUPF1 downregulates miRNA targets. The helicase domain mutant of hUPF1 fails to suppress miRNA targets. hUPF1 interacts with human Argonaute 1 (hAGO1) and hAGO2 and colocalizes with hAGO1 and hAGO2 in processing bodies, which are known to be the sites for translational repression and mRNA destruction. We further find that the amounts of target messages bound to hAGO2 are reduced when hUPF1 is depleted. Our data thus suggest that hUPF1 may participate in RNA silencing by facilitating the binding of the RNA-induced silencing complex to the target and by accelerating the decay of the mRNA.

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Shaghaghi Torkdari, Zeynab, Mohammad Khalaj-Kondori, and Mohamad Ali Hosseinpour. "Prohibitin 2 mRNA Downregulation in Breast Cancer Tumor Tissues." Iranian Quarterly Journal of Breast Diseases 14, no. 1 (May 1, 2021): 78–84. http://dx.doi.org/10.30699/ijbd.14.1.78.

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Zheng, Cuihong, Thippeswamy Gulappa, Bindu Menon, and K. M. J. Menon. "Association between LH receptor regulation and ovarian hyperstimulation syndrome in a rodent model." Reproduction 160, no. 2 (August 2020): 239–45. http://dx.doi.org/10.1530/rep-20-0058.

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Ovarian hyperstimulation syndrome (OHSS) is a common complication of ovarian stimulation associated with the administration of human chorionic gonadotropin (hCG) during assisted reproduction. We have determined the expression of luteinizing hormone receptor (Lhcgr) mRNA, vascular endothelial growth factor (VEGF), and its transcription factor, HIF1α, during the periovulatory period in a rodent model of OHSS and compared these results with normal ovulatory periods. These results showed that the downregulation of Lhcgr mRNA in response to conditions that mimic preovulatory LH surge was significantly impaired in the OHSS group compared to the complete downregulation seen in the control group. Most importantly, the downregulation of luteinizing hormone receptor mRNA expression following hCG administration was sustained in the control group up to 48 h, whereas it remained at significantly higher levels in the OHSS group. This impairment of hCG-induced Lhcgr downregulation in the OHSS group was accompanied by significantly elevated levels of VEGF and its transcription factor, HIF1α. Furthermore, the downregulation of Lhcgr that occurs in response to a preovulatory LH surge in normal cycles was accompanied by low levels of VEGF. This study shows that, while downregulation of Lhcgr as well as low VEGF levels are seen in response to a preovulatory LH surge in normal ovarian cycle, impaired Lhcgr downregulation and elevated VEGF levels were found in the OHSS group.

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Ge, Changhui, Fei Su, Hanjiang Fu, Yuan Wang, Baolei Tian, Bin Liu, Jie Zhu, Yong Ding, and Xiaofei Zheng. "RNA Profiling Reveals a Common Mechanism of Histone Gene Downregulation and Complementary Effects for Radioprotectants in Response to Ionizing Radiation." Dose-Response 18, no. 4 (October 1, 2020): 155932582096843. http://dx.doi.org/10.1177/1559325820968433.

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High-dose ionizing radiation (IR) alters the expression levels of non-coding RNAs (ncRNAs). However, the roles of ncRNAs and mRNAs in mediating radiation protection by radioprotectants remain unknown. Microarrays were used to determine microRNA (miRNA), long ncRNA (lncRNA), and mRNA expression profiles in the bone marrow of irradiated mice pretreated with amifostine, CBLB502, and nilestriol. Differentially expressed mRNAs were functionally annotated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Some histone cluster genes were validated by real-time PCR, and the effects of radioprotectant combinations were monitored by survival analysis. We found that these radioprotectants increased the induction of lncRNAs and mRNAs. miRNA, lncRNA, and mRNA expression patterns were similar with amifostine and CBLB502, but not nilestriol. The radioprotectants exhibited mostly opposite effects against IR-induced miRNAs, lncRNAs, and mRNAs while inducing a common histone gene downregulation following IR, mainly via nucleosome assembly and related signaling pathways. Notably, the effects of nilestriol significantly complemented those of amisfostine or CBLB502; low-dose drug combinations resulted in better radioprotective effects in pretreated mice. Thus, we present histone gene downregulation by radioprotectants, together with the biological functions of miRNA, lncRNA, and mRNA, to explain the mechanism underlying radioprotection.

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Zollner, Gernot, Peter Fickert, Dagmar Silbert, Andrea Fuchsbichler, Conny Stumptner, Kurt Zatloukal, Helmut Denk, and Michael Trauner. "Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 282, no. 1 (January 1, 2002): G184—G191. http://dx.doi.org/10.1152/ajpgi.00215.2001.

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Cholestasis is associated with retention of bile acids and reduced expression of the Na+/taurocholate cotransporter (Ntcp), the major hepatocellular bile acid uptake system. This study aimed to determine whether downregulation of Ntcp in obstructive cholestasis 1) is a consequence of bile acid retention and 2) is mediated by induction of the transcriptional repressor short heterodimer partner 1 (SHP-1). To study the time course for the changes in serum bile acid levels as well as SHP-1 and Ntcp steady-state mRNA levels, mice were subjected to common bile duct ligation (CBDL) for 3, 6, 12, 24, 72, and 168 h and compared with sham-operated controls. Serum bile acid levels were determined by radioimmunoassay. SHP-1 and Ntcp steady-state mRNA expression were assessed by Northern blotting. In addition, Ntcp protein expression was studied by Western blotting and immunofluorescence microscopy. Increased SHP-1 mRNA expression paralleled elevations of serum bile acid levels and was followed by downregulation of Ntcp mRNA and protein expression in CBDL mice. Maximal SHP-1 mRNA expression reached a plateau phase after 6-h CBDL (12-fold; P < 0.001) and preceded the nadir of Ntcp mRNA levels (12%, P < 0.001) by 6 h. In conclusion, bile acid-induced expression of SHP-1 may, at least in part, mediate downregulation of Ntcp in CBDL mice. These findings support the concept that downregulation of Ntcp in cholestasis limits intracytoplasmatic accumulation of potentially toxic bile acids.

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Vohradsky, Jiri, Josef Panek, and Tomas Vomastek. "Numerical modelling of microRNA-mediated mRNA decay identifies novel mechanism of microRNA controlled mRNA downregulation." Nucleic Acids Research 38, no. 14 (April 5, 2010): 4579–85. http://dx.doi.org/10.1093/nar/gkq220.

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18

Tsumura, Keiko, Xuefei Li, Kwartarini Murdiastuti, Most Nahid Parvin, Tetsuya Akamatsu, Chenjuan Yao, Norio Kanamori, Kiyotoshi Inenaga, Hiroshi Yamashita, and Kazuo Hosoi. "Downregulation of AQP2 expression in the kidney of polydipsic STR/N mice." American Journal of Physiology-Renal Physiology 290, no. 2 (February 2006): F478—F485. http://dx.doi.org/10.1152/ajprenal.00029.2005.

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Aquaporin-2 (AQP2) is responsible for the concentration of urine in the kidney collecting tubule under the regulation of vasopressin. The mRNA level of this water channel in polydipsic STR/N mice was extremely reduced compared with that in normal ICR mice. In male mice, reduction of the AQP2 mRNA level was not evident at 3 wk of age, at which time water intake was not increased. At 10 wk of age, however, the AQP2 mRNA level was reduced to 10% of that in control mice, whereas water intake was increased by 36%. At 44 wk, the water intake became five times that of the control ICR mice, and the AQP2 mRNA level in these polydipsic mice was only ∼5% of control. Similar changes were observed in the AQP2 protein level, suggesting that the mRNA level of AQP2 reflects the protein level of AQP2. These inverse changes in the AQP2 mRNA level and water intake were also evident in female mice. The data imply that polydipsia in STR/N mice may have affected AQP2 mRNA transcription in the kidney, resulting in reduced AQP2 expression, which would contribute to a reduction in overretention of water.

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Cassis, L. A. "Downregulation of the renin-angiotensin system in streptozotocin-diabetic rats." American Journal of Physiology-Endocrinology and Metabolism 262, no. 1 (January 1, 1992): E105—E109. http://dx.doi.org/10.1152/ajpendo.1992.262.1.e105.

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To determine if insulin has the ability to regulate components of the renin-angiotensin system, renin and angiotensinogen mRNA and plasma concentrations were determined in 4-wk streptozotocin (STZ)-diabetic rats. In another group of STZ-diabetic rats, replacement insulin therapy was given over the 4-wk period, and the above parameters were examined. In STZ-diabetic rats, there was a significant regression of white adipose tissue that was accompanied by an increase in the yield of RNA obtained. Changes in white adipose tissue were reversed by insulin replacement therapy in STZ-diabetic rats. There were no changes in brown adipose tissue weight or RNA yield in STZ-diabetic rats. Plasma renin activity (PRA) was significantly decreased in STZ-diabetic rats; however, plasma angiotensinogen concentration was not significantly affected by diabetes. PRA was restored to control levels in STZ-diabetic rats with insulin replacement. Kidney renin mRNA as well as liver, epididymal, and interscapular fat angiotensinogen mRNA were significantly decreased in STZ-diabetic rats. Renin and angiotensinogen mRNA were not significantly different from control in all tissues examined in STZ-diabetic rats with insulin replacement therapy. Results from this study suggest a downregulation of the renin-angiotensin system in 4-wk STZ-diabetic rats at the level of mRNA expression that is restored by replacement therapy with insulin; therefore, insulin may directly or indirectly regulate the renin-angiotensin system.

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Kurita, Masako, Yoshikazu Matsuoka, Kosuke Nakatsuka, Daisuke Ono, Noriko Muto, Ryuji Kaku, and Hiroshi Morimatsu. "Norepinephrine-induced downregulation of GLT-1 mRNA in rat astrocytes." Biochemical and Biophysical Research Communications 504, no. 1 (September 2018): 103–8. http://dx.doi.org/10.1016/j.bbrc.2018.08.137.

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Joseph, Rajiv, Wayne Tsang, Dexian Dou, Kevin Nelson, and Klaus Edvardsen. "Neuronatin mRNA in PC12 cells: downregulation by nerve growth factor." Brain Research 738, no. 1 (October 1996): 32–38. http://dx.doi.org/10.1016/0006-8993(96)00768-8.

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Carrière, Véronique, Annie Rodolosse, Michel Lacasa, Danièle Cambier, Alain Zweibaum, and Monique Rousset. "Hypoxia and CYP1A1 induction-dependent regulation of proteins involved in glucose utilization in Caco-2 cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 274, no. 6 (June 1, 1998): G1101—G1108. http://dx.doi.org/10.1152/ajpgi.1998.274.6.g1101.

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Although induction of cytochrome P-450 1A1 (CYP1A1) in the Caco-2 clone TC7 alters glucose utilization and modifies the expression of sucrase-isomaltase (SI) and hexose transporters, nothing is known of the events that control these effects. In this study, we analyzed the effects of β-naphthoflavone (β-NF) and hypoxia on these parameters and expression of key enzymes of glucose metabolism. Both β-NF and hypoxia induce similar changes: 1) induction of CYP1A1 mRNA; 2) increased glucose consumption and lactic acid production and lower glycogen content; 3) downregulation of SI and upregulation of GLUT1 mRNAs; 4) downregulation of fructose-1,6-bisphosphatase and pyruvate kinase mRNAs and upregulation of phospho enolpyruvate carboxykinase, pyruvate dehydrogenase, lactate dehydrogenase, and phosphofructokinase mRNAs; and 5) upregulation of c- fos and c- jun mRNAs. Although addition of inhibitors of CYP1A1 catalytic activity to β-NF-treated cells totally inhibits the enzyme activity, it does not modify CYP1A1 mRNA response and associated effects, thus excluding a direct role for the enzyme per se. These results point to a possible physiological implication of the signal-transduction pathway responsible for CYP1A1 induction.

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Terashima, Y., K. Kondo, Y. Mizuno, Y. Iwasaki, and Y. Oiso. "Influence of acute elevation of plasma AVP level on rat vasopressin V2 receptor and aquaporin-2 mRNA expression." Journal of Molecular Endocrinology 20, no. 2 (April 1, 1998): 281–85. http://dx.doi.org/10.1677/jme.0.0200281.

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It is known that vasopressin V2 receptor (V2R) mRNA is downregulated by elevated plasma arginine vasopressin (AVP) following chronic osmotic stimulation. To elucidate the response in V2R mRNA expression to acute elevation of the plasma AVP level, we investigated the time-course change of rat V2R mRNA expression after subcutaneous injection of AVP (10 microg/body). Plasma AVP levels increased from 1.4+/-0.3 pg/ml to 56.8+/-10.7 pg/ml by an hour after injection,and returned to the control level at 6 h. By Northern blotanalysis, V2R mRNA expression decreased to 52.7+/-3.7% of the control level at 2 h, and then returned to the control level by 6 h. Furthermore we investigated the time-course change of aquaporin-2 (AQP2) mRNA expression. AQP2 mRNA expression increased gradually after injection and reached 240.3+/-7.5% of the control level at 6 h. Then it returned to the control level. This study showed that the downregulation of V2R mRNA occurred rapidly after acute elevation of the plasma AVP level, and AQP2 mRNA expression was upregulated despite the downregulation of V2R mRNA.

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Hilal-Dandan, Randa, Huaping He, Jody L. Martin, Laurence L. Brunton, and Wolfgang H. Dillmann. "Endothelin downregulates SERCA2 gene and protein expression in adult rat ventricular myocytes: regulation by pertussis toxin-sensitive Gi protein and cAMP." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 3 (March 2009): H728—H734. http://dx.doi.org/10.1152/ajpheart.00584.2008.

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Downregulation of the sarcoplasmic reticulum calcium ATPase (SERCA2) is associated with diastolic dysfunction in the failing heart. Elevated plasma endothelin-1 (ET) levels are correlated with congestive heart failure suggesting that ET may play a pathophysiological role. We have investigated the ability of ET to regulate SERCA2 gene expression in isolated adult rat ventricular myocytes. We find that ET enhances net protein synthesis by ∼40% but significantly downregulates SERCA2 mRNA expression, time dependently, by ∼30–50%, and the expression of SERCA2 protein by ∼ 50%. In myoyctes, ET binds to ETA receptor that couples to Gq and Gi proteins. Inhibition of Gq-PLC-induced phosphoinositide (PI) hydrolysis with U73122 (1 μM) or inhibition of Gi protein with pertussis toxin (PTX) abolishes the ability of ET to downregulate SERCA2 mRNA gene expression. Further investigation suggests that ET coupling to PTX-sensitive Gi with consequent lowering of cAMP is required for downregulation of SERCA2 mRNA levels. Increasing intracellular cAMP quantity using cAMP-specific PDE inhibitor Ro20-1724 or cAMP analog dibutyryl-cAMP reverses ET-induced downregulation of SERCA2 mRNA levels. The data indicate that, in adult myocytes, ET downregulates SERCA2 mRNA and protein levels, and the effect requires cross-talk between Gq and PTX-sensitive Gi pathways.

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Dayal, Sanjana, Roman N. Rodionov, Erland Arning, Teodoro Bottiglieri, Masumi Kimoto, Daryl J. Murry, John P. Cooke, Frank M. Faraci, and Steven R. Lentz. "Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 2 (August 2008): H816—H825. http://dx.doi.org/10.1152/ajpheart.01348.2007.

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Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, has been proposed to be a mediator of vascular dysfunction during hyperhomocysteinemia. Levels of ADMA are regulated by dimethylarginine dimethylaminohydrolase (DDAH). Using both in vitro and in vivo approaches, we tested the hypothesis that hyperhomocysteinemia causes downregulation of the two genes encoding DDAH ( Ddah1 and Ddah2). In the MS-1 murine endothelial cell line, the addition of homocysteine decreased NO production but did not elevate ADMA or alter levels of Ddah1 or Ddah2 mRNA. Mice heterozygous for cystathionine β-synthase ( Cbs) and their wild-type littermates were fed either a control diet or a high-methionine/low-folate (HM/LF) diet to produce varying degrees of hyperhomocysteinemia. Maximal relaxation of the carotid artery to the endothelium-dependent dilator acetylcholine was decreased by ∼50% in Cbs+/− mice fed the HM/LF diet compared with Cbs+/+ mice fed the control diet ( P < 0.001). Compared with control mice, hyperhomocysteinemic mice had lower levels of Ddah1 mRNA in the liver ( P < 0.001) and lower levels of Ddah2 mRNA in the liver, lung, and kidney ( P < 0.05). Downregulation of DDAH expression in hyperhomocysteinemic mice did not result in an increase in plasma ADMA, possibly due to a large decrease in hepatic methylation capacity ( S-adenosylmethionine-to- S-adenosylhomocysteine ratio). Our findings demonstrate that hyperhomocysteinemia causes tissue-specific decreases in DDAH expression without altering plasma ADMA levels in mice with endothelial dysfunction.

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Qi, M., J. W. Bassani, D. M. Bers, and A. M. Samarel. "Phorbol 12-myristate 13-acetate alters SR Ca(2+)-ATPase gene expression in cultured neonatal rat heart cells." American Journal of Physiology-Heart and Circulatory Physiology 271, no. 3 (September 1, 1996): H1031—H1039. http://dx.doi.org/10.1152/ajpheart.1996.271.3.h1031.

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Primary cultures of neonatal rat ventricular myocytes were used to examine how the cardiac myocyte cytoplasmic Ca2+ ([Ca2+]i) transient and sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) gene expression change in response to treatment with the protein kinase C activator phorbol 12-myristate 13-acetate (PMA). Exposure of neonatal myocytes to PMA (200 nM, 48-72 h) produced myocyte growth and a 70% prolongation of the half-time for [Ca2+]i decline induced by potassium depolarization in the absence of extracellular Na+ (in which the sarcoplasmic reticulum Ca2+ pump is the main mechanism responsible for [Ca2+]i decline). The reduced rate of [Ca2+]i transient decline corresponded to a 53% reduction in SERCA2 protein levels and a 43% reduction in SERCA2 mRNA levels as compared with control myocytes. Exposure to PMA for as little as 30 min or for as long as 48 h produced a similar degree of SERCA2 mRNA downregulation over time. PMA-induced downregulation of SERCA2 mRNA levels was blocked by either 10 nM staurosporine or 4 microM chelerythrine, whereas treatment with either agent alone increased SERCA2 mRNA levels as compared with control cells. Actinomycin D mRNA stability assays revealed that PMA treatment appeared to markedly destabilize the relatively long-lived SERCA2 mRNA transcript. Taken together, these results indicate that downregulation of SERCA2 gene by PMA in cultured neonatal myocytes occurs at least in part by alterations in mRNA stability and results in functional alterations in [Ca2+]i decline that are similar to that observed in the hypertrophied and failing adult myocardium.

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Cakmakci, Nihal G., Rachel S. Lerner, Eric J. Wagner, Lianxing Zheng, and William F. Marzluff. "SLIP1, a Factor Required for Activation of Histone mRNA Translation by the Stem-Loop Binding Protein." Molecular and Cellular Biology 28, no. 3 (November 19, 2007): 1182–94. http://dx.doi.org/10.1128/mcb.01500-07.

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ABSTRACT Replication-dependent histone mRNAs are the only eukaryotic cellular mRNAs that are not polyadenylated, ending instead in a conserved stem-loop. The 3′ end of histone mRNA is required for histone mRNA translation, as is the stem-loop binding protein (SLBP), which binds the 3′ end of histone mRNA. We have identified five conserved residues in a 15-amino-acid region in the amino-terminal portion of SLBP, each of which is required for translation. Using a yeast two-hybrid screen, we identified a novel protein, SLBP-interacting protein 1 (SLIP1), that specifically interacts with this region. Mutations in any of the residues required for translation reduces SLIP1 binding to SLBP. The expression of SLIP1 in Xenopus oocytes together with human SLBP stimulates translation of a reporter mRNA ending in the stem-loop but not a reporter with a poly(A) tail. The expression of SLIP1 in HeLa cells also stimulates the expression of a green fluorescent protein reporter mRNA ending in a stem-loop. RNA interference-mediated downregulation of endogenous SLIP1 reduces the rate of translation of endogenous histone mRNA and also reduces cell viability. SLIP1 may function by bridging the 3′ end of the histone mRNA with the 5′ end of the mRNA, similar to the mechanism of translation of polyadenylated mRNAs.

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Komatsu, Norio, Keita Kirito, Yoshifumi Kashii, Yusuke Furukawa, Jiro Kikuchi, Naruyoshi Suwabe, Masayuki Yamamoto, and Yasusada Miura. "Cell-Cycle–Dependent Regulation of Erythropoietin Receptor Gene." Blood 89, no. 4 (February 15, 1997): 1182–88. http://dx.doi.org/10.1182/blood.v89.4.1182.

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Abstract To understand the regulatory mechanism of erythropoietin (EPO) receptor (EPOR) gene expression, the effect of EPO on the steady-state level of EPOR mRNA was examined using the human EPO-dependent cell line UT-7 as a model system. We found that the treatment of UT-7 cells with EPO resulted in a transient decrease of the EPOR mRNA level. This transient downregulation was also induced by stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF ), another stimulator of UT-7 cell growth. These results raised the possibility that EPOR gene expression is in part related to cell growth. Moreover, it was found that EPO-induced downregulation of EPOR mRNA level was preceded by a transient downregulation of GATA-1 mRNA. To examine the relationship between the expression of EPOR, GATA-1, and GATA-2 mRNA levels and the cell cycle, logarithmically growing UT-7 cells were centrifugically fractionated according to the cell-cycle phase. Both EPOR and GATA-1 mRNA levels, but not the GATA-2 mRNA level, concomitantly decreased at the G0/G1 phase and increased at the S and G2/M phases. An electrophoretic mobility shift assay (EMSA) showed that in EPO-stimulated UT-7 cells, the dynamic changes in EPOR gene expression paralleled the GATA-1 DNA-binding activity to the oligonucleotide probe containing a GATA-binding site located at the promoter region of the EPOR gene. These findings suggest that the regulation of EPOR mRNA level is mainly associated with GATA-1 gene expression in UT-7 cells undergoing proliferation, and that these serial events are under the control of, or related to, the cell cycle.

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Hu, Shien, Xiaorong Zhu, Joseph R. Triggs, Yun Tao, Yunwei Wang, Lev Lichtenstein, Marc Bissonnette, Mark W. Musch, and Eugene B. Chang. "Inflammation-induced, 3′UTR-dependent translational inhibition of Hsp70 mRNA impairs intestinal homeostasis." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 5 (May 2009): G1003—G1011. http://dx.doi.org/10.1152/ajpgi.00027.2009.

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Although the inducible heat shock protein 70 (Hsp70) is essential for maintaining intestinal homeostasis in colitis, it is translationally downregulated in inflamed colonic mucosa, paradoxically rendering the gut more susceptible to injury. We examined the basis for this process by analyzing the role of untranslated regions (UTR) of Hsp70 mRNA in inflammation-associated downregulation in vitro and in vivo. Using luciferase-reporter assays in young adult mouse intestinal epithelial cells, we determined that cytokine-induced translational inhibition of Hsp70 mRNA was mediated by the 3′UTR, but not 5′UTR. In vivo, dextran sodium sulfate (DSS) colitis was induced in wild-type (WT) and villin-promoter regulated “UTR-less” Hsp70 transgenic (TG) mice, the latter exhibiting intestinal epithelial-specific transgene expression. Progressive downregulation of colonic Hsp70 protein expression was observed in WT, but not in TG, mice with increasing severity of mucosal inflammation, confirming the essential role of the 3′UTR in mediating inflammation-associated downregulation of Hsp70. Hsp70 TG mice demonstrated significantly lower endoscopic and histological inflammation scores in DSS-induced colitis than WT. In conclusion, downregulation of Hsp70 expression in inflamed mucosa is mediated by translational inhibition requiring the 3′UTR, resulting in increased mucosal injury. By forcing intestinal epithelial-specific Hsp70 expression in vivo, the severity of experimentally induced colitis was significantly reduced.

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Zhuang, Daming, Poonam Balani, Qinghua Pu, Shalini Thakran, and Aviv Hassid. "Suppression of PKG by PDGF or nitric oxide in differentiated aortic smooth muscle cells: obligatory role of protein tyrosine phosphatase 1B." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 1 (January 2011): H57—H63. http://dx.doi.org/10.1152/ajpheart.00225.2010.

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Treatment of aortic smooth muscle cells with PDGF induces the upregulation of protein tyrosine phosphatase 1B (PTP1B). PTP1B, in turn, decreases the function of several growth factor receptors, thus completing a negative feedback loop. Studies have reported that PDGF induces the downregulation of PKG as part of a repertoire of dedifferentiation of vascular smooth muscle cells. Other studies have reported that chronic nitric oxide (NO) treatment also induces the downregulation of PKG. In the present study, we tested the hypothesis that the downregulation of PKG by PDGF or NO in differentiated rat aortic smooth muscle cells can be attributed to the upregulation of PTP1B. We found that treatment with PDGF or NO induced an upregulation of PTP1B levels. Overexpression of PTP1B induced a marked downregulation of PKG mRNA and protein levels, whereas the expression of dominant negative PTP1B or short interfering RNA directed against PTP1B blocked the capacity of PDGF or NO to decrease PKG levels. We conclude that the upregulation of PTP1B by PDGF or NO is both necessary and sufficient to induce the downregulation of PKG via an effect on PKG mRNA levels.

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Akar, Fadi G., Richard C. Wu, George J. Juang, Yanli Tian, Mirka Burysek, Deborah DiSilvestre, Wei Xiong, Antonis A. Armoundas, and Gordon F. Tomaselli. "Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 6 (June 2005): H2887—H2896. http://dx.doi.org/10.1152/ajpheart.00320.2004.

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Heart failure (HF) is characterized by marked prolongation of action potential duration and reduction in cellular repolarization reserve. These changes are caused in large part by HF-induced K+ current downregulation. Molecular mechanisms underlying these changes remain unclear. We determined whether downregulation of K+ currents in a canine model of tachycardia-induced HF is caused by altered expression of underlying K+ channel α- and β-subunits encoding these currents. K+ channel subunit expression was quantified in normal and failing dogs at the mRNA and protein levels in epicardial (Epi), midmyocardial (Mid), and endocardial (Endo) layers of left ventricle. Analysis of mRNA and protein levels of candidate genes encoding the transient outward K+ current ( Ito) revealed marked reductions in canine cKv4.3 expression in HF in Epi (44% mRNA, 39% protein), Mid (52% mRNA, 34% protein), and Endo (49% mRNA, 73% protein) layers and a paradoxical enhancement (41% Epi, 97% Mid, 113% Endo) in cKv1.4 protein levels, without significant changes in Kv channel-interacting protein cKChIP2 expression. Expression of cKir2.1, the gene underlying inward rectifier K+ current ( IK1), was unaffected by HF at mRNA and protein levels despite significant reduction in IK1, whereas canine ether-à-go-go-related gene (cERG), which encodes the rapidly activating component of the delayed rectifier current ( IK), exhibited increased protein expression. HF was not accompanied by significant changes in cKvLQT1 or cMinK mRNA and protein levels. These data indicate that 1) downregulation of Ito in HF is associated with decreased cKv4.3 and not cKv1.4 or cKChIP2, and 2) alterations in both the rapidly activating and slowly activating components of IK as well as IK1 in nonischemic dilated cardiomyopathy are not caused by changes in either transcript or immunoreactive protein levels of relevant channel subunits, which suggests posttranslational modification of these currents by HF.

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DiCamillo, Sandra J., Shenghong Yang, Maria V. Panchenko, Paul A. Toselli, Estee F. Naggar, Celeste B. Rich, Phillip J. Stone, Matthew A. Nugent, and Mikhail P. Panchenko. "Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-β on tropoelastin mRNA in lung fibroblasts." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 2 (August 2006): L232—L243. http://dx.doi.org/10.1152/ajplung.00530.2005.

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Neutrophil elastase (NE) plays an important role in emphysema, a pulmonary disease associated with excessive elastolysis and ineffective repair of interstitial elastin. Besides its direct elastolytic activity, NE releases soluble epidermal growth factor receptor (EGFR) ligands and initiates EGFR/MEK/ERK signaling to downregulate tropoelastin mRNA in neonatal rat lung fibroblasts (DiCamillo SJ, Carreras I, Panchenko MV, Stone PJ, Nugent MA, Foster JA, and Panchenko MP. J Biol Chem 277: 18938–18946, 2002). We now report that NE downregulates tropoelastin mRNA in the rat fetal lung fibroblast line RFL-6. The tropoelastin mRNA downregulation is preceded by release of EGF-like and TGF-α-like polypeptides and requires EGFR/MEK/ERK signaling, because it is prevented by the EGFR inhibitor AG1478 and the MEK/ERK uncoupler U0126. Tropoelastin expression in RFL-6 fibroblasts is governed by autocrine TGF-β signaling, because TGF-β type I receptor kinase inhibitor or TGF-β neutralizing antibody dramatically decreases tropoelastin mRNA and protein levels. Half-life of tropoelastin mRNA in RFL-6 cells is >24 h, but it is decreased to ∼8 h by addition of TGF-β neutralizing antibody, EGF, TGF-α, or NE. Tropoelastin mRNA destabilization by NE, EGF, or TGF-α is abolished by AG1478 or U0126. EGF-dependent tropoelastin mRNA downregulation is reversed upon ligand withdrawal, whereas chronic EGF treatment leads to persistent downregulation of tropoelastin mRNA and protein levels and decreases insoluble elastin deposition. We conclude that NE-initiated EGFR/MEK/ERK signaling cascade overrides the autocrine TGF-β signaling on tropoelastin mRNA stability and, therefore, decreases the elastogenic response in RFL-6 fibroblasts. We hypothesize that persistent EGFR/MEK/ERK signaling could impede the TGF-β-induced elastogenesis/elastin repair in the chronically inflamed, elastase/anti-elastase imbalanced lung in emphysema.

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Ekblom, M., R. Fässler, B. Tomasini-Johansson, K. Nilsson, and P. Ekblom. "Downregulation of tenascin expression by glucocorticoids in bone marrow stromal cells and in fibroblasts." Journal of Cell Biology 123, no. 4 (November 15, 1993): 1037–45. http://dx.doi.org/10.1083/jcb.123.4.1037.

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Tenascin, a predominantly mesenchymal extracellular matrix (ECM) glycoprotein has a rather restricted tissue distribution, but until now factors that inhibit its expression have not been identified. Glucocorticoids are known to be beneficial for establishment of myelopoiesis in long-term bone marrow cultures. Tenascin was found to be expressed in the bone marrow, and glucocorticoids were found to affect bone marrow tenascin expression. Both tenascin mRNAs and the mRNA of another ECM protein, laminin B1 chain, were drastically downregulated by glucocorticoids during initiation of bone marrow cultures. However, in already established long-term cultures glucocorticoids did not affect laminin B1 chain mRNA levels although tenascin mRNAs continued to be downregulated. Studies with a stromal cell line (MC3T3-G2/PA6) and fibroblasts (3T3) suggested that glucocorticoids act directly on the stromal cells that produce tenascin. In 3T3 cells this downregulation occurred within 12 h of glucocorticoid-treatment, suggesting that glucocorticoids acted through cis regulatory elements of the tenascin gene. We suggest that glucocorticoids in part regulate hematopoiesis by modifying the ECM. Furthermore, downregulation of tenascin expression by glucocorticoids may in part explain the restricted tissue distribution of tenascin in other tissues.

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Hour, Tzyh-Chyuan, Yi-Zih Kuo, Guang-Yaw Liu, Wang-Yi Kang, Chao-Yuan Huang, Yu-Chieh Tsai, Wen-Jeng Wu, Shu-Pin Huang, and Yeong-Shiau Pu. "Downregulation of ABCD1 in Human Renal Cell Carcinoma." International Journal of Biological Markers 24, no. 3 (July 2009): 171–78. http://dx.doi.org/10.1177/172460080902400307.

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Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. Delayed diagnosis may result in progression and metastasis. Markers for early detection of RCC are lacking. The ATP-binding cassette transporter D1 (ABCD1) is located in the human peroxisome membrane. Its mutation causes X-linked adrenoleukodystrophy (X-ALD), a peroxisomal disorder affecting lipid storage. The role of ABCD1 in human renal tumorigenesis was unclear. In this study, three pairs of RCC tissues were examined by cDNA microarray and data suggested that ABCD1 mRNA is downregulated. Downregulation of ABCD1 expression was confirmed by real-time PCR. ABCD1 expression was also downregulated in four renal cancer cell lines compared to immortalized benign renal tubular cells. ABCD1 mRNA and protein expression levels assessed by immunohistochemistry in the RCC tissues were similar between genders, tumor grades, and tumor stages. Immunohisto-chemical assays also showed that ABCD1 expression was significantly higher in normal than in cancerous tissues (p<0.001). ABCD1 downregulation may be involved in human renal tumorigenesis.

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Machida, Kenji, Shiho Wakamatsu, Yuichiro Izumi, Tatjana Yosifovska, Takanobu Matsuzaki, Yushi Nakayama, Yukimasa Kohda, et al. "Downregulation of the V2 vasopressin receptor in dehydration: mechanisms and role of renal prostaglandin synthesis." American Journal of Physiology-Renal Physiology 292, no. 4 (April 2007): F1274—F1282. http://dx.doi.org/10.1152/ajprenal.00154.2006.

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The vasopressin-aquaporin 2 system plays a key role in urine concentration in dehydration. In contrast to the upregulation of aquaporin 2, the downregulation of the vasopressin V2 receptor in dehydration is known. We investigated the mechanisms of this downregulation in dehydration using reverse transcription-competitive polymerase chain reaction (RT-competitive PCR) and Western blot analysis. The incubation of microdissected inner medullary collecting ducts (IMCDs) in a hypertonic medium or with vasopressin stimulated V2 receptor mRNA and protein expression, showing that dehydration-induced hyperosmolality in renal medulla and increased plasma arginine vasopressin (AVP) concentration should upregulate V2 receptor. The presence of inhibitory factors on the V2 receptor in dehydration was suggested. Prostaglandin E2 (PGE2) is known to inhibit AVP-induced cAMP production and to increase production in dehydration. PGE2 slightly stimulated V2 receptor mRNA expression in IMCD in vitro. However, PGE2 inhibited V2 receptor mRNA expression in IMCD in the presence of 10−9 M vasopressin. The blockade of PGE2 synthesis by indomethacin in dehydrated rats increased V2 receptor protein expression after 24–48 h with an early increase in V2 receptor mRNA expression. In summary, these data suggest that increased production of PGE2 in renal medulla plays a key role in the downregulation of V2 receptor in dehydration.

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Labbaye, C., J. Zhang, JL Casanova, M. Lanotte, J. Teng, WH Jr Miller, and YE Cayre. "Regulation of myeloblastin messenger RNA expression in myeloid leukemia cells treated with all-trans retinoic acid." Blood 81, no. 2 (January 15, 1993): 475–81. http://dx.doi.org/10.1182/blood.v81.2.475.475.

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Abstract Retinoic acid is known to induce differentiation of human myeloid leukemia cells in vitro. Recently, all-trans retinoic acid has been used to induce remissions in patients with acute promyelocytic leukemia, probably through differentiation of the leukemia cells. Myeloblastin (mbn) is a protease that has been identified in the human leukemia cell line HL-60. Downregulation of this protease can inhibit proliferation and induce differentiation of HL-60-derived leukemia cells. Here we have investigated the regulation of mbn messenger RNA (mRNA) expression in two human leukemia cell lines, HL-60 and NB4, treated with all-trans retinoic acid. Under this treatment, downregulation of mbn mRNA was observed in both cell lines, but was considerably delayed in NB4 cells that carry the t(15;17) translocation characteristic of acute promyelocytic leukemia. We have found that multiple mechanisms were involved in the control of mbn mRNA expression. These mechanisms were different in HL-60 and NB4 cells. Our results show that in HL-60 cells, all-trans retinoic acid rapidly decreased transcription of mbn. In contrast, in the t(15;17)-positive NB4 cells treated with all-trans retinoic acid, upregulation of mbn mRNA expression was followed by a late downregulation, both achieved via posttranscriptional mechanisms.

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Labbaye, C., J. Zhang, JL Casanova, M. Lanotte, J. Teng, WH Jr Miller, and YE Cayre. "Regulation of myeloblastin messenger RNA expression in myeloid leukemia cells treated with all-trans retinoic acid." Blood 81, no. 2 (January 15, 1993): 475–81. http://dx.doi.org/10.1182/blood.v81.2.475.bloodjournal812475.

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Retinoic acid is known to induce differentiation of human myeloid leukemia cells in vitro. Recently, all-trans retinoic acid has been used to induce remissions in patients with acute promyelocytic leukemia, probably through differentiation of the leukemia cells. Myeloblastin (mbn) is a protease that has been identified in the human leukemia cell line HL-60. Downregulation of this protease can inhibit proliferation and induce differentiation of HL-60-derived leukemia cells. Here we have investigated the regulation of mbn messenger RNA (mRNA) expression in two human leukemia cell lines, HL-60 and NB4, treated with all-trans retinoic acid. Under this treatment, downregulation of mbn mRNA was observed in both cell lines, but was considerably delayed in NB4 cells that carry the t(15;17) translocation characteristic of acute promyelocytic leukemia. We have found that multiple mechanisms were involved in the control of mbn mRNA expression. These mechanisms were different in HL-60 and NB4 cells. Our results show that in HL-60 cells, all-trans retinoic acid rapidly decreased transcription of mbn. In contrast, in the t(15;17)-positive NB4 cells treated with all-trans retinoic acid, upregulation of mbn mRNA expression was followed by a late downregulation, both achieved via posttranscriptional mechanisms.

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Valinezhad Orang, Ayla, Reza Safaralizadeh, and Mina Kazemzadeh-Bavili. "Mechanisms of miRNA-Mediated Gene Regulation from Common Downregulation to mRNA-Specific Upregulation." International Journal of Genomics 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/970607.

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Discovered in 1993, micoRNAs (miRNAs) are now recognized as one of the major regulatory gene families in eukaryotes. To date, 24521 microRNAs have been discovered and there are certainly more to come. It was primarily acknowledged that miRNAs result in gene expression repression at both the level of mRNA stability by conducting mRNA degradation and the level of translation (at initiation and after initiation) by inhibiting protein translation or degrading the polypeptides through binding complementarily to 3′UTR of the target mRNAs. Nevertheless, some studies revealed that miRNAs have the capability of activating gene expression directly or indirectly in respond to different cell types and conditions and in the presence of distinct cofactors. This reversibility in their posttranslational gene regulatory natures enables the bearing cells to rapidly response to different cell conditions and consequently block unnecessary energy wastage or maintain the cell state. This paper provides an overview of the current understandings of the miRNA characteristics including their genes and biogenesis, as well as their mediated downregulation. We also review up-to-date knowledge of miRNA-mediated gene upregulation through highlighting some notable examples and discuss the emerging concepts of their associations with other posttranscriptional gene regulation processes.

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Utgikar, Rucha, and David S. Riddick. "Downregulation of cytochrome P450 2C8 by 3-methylcholanthrene in human hepatocellular carcinoma cell lines." Canadian Journal of Physiology and Pharmacology 95, no. 6 (June 2017): 768–71. http://dx.doi.org/10.1139/cjpp-2017-0014.

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The marked induction of cytochromes P450 such as CYP1A1 caused by polycyclic aromatic hydrocarbons (PAHs) like 3-methylcholanthrene (MC) is often accompanied by suppression of other hepatic P450s. The molecular mechanisms, functional consequences, and human relevance of P450 downregulation by PAHs are poorly understood. MC suppresses mRNA levels for CYP2C8, an important human P450, in cultured human hepatocytes. To avoid hepatocyte lot-to-lot variability, we assessed CYP2C8 regulation by MC in HepaRG cells, a terminally differentiated human hepatocellular carcinoma cell line that maintains high P450 expression. MC strongly induced CYP1A1 mRNA levels and markedly downregulated CYP2C8 mRNA levels in HepaRG cells. Although MC also suppressed CYP2C8 mRNA levels in the HepG2 human hepatocellular carcinoma cell line, basal CYP2C8 expression was extremely low. HepaRG cells appear to be an appropriate model system for studying the mechanisms and functional consequences of CYP2C8 downregulation by PAHs.

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Gao, Ying, Ge Lou, Guang-Mei Zhang, Xi-Wen Sun, Yu-Yan Ma, Yan-Mei Yang, and Ge Liu. "CHFR Promoter Hypermethylation and Reduced CHFR mRNA Expression in Ovarian Cancer." International Journal of Biological Markers 24, no. 2 (April 2009): 83–89. http://dx.doi.org/10.1177/172460080902400204.

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Background Ovarian cancer is one of the most common cancers and can be treated with microtubule-targeting drugs. Checkpoint with forkhead and ring finger domains (CHFR) is a protein implicated in cancer sensitivity to microtubule-targeting drugs. Whereas CHFR downregulation, often with CHFR promoter hypermethylation, has been identified in a large number of tumor types, it has not been in ovarian cancer. We therefore searched for CHFR downregulation in primary ovarian tumors. Methods Fresh ovarian cancer tissues from 53 patients (test) and normal ovarian tissues from 21 patients (control) were tested for CHFR promoter hypermethylation and CHFR mRNA levels. Results The CHFR promoter was hypermethylated in 20.75% (11/53) of the ovarian cancers and none (0/21) of the normal controls. The normal controls had a mean mRNA level of 1.89 relative fluorescence units (RFU) with a range of 0.04–24.78 RFU. The cancer tissues had a mean mRNA level of 0.77 RFU with a range of 0.00–68.75 RFU. The median value of the cancer group was significantly lower than that of the control group (p=0.0067). Those cancer samples that had hypermethylated CHFR promoters also had low (n=3) or undetectable (n=8) CHFR mRNA levels. Conclusions In contrast to previous reports, we found that alterations in CHFR mRNA and CHFR methylation can be frequently found in ovarian cancers. CHFR hypermethylation was strongly associated with the loss of CHFR mRNA expression. CHFR downregulation in ovarian tumors may be clinically relevant as a staging biomarker, as an indicator of sensitivity to microtubule-targeting drugs, and as a future drug target.

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Oron, Y., R. Straub, P. Traktman, and M. Gershengorn. "Decreased TRH receptor mRNA activity precedes homologous downregulation: assay in oocytes." Science 238, no. 4832 (December 4, 1987): 1406–8. http://dx.doi.org/10.1126/science.2825350.

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Jiao, Jing, Hong Cao, Xiao-Wei Chen, Mei-juan Zhou, Zhi-hua Liu, and Zhen-hua Ding. "Downregulation of HBx mRNA in HepG2.2.15 cells by small interfering RNA." European Journal of Gastroenterology & Hepatology 19, no. 12 (December 2007): 1114–18. http://dx.doi.org/10.1097/meg.0b013e3282748ee2.

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Hoshino, Koyu, Alfonso Quintás-Cardama, Jerald Radich, Hongyui Dai, Hui Yang, and Guillermo Garcia-Manero. "Downregulation of JUNB mRNA expression in advanced phase chronic myelogenous leukemia." Leukemia Research 33, no. 10 (October 2009): 1361–66. http://dx.doi.org/10.1016/j.leukres.2009.03.044.

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Uddén, J., R. Folkesson, and J. Hoffstedt. "Downregulation of uncoupling protein 2 mRNA in women treated with glucocorticoids." International Journal of Obesity 25, no. 11 (November 2001): 1615–18. http://dx.doi.org/10.1038/sj.ijo.0801801.

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Azouz, Francine, Komal Arora, Keeton Krause, Vivek Nerurkar, and Mukesh Kumar. "Integrated MicroRNA and mRNA Profiling in Zika Virus-Infected Neurons." Viruses 11, no. 2 (February 16, 2019): 162. http://dx.doi.org/10.3390/v11020162.

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Zika virus (ZIKV) infections have caused a wide spectrum of neurological diseases, such as Guillain-Barré syndrome, myelitis, meningoencephalitis, and congenital microcephaly. No effective therapies currently exist for treating patients infected with ZIKV. MicroRNAs (miRNAs) are a group of small RNAs involved in the regulation of a wide variety of cellular and physiological processes. In this study, we analyzed digital miRNA and mRNA profiles in ZIKV-infected primary mouse neurons using the nCounter technology. A total of 599 miRNAs and 770 mRNAs were examined. We demonstrate that ZIKV infection causes global downregulation of miRNAs with only few upregulated miRNAs. ZIKV-modulated miRNAs including miR-155, miR-203, miR-29a, and miR-124-3p are known to play critical role in flavivirus infection, anti-viral immunity and brain injury. ZIKV infection also results in downregulation of miRNA processing enzymes. In contrast, ZIKV infection induces dramatic upregulation of anti-viral, inflammatory and apoptotic genes. Furthermore, our data demonstrate an inverse correlation between ZIKV-modulated miRNAs and target host mRNAs induced by ZIKV. Biofunctional analysis revealed that ZIKV-modulated miRNAs and mRNAs regulate the pathways related to neurological development and neuroinflammatory responses. Functional studies targeting specific miRNA are warranted to develop therapeutics for the management of ZIKV neurological disease.

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Miakotina, Olga L., and Jeanne M. Snyder. "Signal transduction events involved in TPA downregulation of SP-A gene expression." American Journal of Physiology-Lung Cellular and Molecular Physiology 286, no. 6 (June 2004): L1210—L1219. http://dx.doi.org/10.1152/ajplung.00416.2003.

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Surfactant protein A (SP-A), the most abundant pulmonary surfactant protein, plays a role in innate host defense and blocks the inhibitory effects of serum proteins on surfactant surface tension-lowering properties. SP-A mRNA and protein are downregulated by phorbol esters (TPA) via inhibition of gene transcription. We evaluated the TPA signaling pathways involved in SP-A inhibition in a lung cell line, H441 cells. TPA caused sustained phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), p38 MAPK, and c-Jun-NH2-terminal kinase. An inhibitor of conventional and novel isoforms of protein kinase C (PKC) and two inhibitors of p44/42 MAPK kinase partially or completely blocked the inhibitory effects of TPA on SP-A mRNA levels. In contrast, inhibitors of conventional PKC-α and -β, stress-activated protein kinases, protein phosphatases, protein kinase A, and the phosphatidylinositol 3-kinase pathway had no effect on the TPA-mediated inhibition of SP-A mRNA. TPA also stimulated the synthesis of c-Jun mRNA and protein in a time-dependent manner. Inhibitors of the p44/42 MAPK signaling pathway and PKC blocked the TPA-mediated phosphorylation of p44/42 MAPK and the increase in c-Jun mRNA. We conclude that TPA inhibits SP-A gene expression via novel isoforms of PKC, the p44/42 MAPK pathway, and the activator protein-1 complex.

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Nakao, A., T. Watanabe, H. Bitoh, H. Imaki, T. Suzuki, K. Asano, S. Taniguchi, K. Nosaka, T. Shimizu, and K. Kurokawa. "cAMP mediates homologous downregulation of PAF receptor mRNA expression in mesangial cells." American Journal of Physiology-Renal Physiology 273, no. 3 (September 1, 1997): F445—F450. http://dx.doi.org/10.1152/ajprenal.1997.273.3.f445.

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To clarify the molecular mechanism and significance of homologous desensitization of platelet-activating factor (PAF) signaling, we examined the effect of PAF on PAF receptor mRNA expression in rat mesangial cells by Northern blot analysis. Treatment of the cells with PAF (10(-7)-10(-8) M) reduced the expression of PAF receptor mRNA in 1 h, and this reduction was recovered by pretreatment of mesangial cells with a specific PAF receptor antagonist, WEB-2086 (10(-6) M), or a cyclooxygenase inhibitor, indomethacin (10(-6) M), for 10 min. PAF-stimulated prostaglandin E2 (PGE2) and adenosine 3',5'-cyclic monophosphate (cAMP) formation was measured by radioimmunoassays specific for each substance. Reduction of PAF receptor mRNA expression was mimicked by treatment of the cells with PGE2 (10(-6) M) or dibutyryl-cAMP (10(-3) M), a cell-permeable analog of cAMP. These results, taken together, suggest that PAF receptor mRNA expression is downregulated by exposure to PAF in cultured mesangial cells. This homologous downregulation is mediated by cAMP production through PGE2 synthesis.

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Jeon, Un Sil, Ki-Hwan Han, Soo-Hyun Park, Sang Do Lee, Mee Rie Sheen, Ju-Young Jung, Wan Young Kim, Jeff M. Sands, Jin Kim, and H. Moo Kwon. "Downregulation of renal TonEBP in hypokalemic rats." American Journal of Physiology-Renal Physiology 293, no. 1 (July 2007): F408—F415. http://dx.doi.org/10.1152/ajprenal.00502.2006.

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Hypokalemia causes a significant decrease in the tonicity of the renal medullary interstitium in association with reduced expression of sodium transporters in the distal tubule. We asked whether hypokalemia caused downregulation of the tonicity-responsive enhancer binding protein (TonEBP) transcriptional activator in the renal medulla due to the reduced tonicity. We found that the abundance of TonEBP decreased significantly in the outer and inner medullas of hypokalemic rats. Underlying mechanisms appeared different in the two regions because the abundance of TonEBP mRNA was lower in the outer medulla but unchanged in the inner medulla. Immunohistochemical examination of TonEBP revealed cell type-specific differences. TonEBP expression decreased dramatically in the outer and inner medullary collecting ducts, thick ascending limbs, and interstitial cells. In the descending and ascending thin limbs, TonEBP abundance decreased modestly. In the outer medulla, TonEBP shifted to the cytoplasm in the descending thin limbs. As expected, transcription of aldose reductase, a target of TonEBP, was decreased since the abundance of mRNA and protein was reduced. Downregulation of TonEBP appeared to have also contributed to reduced expression of aquaporin-2 and UT-A urea transporters in the renal medulla. In cultured cells, expression and activity of TonEBP were not affected by reduced potassium concentrations in the medium. These data support the view that medullary tonicity regulates expression and nuclear distribution of TonEBP in the renal medulla in cell type-specific manners.

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Takeda, Yoshinori, Asako Itaya-Hironaka, Akiyo Yamauchi, Mai Makino, Sumiyo Sakuramoto-Tsuchida, Hiroyo Ota, Ryuji Kawaguchi, and Shin Takasawa. "Intermittent Hypoxia Upregulates the Renin and Cd38 mRNAs in Renin-Producing Cells via the Downregulation of miR-203." International Journal of Molecular Sciences 22, no. 18 (September 19, 2021): 10127. http://dx.doi.org/10.3390/ijms221810127.

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Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), and it is a known risk factor for hypertension. The upregulation of the renin-angiotensin system has been reported in IH, and the correlation between renin and CD38 has been noted. We exposed human HEK293 and mouse As4.1 renal cells to experimental IH or normoxia for 24 h and then measured the mRNA levels using a real-time reverse transcription polymerase chain reaction. The mRNA levels of Renin (Ren) and Cd38 were significantly increased by IH, indicating that they could be involved in the CD38-cyclic ADP-ribose signaling pathway. We next investigated the promotor activities of both genes, which were not increased by IH. Yet, a target mRNA search of the microRNA (miRNA) revealed both mRNAs to have a potential target sequence for miR-203. The miR-203 level of the IH-treated cells was significantly decreased when compared with the normoxia-treated cells. The IH-induced upregulation of the genes was abolished by the introduction of the miR-203 mimic, but not the miR-203 mimic NC negative control. These results indicate that IH stress downregulates the miR-203 in renin-producing cells, thereby resulting in increased mRNA levels of Ren and Cd38, which leads to hypertension.

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Kuang, Ping-Ping, and Ronald H. Goldstein. "Regulation of elastin gene transcription by proteasome dysfunction." American Journal of Physiology-Cell Physiology 289, no. 3 (September 2005): C766—C773. http://dx.doi.org/10.1152/ajpcell.00525.2004.

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Elastin, a major extracellular matrix protein and the core component of elastic fiber, is essential to maintain lung structural integrity and normal physiological function. We previously found that the downregulation of elastin gene transcription by IL-1β is mediated via activation of NF-κB and CCAAT/enhancer binding protein (C/EBP)β, both targets of the ubiquitin-proteasome pathway. To further investigate the molecular mechanisms that underlie the control of elastin gene expression, we disrupted the ubiquitin-proteasome pathway with specific proteasome inhibitors. We found that specific proteasome inhibitors decreased the steady-state level of elastin mRNA in a dose-responsive manner. Run-on assay and promoter reporter study indicated that the proteasome inhibitor MG-132 repressed the rate of elastin transcription. MG-132 did not affect mRNA levels of NF-κB and C/EBPβ, or the nuclear presence of NF-κB, but markedly increased C/EBPβ isoforms, including liver-enriched transcriptional activating protein and liver-enriched transcriptional inhibitory protein. Addition of cycloheximide blocked these increases and the downregulation of elastin mRNA by MG-132. The MG-132-induced downregulation of elastin transcription was dependent on C/EBPβ expression as assessed with small interfering RNA. These results indicate that the ubiquitin-proteasome pathway plays an essential role in maintaining elastin gene expression in lung fibroblasts. Disruption of this pathway results in the downregulation of tropoelastin transcription via posttranscriptionally induced C/EBPβ isoforms.

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Journal articles on the topic 'MRNA downregulation'

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