Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear factor-activated T cell 5 (NFAT5), a novel member of the NFAT family of proteins, was originally identified as a transcriptional factor responsible for adaptation to hyperosmotic stress. Though NFAT5 is ubiquitously expressed, the biological functions of NFAT5 remain to be clarified, especially in the tissues that are not exposed to hypertonicity, including hearts. In the present study, we focused on the cardioprotective roles of NFAT5 against the cardiotoxic anti-tumor agent doxorubicin (Dox). In cultured cardiomyocytes, transcripts of the hypertonicity-inducible genes, such as taurine transporter (TauT) and sodium/myo-inositol transporter, were down-regulated by Dox. Interestingly, NFAT5 protein, but not mRNA, was decreased in cardiomyocytes exposed to Dox. Treatment of proteasome inhibitors, MG-132 or proteasome-specific inhibitor 1, prevented the Dox-mediated decrease of NFAT5 protein. Further, ubiquitin-conjugated NFAT5 was not detected in cultured cardiomyocytes treated with MG-132 and/or Dox, as assessed by immunoprecipitation assay, suggesting Dox-induced degradation through ubiquitin-independent proteasome pathway. Importantly, inhibition of NFAT5 with overexpression of dominant-negative NFAT5 decreased cell viability and increased creatine kinase leakage into culture medium. Consistently, small interfering RNA targeting NFAT5 gene enhanced myocyte death. These findings suggest that Dox promoted the degradation of NFAT5 protein, reducing cell viability in cardiomyocytes. This is the first demonstration that NFAT5 is a positive regulator of cardiomyocyte survival.
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PMID:Degradation of NFAT5, a transcriptional regulator of osmotic stress-related genes, is a critical event for doxorubicin-induced cytotoxicity in cardiac myocytes. 1710 21

Vascular cells are continuously exposed to mechanical stress that may wreak havoc if exceeding physiological levels. Consequently, mechanisms facing such a challenge are indispensable and contribute to the adaptation of the cellular phenotype. To this end, vascular smooth muscle cells (VSMCs) activate mechanoresponsive transcription factors promoting their proliferation and migration to initiate remodeling the arterial wall. In mechanostimulated VSMCs, we identified nuclear factor of activated T-cells 5 (NFAT5) as transcriptional regulator protein and intended to unravel mechanisms controlling its expression and nuclear translocation. In cultured human VSMCs, blocking RNA synthesis diminished both baseline and stretch-induced NFAT5 mRNA expression while inhibition of the proteasome promoted accumulation of the NFAT5 protein. Detailed PCR analyses indicated a decrease in expression of NFAT5 isoform A and an increase in isoform C in mechanoactivated VSMCs. Upon overexpression, only NFAT5c was capable to enter the nucleus in control- and stretch-stimulated VSMCs. As evidenced by analyses of NFAT5c mutants, nuclear translocation required palmitoylation, phosphorylation at Y143 and was inhibited by phosphorylation at S1197. On the functional level, overexpression of NFAT5c forces its accumulation in the nucleus as well as transcriptional activity and stimulated VSMC proliferation and migration. These findings suggest that NFAT5 is continuously expressed and degraded in resting VSMCs while expression and accumulation of isoform C in the nucleus is facilitated during biomechanical stress to promote an activated VSMC phenotype.
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PMID:NFAT5 Isoform C Controls Biomechanical Stress Responses of Vascular Smooth Muscle Cells. 3019 Jun 82