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TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma.

Daniel P Hall, Nicholas G Cost, Shailaja Hegde, Emily Kellner, Olga Mikhaylova, Yiwen Stratton, Birgit Ehmer, William A Abplanalp, Raghav Pandey, Jacek Biesiada, Christian Harteneck, David R Plas, Jarek Meller, Maria F Czyzyk-Krzeska

Cancer Cell, 2014 Nov 10 , 26, 738-53

Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant-negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes the growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca(2+) influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca(2+) and Zn(2+) fluxes inhibit miR-214, which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 directly through miR-204 and indirectly through another miR-204 target, Caveolin 1 (CAV1).

http://www.ncbi.nlm.nih.gov/pubmed/25517751