ИСТИНА

Tumor suppressor p53 is activated in response to different cellular stresses, particularly as a result of mitochondrial dysfunction induced by the inhibition of mitochondrial respiratory chain complex III. ISR (Integrated Stress Response) is a program of gene expression regulated by transcription factor ATF4 and aimed to increase cell survival. The interrelation of p53 activation and ISR gene expression under mitochondrial dysfunction has been studied in this work. Gene expression in human colon cancer cells exposed to mitochondrial respiratory chain complex III inhibitor myxothiazol has been analyzed by RT qPCR. Expression of ATF4 and several its target genes has been found to be induced at early time points (5 h), but drop at later time points (13 h) after activation of p53 tumor suppressor. Prevention of myxothiazol-induced p53 activation by uridin supplementation resulted in recovery of increased expression of ISR-related genes. In contrast, preliminary p53 activation by nutlin-3 before addition of complex III inhibitor has led to the abolishment of ATF4 gene induction in response to short incubation with myxothiazol. The findings indicate that p53 activation negatively regulates expression of ISR genes induced at early stage of III complex inhibition, probably due to suppression of transcriptional factor ATF4. This conclusion is consistent with the fact that in contrast to complex III inhibition mitochondrial respiratory chain complex I inhibition by piericidine did not result in p53 activation and led to the long-term enhanced expression of ATF4 and its target genes. Work was supported by Russian Foundation for Basic Research grant 12-04-01444.