SNF5, a core component of the Swi/Snf complex, is necessary for p53 expression and cell survival in part via eIF4E

SNF5, a core component of the SWI/SNF chromatin remodeling complex, is expressed as two isoforms, SNF5a and SNF5b. SNF5 is a tumor suppressor as mutation of SNF5 leads to tumor formation and cooperates with p53 deficiency to enhance cancer susceptibility. Interestingly, lack of SNF5 inhibits cell survival and embryonic development potentially via abnormal activation of p53. To further examine this, we generated cell lines in that SNF5a, SNF5b, or both can be inducibly knocked down. We found that SNF5 knockdown leads to cell cycle arrest in G1, and SNF5a and SNF5b are functionally redundant. We also showed that SNF5 knockdown impairs p53-dependent transcription of p21 and MDM2. However, contrary to earlier reports that p53 is activated by SNF5 knockout in murine cells, SNF5 knockdown leads to decreased, but not increased, expression of both basal and stress-induced p53 in multiple human cell lines. In addition, we showed that SNF5 knockdown induces AMPK activation and inhibits eIF4E expression. Finally, we demonstrated that SNF5 knockdown inhibits p53 translation via eIF4E and replacement of eIF4E in SNF5-knockdown cells restores p53 expression and cell survival. Together, our results suggest that the p53 pathway is regulated by, and mediates the activity of, SNF5 in tumor suppression and pro-survival.