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 through abnormal activation of p53. To further examine this, we generated cell lines in which SNF5a, SNF5b or both can be inducibly knocked down. We found that SNF5 knockdown leads to cell-cycle arrest in G 1, and SNF5a and SNF5b are functionally redundant. We also showed that SNF5 knockdown impairs p53-dependent transcription of p21 and murine double minute 2. 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 adenosine monophosphate-activated protein kinase activation and inhibits eIF4E expression. Finally, we showed that SNF5 knockdown inhibits p53 translation by eIF4E and replacement of eIF4E in SNF5 knockdown cells restores p53 expression and cell survival. Together, our study results suggest that the p53 pathway is regulated by, and mediates the activity of, SNF5 in tumor suppression and prosurvival. © 2010 Macmillan Publishers Limited. All rights reserved.