A MUTANT P53 THAT DISCRIMINATES BETWEEN P53-RESPONSIVE GENES CANNOT INDUCE APOPTOSIS

Human wild-type (wt) p53 can induce apoptosis in transiently transfect ed H1299 cells maintained at 37 degrees C, whereas tumor-derived mutan t forms of p53 (with the mutation Ala-143, His-175, or Trp-248) fail t o do so. At 37 degrees C, p53 with a mutation to Ala at amino acid 143 (p53Ala143) was transcriptionally inactive. However, at 32 degrees C, p53Ala143 strongly activated transcription from several physiological ly relevant p53-responsive promoters, to extents similar or greater th an that of wt p53. Unexpectedly, p53Ala143 was defective in inducing a poptosis in H1299 cells at 32 degrees C. Concomitantly with the loss o f apoptotic activity, p53Ala143 was found to be deficient in its abili ty to activate transcription from the p53-responsive portions of the B ar and insulin-like growth factor-binding protein 3 gene promoters. It is proposed that there may exist distinct classes of p53-responsive p romoters, whose ability to be activated by p53 can be regulated differ entially. Such differential regulation may have functional consequence s for the effects of p53 on cell fate.