Mutant p53 can provoke apoptosis in p53-deficient Hep3B cells with delayedkinetics relative to wild-type p53

Wild-type (wt) p53 frequently induces apoptosis when expressed in tumor cel ls whereas mutant p53 acts as an oncoprotein and consequently, stimulates c ell proliferation. We report here exceptions to that rule, p53 conformation al mutant 175H and DNA contact mutant 273H provoke apoptosis in human p53-d eficient Hep3B hepatoma cells with delayed kinetics relative to wt p53. Sim ilarly, c-Myc strongly stimulates apoptosis in these cells. In contrast,, v iral oncoproteins EIA and E7, and the cellular oncoprotein MDM-2, fail to e licit cytocidal responses. Efficient apoptotic cell death by mutant p53 req uires oligomerization as 175H and 273H with deletions between amino acid re sidues 326 and 347 of the oligomerization domain are nontoxic. Apoptosis by mutant or wt p53 was significantly inhibited by the serine protease inhibi tor AEBSF but not by the inactive analog AEBSA, Together, these results sug gest that a nit p53-independent control mechanism is operational in Hep3B c ells that eliminates cells upon sensing illegitimate proliferation signals originating from certain oncoproteins, including mutant p53 and Myc. We sug gest that some tumor cell types lack p53 altogether because they tolerate n either wild-type nor mutant forms of the protein.