Mutant p53 can provoke apoptosis in p53-deficient Hep3B cells with delayed kinetics relative to wild-type p53.
Wild-type (wt) p53 frequently induces apoptosis when expressed in tumor cells whereas mutant p53 acts as an oncoprotein and consequently, stimulates cell proliferation. We report here exceptions to that rule. p53 conformational mutant 175H and DNA contact mutant 273H provoke apoptosis in human p53-deficient Hep3B hepatoma cells with delayed kinetics relative to wt p53. Similarly, c-Myc strongly stimulates apoptosis in these cells. In contrast, viral oncoproteins E1A and E7, and the cellular oncoprotein MDM-2, fail to elicit cytocidal responses. Efficient apoptotic cell death by mutant p53 requires oligomerization as 175H and 273H with deletions between amino acid residues 326 and 347 of the oligomerization domain are nontoxic. Apoptosis by mutant or wt p53 was significantly inhibited by the serine protease inhibitor AEBSF but not by the inactive analog AEBSA. Together, these results suggest that a wt p53-independent control mechanism is operational in Hep3B cells that eliminates cells upon sensing illegitimate proliferation signals originating from certain oncoproteins, including mutant p53 and Myc. We suggest that some tumor cell types lack p53 altogether because they tolerate neither wild-type nor mutant forms of the protein.
Department of Virology, University of Saarland Medical School, Homburg/Saar, Germany.
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Stähler
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Roemer
D017500:Adenovirus E1A Proteins / Q000235:genetics; D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins; D009842:Oligopeptides / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D015853:Cysteine Proteinase Inhibitors; D009687:Nuclear Proteins; D009842:Oligopeptides; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D013450:Sulfones; D016159:Tumor Suppressor Protein p53; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D001616:beta-Galactosidase