The growth-inhibitory function of p53 is separable from transactivation, apoptosis and suppression of transformation by E1a and Ras.
p53 is known to suppress oncogenic cell transformation, inhibit cell growth, induce apoptosis and activate and repress gene transcription. To investigate the relationships between these functions, we have examined various mutant forms of p53 for their abilities to perform each activity. This study has shown that growth inhibition is not a prerequisite for apoptotic cell death as these two functions are separate and alternative activities of p53. Additionally, we have demonstrated that the ability of p53 to suppress transformation (by adenovirus E1a and activated Ras) correlates with its ability to induce apoptosis and not with its ability to inhibit cell growth. Although p53 is thought to inhibit growth through the transactivation of p21WAFI, our study has demonstrated that transcriptional activation and repression are neither sufficient nor necessary for growth inhibition. This indicates that p53 has more than one mechanism for inhibiting cell growth and that another type of biochemical function must be involved. Furthermore, we have shown that transcriptional activation and repression may each be necessary, and the combination of these activities may even be sufficient, for p53-dependent apoptosis. In summary, our results have provided new information about the cellular and biochemical mechanisms through which p53 acts as a tumor suppressor.
Hansen
R S
RS
Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Braithwaite
A W
AW
D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
D017500:Adenovirus E1A Proteins; C493956:CDKN1A protein, human; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53