Cross-Talk between p53-dependent and p53-independent Apoptotic Pathways
There is ample evidence for participation of wild type p53 in the positive regulation of apoptosis. Much less is known about the effects of various p53 mutants on apoptosis. Conceivably, in cells which have endogenous wild type p53, the addition of mutant p53 could inhibit the apoptotic activity of this endogenous wild type p53 in a negative transdominant fashion. However, the more challenging issue is whether mutant p53, on its own, has any effects on the cellular response to p53-independent apoptotic signals. This question is highly important because most tumors express mutant p53 protein types. Hence, a negative dominant effect over endogenous wild type p53 is irrelevant there. Yet, it is now known that in order for cancer therapy to eradicate such tumors, the therapy must be able to induce effective apoptotic death of the tumor cells.
To further evaluate the relationship between the p53-dependent and p53-independent apoptotic pathways, and to elucidate the function of mutant p53 in modulating these processes, we investigated the role of a p53 temperature-sensitive (ts) mutant in a number of apoptotic pathways induced by chemotherapeutic drugs that are currently used in cancer therapy. To that end, we studied the M1/2, myeloid p53 non-producer cells, and M1/2-derived temperature-sensitive mutant p53 expressing clones. Apoptosis caused by DNA damage induced with g-irradiation, Doxorubicin or Cisplatin, was enhanced in cells expressing wild type p53 as compared to that seen in parental p53 non-producer cells; mutant p53 expressing clones were found to be more resistant to apoptosis induced by these factors. Actinomycin D, a potent inhibitor of transcription, as well as a DNA damaging agent, abrogated the restraint apoptosis mediated by mutant p53.
These observations suggest that while loss of wild type p53 function clearly reduces the rate of apoptosis, p53 mutations may result in a gain of function which significantly interferes with chemotherapy induced apoptosis. Therefore, to achieve a successful cancer therapy, it is critical to consider the specific relationship between a given mutation in p53 and the chemotherapy selected.
Department of Molecular Cell Biology,