Mutant p53 protein expression interferes with p53-independent apoptotic pathways

Abstract

Loss of normal p53 function was found frequently to interfere with response of cancer cells to conventional anticancer therapies. Since more than half of all human cancers possess p53 mutations, we decided to explore the involvement of mutant p53 in drug induced apoptosis. 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 signi®cantly interferes with chemotherapy induced apoptosis. Therefore, to achieve a successful cancer therapy, it is critical to consider the speci®c relationship between a given mutation in p53 and the chemotherapy selected.

Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy

“…This is manifested as increased resistance to etoposide and cisplatin (cis-DDP), two agents commonly employed for cancer chemotherapy. A similar picture has recently been described for murine leukemic M1 cells, where overexpression of the mouse p53vall35 mutant caused increased resistance to apoptosis induced by cisplatin, doxorubicin or g-irradiation (Li et al, 1998). It is conceivable that not all cell types may Figure 4 Transient overexpression of mutant p53 confers increased resistance to cell killing by etoposide.…”

Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells

“…Thus, mutant p53 can regulate gene expression independently of wt p53 (Kim and Deppert 2004), and transfection of mutant p53 into p53-null cell lines enhances their tumorigenic potential (Dittmer et al, 1993) and renders them resistant to apoptosis (Li et al, 1998;Blandino et al, 1999;Matas et al, 2001). In keeping with these observations, p53-mutant transgenic mice are more prone to cancer than p53 knockout mice (Harvey et al, 1995;Liu et al, 2000).…”

Transcription regulation by mutant p53

“…These findings implied a coupling between transcriptional activation by mutp53 and its prooncogenic effects, suggesting that a transcriptional regulation mechanism underlies mutp53 oncogenic GOF. Further support for a role of mutp53 in gene regulation was provided by the observation that treating cells with actinomycin D, a potent transcriptional inhibitor, abolished mutp53 GOF as reflected in resistance of L12 cells to DNA damage-induced apoptosis (Li et al, 1998). Many subsequent studies have since then confirmed that a variety of p53 mutants can upregulate the expression of genes involved in various cellular processes implicated in cancerous progression, including growth regulation, metabolism, angiogenesis, drug resistance and genomic instability.…”

“…Particular attention was devoted to the ability of mutp53 to impinge upon apoptotic pathways, primarily as this might be important in the context of efficient killing of tumor cells by chemotherapy and radiotherapy. Here, mutp53 gain of oncogenic function was manifested as the ability of various p53 mutants to interfere with apoptotic cell death upon treatment with various stress inducers, including growth factor deprivation and genotoxic agents such as IR, UV radiation, cisplatin, etoposide, doxorubicin, and a-amanitin (Peled et al, 1996;Li et al, 1998;Blandino et al, 1999;Murphy et al, 2000;Matas et al, 2001;Sigal et al, 2001;Yap et al, 2004). Mutp53 was also reported to protect hepatocytes from a combination of HBV-X protein and TNFa (Lee et al, 2000).…”