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

Abstract

Many tumors overexpress mutant forms of p53. A growing number of studies suggest that the nature of a p53 mutation in a cell can impact upon cellular properties, clinical responses to therapy and prognosis of a tumor. To explore the cellular basis of these observations, experiments were designed to compare the properties of cells with and without p53 mutations within the same cell population. To that end, various tumorderived human p53 mutants were introduced into p53-null H1299 lung adenocarcinoma cells. Clonogenic survival assays revealed that cells overexpressing the p53His175 mutant, but not the p53His273 mutant, recover preferentially from etoposide treatment. Moreover, p53His175 as well as p53His179 reduced substantially the rate of etoposide-induced apoptosis, whereas p53His273 and p53Trp248 had a much milder protective e ect. In contrast, p53His175 and p53His273 exerted very similar e ects on the cellular response to cisplatin; both conferred increased resistance to low concentrations of the drug (2.5 mg/ml), but did not protect at all against high concentrations (10 mg/ml). Hence particular p53 mutants may confer upon tumor cells a selective survival advantage during chemotherapy. These ®ndings de®ne a new type of mutant p53 selective gain of function, which may compromise the e cacy of cancer chemotherapy.

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

“…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).…”

Mutant p53: an oncogenic transcription factor

“…The attempt to verify whether the structural classification of p53 mutants reveals similar differences in terms of biological activities has been quite difficult to tackle. In vitro studies have shown that the overexpression of conformational p53 mutants renders cell cultures more resistant to etoposide, whereas DNA defective mutants increases the resistance to cisplatin (Gualberto et al, 1998;Li et al, 1998;Blandino et al, 1999;Sigal and Rotter, 2000). The presence of conformational mutants has been associated with breast cancer patients, whose relapse after conventional chemotherapy occurred more frequently when compared with patients carrying DNA contact defective p53 mutants (Aas et al, 1996;Berns et al, 2000;Geisler et al, 2003).…”