No anti-apoptotic effects of single copies of mutant p53 genes in drug-treated tumor cells

Abstract

Some mutant forms of the p53 tumor suppressor have been documented to exert novel oncogenic functions including the increase of tumorigenicity, metastatic potential, genomic instability and therapy resistance of tumor cells. The latter has been suggested to be caused, primarily, by inhibition of apoptosis and, in part, through the activation of genes by mutant p53 whose products can counteract drug activities. Recently described in this context was the dUTPase, which may confer resistance to fluoropyrimidine drugs such as 5-fluorouracil (5-FU). We report here findings that call in question the existence of a direct anti-apoptotic effect of mutant p53. Wild-type p53-negative human fibroblasts, and Saos-2, H1299 and HCT116 tumor cells, treated with adriamycin, etoposide, cisplatin or 5-FU, failed to show apoptosis resistance when retrovirally bulk-infected to express the p53 mutants 175H or 273H at levels observed in naturally mutant p53-producing tumor cells. Furthermore, dUTPase gene expression was not stimulated by mutant p53, but instead by cellular events that involve DNA synthesis. We interpret the combined available data to suggest that much of the anti-apoptotic effect of mutant p53 is indirect and secondary to DNA-damaging and/or repair-interfering effects of these proteins.

Resistance of mitochondrial p53 to dominant inhibition

“…pLRNL-175ΔC, pLRNL-175ΔO, pLRNL-273ΔC, pLRNL-273ΔO pLRNL-175H and pLRNL-273H have been described elsewhere [ 50 ]. Full-length mutant p53 genes 175H, 273H and 248W were cloned into expression plasmid pCMV-pA. Plasmid pLXSNp53DD was kindly provided by Moshe Oren, Rehovot, Israel.…”

Fluorodeoxyuridine Modulates Cellular Expression of the DNA Base Excision Repair Enzyme Uracil-DNA Glycosylase

“…This variability may be associated with certain mutant forms of p53. Pugacheva et al (14) determined that certain types of mutant p53s are capable of inducing expression of dUTPase with the result being an increase in resistance of these cells to fluoropyrimidine drugs, although recent work has called into question a direct effect of mutant p53 on dUTPase expression and may be the consequence of indirect effects caused by cancer agent-induced DNA damage and repair (15). In any event, there is clear evidence indicating that elevated levels of dUTPase in cancer cells diminish the effectiveness of the fluoropyrimidine anticancer drugs.…”

Characterization of the new human pleomorphic undifferentiated sarcoma TP53-null cell line mfh-val2

“…TP53-null cell lines have a wide diversity of applications: these cell lines can be used as recipients to reintroduce either wild-type of mutant TP53 in the study of the functional roles of p53 isoforms in cancer (Silden et al 2013;Hafsi et al 2013;Fritzsche et al 2004), or as control cells in functional studies about other members of p53 family like p73 (Holcakova et al 2008;Stros et al 2002;Zeng et al 2000). TP53null cell lines are also used as controls in pharmacological and biological studies of molecules that modulate the p53 pathway (Guo et al 2012;Tanner and Barberis 2004;Li et al 2008;Rui et al 2004;Pise-Masison et al 2001), and could be useful in studies of drugs whose treatment result is correlated with TP53 status in the tumor cells (Xu et al 2016).…”