Mutant p53 protein expression interferes with p53-independent apoptotic pathways

Runzhao Li, Patrick D. Sutphin, Dov Schwartz, Devorah Matas, Nava Almog, Roland Wolkowicz, Naomi Goldfinger, Huiping Pei, Miron Prokocimer, Varda Rotter

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

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 γ-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.

Original languageEnglish (US)
Pages (from-to)3269-3277
Number of pages9
JournalOncogene
Volume16
Issue number25
DOIs
StatePublished - Jun 25 1998

Keywords

  • Apoptosis
  • Chemotherapeutic drugs
  • p53-dependent
  • p53-independent

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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