The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells

Nicole Baptiste, Philip Friedlander, Xinbin Chen, Carol Prives

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

In some cell types either DNA damage or p53 expression leads to minimal cell death, while combining the two leads to a strong apoptotic response. To further understand features of p53 that contribute to this increased cell death we used clones of H1299 cells that express wild-type or several mutant forms of p53 under a tetracycline-regulated promoter. In these cells the induction of wild-type p53 leads to significant apoptosis only when combined with exposure to a number of chemotherapeutic agents. A common target of p53, p21, is itself not sufficient to cause apoptosis in the presence of these chemotherapeutic compounds. Many agents also effectively increase cell death when a transcriptionally-defective p53, p53[gln22ser23], is induced, although a dramatic exception is treatment with 5-FU, which strongly cooperates with wild-type but not p53[gln22ser23]. Our results with 5-FU thus show that genetically separable functions of p53 are involved in its ability to respond to DNA-damaging agents to induce apoptosis. Notably as well, deleting the C-terminal 30 amino acids of p53 does not affect this cooperative effect with DNA-damaging agents. By contrast, a p53 mutant lacking the PXXP-domain between residues 60-90, while at least partially transcriptionally-competent, cannot be rendered apoptotic by any compounds that we tested. Thus the PXXP domain provides an essential component of the ability of p53 to respond to DNA-damaging agents to cause cell death.

Original languageEnglish (US)
Pages (from-to)9-21
Number of pages13
JournalOncogene
Volume21
Issue number1
DOIs
StatePublished - Jan 3 2002
Externally publishedYes

Keywords

  • Anti-neoplastics
  • Apoptosis
  • p53
  • Proline-rich domain

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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