p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells

Xinbin Chen, Linda J. Ko, Lata Jayaraman, Carol Prives

Research output: Contribution to journalArticle

621 Citations (Scopus)

Abstract

It is well established that induction of the p53 tumor suppressor protein in cells can lead to either cell cycle arrest or apoptosis. To further understand features of p53 that contribute to these cell responses several p53-null Saos2 and H1299 cell lines were generated that express wild- type or mutant forms of p53, or the cyclin-dependent kinase inhibitor p21/WAF1, under a tetracycline-regulated promoter. Our results show that the cellular level of p53 can dictate the response of the cell such that lower levels of p53 result in arrest whereas higher levels result in apoptosis; nevertheless, DNA damage can heighten the apoptotic response to p53 without altering the protein level of p53 in cells. We also demonstrate that arrest and apoptosis are two genetically separable functions of p53 because a transcriptionally incompetent p53 can induce apoptosis but not arrest, whereas induction of p21/WAF1, which is a major transcriptional target of p53, can induce arrest but not apoptosis. Finally, we show that a full apoptotic response to p53 requires both its amino and carboxyl terminus, and our data suggest that there is synergism between transcription-dependent and -independent functions of p53 in apoptosis. Thus, there are multiple independent cellular responses to p53 that together may account for the extraordinarily high frequency of p53 mutations in diverse types of human tumors. The implications of these results are discussed and a model is proposed.

Original languageEnglish (US)
Pages (from-to)2438-2451
Number of pages14
JournalGenes and Development
Volume10
Issue number19
StatePublished - 1996
Externally publishedYes

Fingerprint

DNA Damage
Apoptosis
Neoplasms
Cyclin-Dependent Kinase Inhibitor p21
Tumor Suppressor Protein p53
Mutation Rate
Cell Cycle Checkpoints
Tetracycline
Cell Line
Proteins

Keywords

  • apoptosis
  • cell-cycle arrest
  • DNA damage
  • p21/WAF1
  • p53

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. / Chen, Xinbin; Ko, Linda J.; Jayaraman, Lata; Prives, Carol.

In: Genes and Development, Vol. 10, No. 19, 1996, p. 2438-2451.

Research output: Contribution to journalArticle

Chen, Xinbin ; Ko, Linda J. ; Jayaraman, Lata ; Prives, Carol. / p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. In: Genes and Development. 1996 ; Vol. 10, No. 19. pp. 2438-2451.
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