Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified

Lindsey Mayo, Young Rok Seo, Mark W. Jackson, Martin L. Smith, Javier Rivera Guzman, Chandrashekhar K. Korgaonkar, David B. Donner

Research output: Contribution to journalArticle

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Abstract

The capacity of DNA damaging agents to induce apoptosis is regulated by target gene induction by p53. We found that p53 targeted MDM2 in cells in which DNA repair was occurring, but persistent DNA damage induced by chemotherapy led p53 to selectively target PTEN. High dose chemotherapy induced the phosphorylation of p53 on serine 46, whereas low dose chemotherapy did not. A nonphosphorylatable serine 46 to alanine p53 mutant (S46A) targeted the MDM2 promoter in preference to that for PTEN. A serine 46 to aspartate mutant (S46D, a phosphorylation mimic) targeted PTEN in preference to MDM2. These observations show that phosphorylation of serine 46 in p53 is sufficient for it to induce the PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor protein in preference to MDM2. S46A induced significantly less cell death than the S46D in cells. The phosphorylation-induced change of p53 promoter targeting suppresses the induction of MDM2 and the formation of the autoregulatory feedback loop. Induction of PTEN by p53 followed by expression of PTEN inhibits AKT-induced translocation of MDM2 into the nucleus and sustains p53 function. The protection of p53 from MDM2 by PTEN and the damage-induced activation of PTEN by phosphorylated p53 leads to the formation of an apoptotic amplification cycle in which p53 and PTEN coordinately increase cellular apoptosis.

Original languageEnglish (US)
Pages (from-to)25953-25959
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number28
DOIs
StatePublished - Jul 15 2005
Externally publishedYes

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Phosphorylation
Serine
Chemotherapy
Apoptosis
Drug Therapy
DNA
PTEN Phosphohydrolase
Tumor Suppressor Proteins
p53 Genes
Cell death
Chromosomes
Aspartic Acid
DNA Repair
Alanine
DNA Damage
Amplification
Repair
Cell Death
Genes
Chemical activation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified. / Mayo, Lindsey; Seo, Young Rok; Jackson, Mark W.; Smith, Martin L.; Guzman, Javier Rivera; Korgaonkar, Chandrashekhar K.; Donner, David B.

In: Journal of Biological Chemistry, Vol. 280, No. 28, 15.07.2005, p. 25953-25959.

Research output: Contribution to journalArticle

Mayo, Lindsey ; Seo, Young Rok ; Jackson, Mark W. ; Smith, Martin L. ; Guzman, Javier Rivera ; Korgaonkar, Chandrashekhar K. ; Donner, David B. / Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 28. pp. 25953-25959.
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abstract = "The capacity of DNA damaging agents to induce apoptosis is regulated by target gene induction by p53. We found that p53 targeted MDM2 in cells in which DNA repair was occurring, but persistent DNA damage induced by chemotherapy led p53 to selectively target PTEN. High dose chemotherapy induced the phosphorylation of p53 on serine 46, whereas low dose chemotherapy did not. A nonphosphorylatable serine 46 to alanine p53 mutant (S46A) targeted the MDM2 promoter in preference to that for PTEN. A serine 46 to aspartate mutant (S46D, a phosphorylation mimic) targeted PTEN in preference to MDM2. These observations show that phosphorylation of serine 46 in p53 is sufficient for it to induce the PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor protein in preference to MDM2. S46A induced significantly less cell death than the S46D in cells. The phosphorylation-induced change of p53 promoter targeting suppresses the induction of MDM2 and the formation of the autoregulatory feedback loop. Induction of PTEN by p53 followed by expression of PTEN inhibits AKT-induced translocation of MDM2 into the nucleus and sustains p53 function. The protection of p53 from MDM2 by PTEN and the damage-induced activation of PTEN by phosphorylated p53 leads to the formation of an apoptotic amplification cycle in which p53 and PTEN coordinately increase cellular apoptosis.",
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