P53's choice of myocardial death or survival

Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53-Lys118 acetylation

Rajan Gogna, Esha Madan, Mahmood Khan, Uttam Pati, Periannan Kuppusamy

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Myocardial infarction, an irreversible cardiac tissue damage, involves progressive loss of cardiomyocytes due to p53-mediated apoptosis. Oxygenation is known to promote cardiac survival through activation of NOS3 gene. We hypothesized a dual role for p53, which, depending on oxygenation, can elicit apoptotic death signals or NOS3-mediated survival signals in the infarct heart. p53 exhibited a differential DNA-binding, namely, BAX-p53RE in the infarct heart or NOS3-p53RE in the oxygenated heart, which was regulated by oxygen-induced, post-translational modification of p53. In the infarct heart, p53 was heavily acetylated at Lys118 residue, which was exclusively reversed in the oxygenated heart, apparently regulated by oxygen-dependent expression of TIP60. The inhibition of Lys118 acetylation promoted the generation of NOS3-promoting prosurvival form of p53. Thus, oxygenation switches p53-DNA interaction by regulating p53 core-domain acetylation, promoting a prosurvival transcription activity of p53. Understanding this novel oxygen-p53 survival pathway will open new avenues in cardioprotection molecular therapy.

Original languageEnglish (US)
Pages (from-to)1662-1683
Number of pages22
JournalEMBO Molecular Medicine
Volume5
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

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Acetylation
Myocardium
Oxygen
DNA
Post Translational Protein Processing
Cardiac Myocytes
Transcriptional Activation
Myocardial Infarction
Apoptosis
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine

Cite this

P53's choice of myocardial death or survival : Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53-Lys118 acetylation. / Gogna, Rajan; Madan, Esha; Khan, Mahmood; Pati, Uttam; Kuppusamy, Periannan.

In: EMBO Molecular Medicine, Vol. 5, No. 11, 11.2013, p. 1662-1683.

Research output: Contribution to journalArticle

Gogna, Rajan ; Madan, Esha ; Khan, Mahmood ; Pati, Uttam ; Kuppusamy, Periannan. / P53's choice of myocardial death or survival : Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53-Lys118 acetylation. In: EMBO Molecular Medicine. 2013 ; Vol. 5, No. 11. pp. 1662-1683.
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