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Nox1 is involved in p53 deacetylation and suppression of its transcriptional activity and apoptosis

Rosa Puca1, Lavinia Nardinocchi, Giuseppe Starace

  • 1Department of Experimental Oncology, Molecular Oncogenesis Laboratory, National Cancer Institute Regina Elena, Rome, Italy.

Free Radical Biology & Medicine
|February 23, 2010
PubMed

Insights

HIPK2 (HIPK2) normally suppresses cancer by activating p53. HIPK2 inhibition upregulates Nox1, which inhibits p53 acetylation and function, promoting tumor progression.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • HIPK2 (HIP11-interacting protein kinase 2) is a stress-induced kinase and transcriptional corepressor cooperating with p53 to suppress cancer.
  • p53 activation involves phosphorylation and acetylation; HIPK2 phosphorylates p53 at Ser46 and induces acetylation at Lys382.

Purpose of the Study:

  • To investigate the role of HIPK2 in p53 activation and its interplay with Nox1 and SIRT1.
  • To elucidate the mechanism by which HIPK2 inhibition impacts p53-mediated apoptosis.

Main Methods:

  • Investigated the effect of HIPK2 inhibition on Nox1 expression.
  • Utilized small interfering RNAs (siRNAs) and a SIRT1 inhibitor (nicotinamide) to assess Nox1-SIRT1-p53 axis.
  • Employed a deacetylase-defective SIRT1 mutant (SIRT1HY) to confirm SIRT1 dependency.

Main Results:

  • HIPK2 inhibition upregulated Nox1, a NADPH oxidase subunit involved in tumor progression.
  • Nox1 inhibited p53 Lys382 acetylation and impaired p53 proapoptotic transcriptional activity.
  • Nox1-mediated inhibition of p53 was dependent on SIRT1 activity, as evidenced by experiments with siRNAs, nicotinamide, and SIRT1HY.

Conclusions:

  • Nox1 upregulation may activate SIRT1, leading to inhibition of p53 acetylation and function.
  • HIPK2's role in cancer suppression involves downregulation of Nox1, maintaining p53 acetylation and proapoptotic activity.
  • p53 Lys382 acetylation is crucial for its proapoptotic function.

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