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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates

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SIRT1 phosphorylation by AMP-activated protein kinase regulates p53 acetylation

Alan W Lau1, Pengda Liu1, Hiroyuki Inuzuka1

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 02215, USA.

American Journal of Cancer Research
|June 25, 2014
PubMed

Insights

AMP-activated protein kinase (AMPK) directly phosphorylates SIRT1, releasing it from DBC1. This pathway negatively regulates p53 acetylation, offering a potential target for cancer therapy.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Oncogenesis

Background:

  • Sirtuin 1 (SIRT1) is a deacetylase involved in metabolism and aging, also regulating the p53 tumor suppressor.
  • SIRT1's activity is modulated by its inhibitor DBC1, with release requiring AMP-activated protein kinase (AMPK) and unknown kinases.
  • Understanding SIRT1 regulation is crucial for comprehending its role in cancer development.

Purpose of the Study:

  • To elucidate the direct interaction between AMPK and SIRT1.
  • To investigate the role of SIRT1 phosphorylation in its regulation by AMPK.
  • To determine the impact of the AMPK/SIRT1 pathway on p53 signaling.

Main Methods:

  • Direct phosphorylation assays to confirm AMPK's action on SIRT1.
  • Mutagenesis studies using phospho-mimetic SIRT1 (T334E) to assess binding to DBC1.
  • Pharmacological inhibition of AMPK using Compound C to observe effects on p53 acetylation.

Main Results:

  • AMPK was confirmed to directly phosphorylate SIRT1 at Threonine 344 (T344).
  • Phosphorylation at T344 disrupts the binding between SIRT1 and its inhibitor DBC1.
  • Inhibition of AMPK activity leads to increased acetylation of p53, indicating pathway involvement.

Conclusions:

  • AMPK negatively regulates p53 acetylation through direct phosphorylation of SIRT1 at T344.
  • The identified AMPK/SIRT1 signaling axis represents a novel regulatory mechanism for p53.
  • This pathway presents a potential therapeutic target for modulating p53 function in cancer.
Keywords:
AMPKDBC1SIRT1 deacetylaseacetylationp53phosphorylation

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