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Group IVA Cytosolic Phospholipase A2 Regulates the G2-to-M Transition by Modulating the Activity of Tumor Suppressor SIRT2.

Abstract
The G2-to-M transition (or prophase) checkpoint of the cell cycle is a critical regulator of mitotic entry. SIRT2, a tumor suppressor gene, contributes to the control of this checkpoint by blocking mitotic entry under cellular stress. However, the mechanism underlying both SIRT2 activation and regulation of the G2-to-M transition remains largely unknown. Here, we report the formation of a multiprotein complex at the G2-to-M transition in vitro and in vivo. Group IVA cytosolic phospholipase A2 (cPLA2α) acts as a bridge in this complex to promote binding of SIRT2 to cyclin A-Cdk2. Cyclin A-Cdk2 then phosphorylates SIRT2 at Ser331. This phosphorylation reduces SIRT2 catalytic activity and its binding affinity to centrosomes and mitotic spindles, promoting G2-to-M transition. We show that the inhibitory effect of cPLA2α on SIRT2 activity impacts various cellular processes, including cellular levels of histone H4 acetylated at K16 (Ac-H4K16) and Ac-α-tubulin. This regulatory effect of cPLA2α on SIRT2 defines a novel function of cPLA2α independent of its phospholipase activity and may have implications for the impact of SIRT2-related effects on tumorigenesis and age-related diseases.
AuthorsSaid Movahedi Naini, Alice M Sheridan, Thomas Force, Jagesh V Shah, Joseph V Bonventre
JournalMolecular and cellular biology (Mol Cell Biol) Vol. 35 Issue 21 Pg. 3768-84 (Nov 2015) ISSN: 1098-5549 [Electronic] United States
PMID26303530 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2015, American Society for Microbiology. All Rights Reserved.
Chemical References
  • Group IV Phospholipases A2
  • SIRT2 protein, human
  • Sirt2 protein, mouse
  • Sirtuin 2
Topics
  • Animals
  • Cell Division
  • Cell Line
  • G2 Phase
  • Gene Deletion
  • Group IV Phospholipases A2 (analysis, genetics, metabolism)
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mitosis
  • Phosphorylation
  • Protein Interaction Maps
  • Sirtuin 2 (analysis, metabolism)

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