Group IVA Cytosolic Phospholipase A2 Regulates the G2-to-M Transition by Modulating the Activity of Tumor Suppressor SIRT2.
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.
Mesh Terms:
Animals, Cell Division, Cell Line, G2 Phase, Gene Deletion, Group IV Phospholipases A2, HEK293 Cells, Humans, Male, Mice, Mitosis, Phosphorylation, Protein Interaction Maps, Sirtuin 2
Animals, Cell Division, Cell Line, G2 Phase, Gene Deletion, Group IV Phospholipases A2, HEK293 Cells, Humans, Male, Mice, Mitosis, Phosphorylation, Protein Interaction Maps, Sirtuin 2
Mol. Cell. Biol.
Date: Nov. 01, 2015
PubMed ID: 26303530
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