title: 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.
authors: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors: Said
authors: S
authors: Movahedi Naini
authors: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors: Alice M
authors: AM
authors: Sheridan
authors: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Thomas
authors: T
authors: Force
authors: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Jagesh V
authors: JV
authors: Shah
authors: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Harvard Stem Cell Institute, Cambridge, Massachusetts, USA joseph_bonventre@hms.harvard.edu.
authors: Joseph V
authors: JV
authors: Bonventre
mesh_terms: D000818:Animals; D002455:Cell Division; D002460:Cell Line; D016195:G2 Phase; D017353:Gene Deletion; D054513:Group IV Phospholipases A2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008938:Mitosis; D010766:Phosphorylation; D060066:Protein Interaction Maps; D056565:Sirtuin 2 / Q000032:analysis / Q000378:metabolism*
chemical_list: D054513:Group IV Phospholipases A2; C474199:SIRT2 protein, human; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2