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

Abstract

The G 2 -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 G 2 -to-M transition remains largely unknown. Here, we report the formation of a multiprotein complex at the G 2 -to-M transition in vitro and in vivo. Group IVA cytosolic phospholipase A 2 (cPLA 2 ␣) 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 G 2 -to-M transition. We show that the inhibitory effect of cPLA 2 ␣ on SIRT2 activity impacts various cellular processes, including cellular levels of histone H4 acetylated at K16 (Ac-H4K16) and Ac-␣-tubulin. This regulatory effect of cPLA 2 ␣ on SIRT2 defines a novel function of cPLA 2 ␣ independent of its phospholipase activity and may have implications for the impact of SIRT2-related effects on tumorigenesis and age-related diseases.

Bone marrow-derived cPLA2α contributes to renal fibrosis progression

“…Another possibility is that silencing cPLA2 in the bone marrow causes intrinsic changes in the leukocytes that affect their ability to hone to the injured kidney independent of downstream eicosanoid expression. cPLA2 is known to have several noncanonical functions most recently implicated in controlling proliferation and cell cycle turnover (24,25). We did not examine cell proliferation or apoptosis in our current studies.…”

“…These enzymes are expressed throughout the nephron (19,20) and their products mediate a host of physiologic and pathologic processes in animal models of renal disease (21)(22)(23). We have shown that cPLA2 expression in human renal tubular epithelial cells promotes epithelial dedifferentiation and proliferation (24), and others have implicated cPLA2 in the control of the G2-M cell cycle checkpoint (25). These biological effects could be sufficient to modify renal injury and fibrosis, given the importance of tubular epithelial damage in renal fibrinogenesis (26,27).…”

Subcellular localization and mitotic interactome analyses identify SIRT4 as a centrosomally localized and microtubule associated protein

“…Expression of SIRT2, which is involved in the regulation of microtubule dynamics 8,10 , is regulated in a cell cycle-dependent manner where SIRT2 localizes to centrosomes and the mitotic spindle 62 . Phosphorylation of SIRT2 by cyclin A-CDK2 reduces binding of SIRT2 to centrosomes and promotes G2/M progression 63 . In line with this, increased SIRT2 levels due to mitotic stress cause an extension of the mitotic phase 64 presumably through the regulatory role of SIRT2 towards the anaphase promoting factor/cyclosome (APC/C) and hence cyclin B1 degradation 65 .…”

Cytosolic phospholipase A2α increases proliferation and de-differentiation of human renal tubular epithelial cells

“…Published data has demonstrated that cPLA 2 α directly regulates mitotic entry through the G2/M checkpoint through its interaction with the tumor suppressor gene SIRT2. (18) Additionally, cPLA 2 α may play a role in intracellular membrane trafficking. (17) Unfortunately, there is limited data regarding the role of cPLA 2 α in non-transformed epithelial cells.…”

“…Furthermore, accumulating evidence supports that cPLA 2 α itself, independent of its canonical functions, may play fundamental roles in membrane trafficking and cellular proliferation. (17, 18)…”