Knockdown of Sec8 promotes cell-cycle arrest at G1/S phase by inducing p21 via control of FOXO proteins

Abstract

p21Cip1 protein inhibits the activity of cyclins at the G 1 checkpoint and influences transition of cells from the G 1 to the S phase of the cell cycle. Moreover, expression of members of the FOXO family (active form of forkhead transcription factors of the O class) in dividing cells promotes cell-cycle arrest at the G1/S boundary via regulation of p21Cip1. Recently, the exocyst complex, including Sec8, has been implicated in various roles independent of its role in secretion, such as cell migration, invadopodia formation, cytokinesis, glucose uptake and neural development. Given the essential roles of the exocyst complex in cellular and developmental processes, disruption of its function may be involved in various diseases such as cancer, diabetes and neuronal disorders. However, the relationship between Sec8 and the cell cycle remains to be elucidated. In this study, knockdown of Sec8 inhibited cell growth and promoted cell-cycle arrest at the G1/S phase by control of p21 expression and retinoblastoma protein phosphorylation. Furthermore, Sec8 regulated FOXO family proteins via ubiquitin-proteasome degradation by regulating the expression of the murine double minute 2 (Mdm2) protein but not S-phase kinase-associated protein 2 (Skp2). © 2013 FEBS.