GSK3β and ERK regulate the expression of 78 kDa SG2NA and ectopic modulation of its level affects phases of cell cycle

Abstract

Striatin and SG2NA are essential constituents of the multi-protein STRIPAK assembly harbouring protein phosphatase PP2A and several kinases. SG2NA has several isoforms generated by mRNA splicing and editing. While the expression of striatin is largely restricted to the striatum in brain, that of SG2NAs is ubiquitous. In NIH3T3 cells, only the 78 kDa isoform is expressed. When cells enter into the S phase, the level of SG2NA increases; reaches maximum at the G2/M phase and declines thereafter. Downregulation of SG2NA extends G1 phase and its overexpression extends G2. Ectopic expression of the 35 kDa has no effects on the cell cycle. Relative abundance of phospho-SG2NA is high in the microsome and cytosol and the nucleus but low in the mitochondria. Okadoic acid, an inhibitor of PP2A, increases the level of SG2NA which is further enhanced upon inhibition of proteasomal activity. Phospho-SG2NA is thus more stable than the dephosphorylated form. Inhibition of GSK3β by LiCl reduces its level, but the inhibition of ERK by PD98059 increases it. Thus, ERK decreases the level of phospho-SG2NA by inhibiting GSK3β. In cells depleted from SG2NA by shRNA, the levels of pGSK3β and pERK are reduced, suggesting that these kinases and SG2NA regulate each other’s expression.

Huaier Extract Induces Apoptosis in Hepatoblastoma Cells Via the MEK/ERK Signaling Pathway

“…In addition to cyclin D1, mitogen-activated protein kinase (MAPK) superfamily members are also associated with increased proliferation, survival, and apoptosis, serving different roles in cellular responses (16). ERK1/2, p38 MAPK, and JNK/SAPK have also been reported to play central roles in the regulation of cyclin D1 expression (17).…”

“…Since the anti-tumor effect is usually closely correlated with down-regulation of cell survival signaling pathways, we hypothesized that Huaier extract treatment may result in the inhibition of the signaling pathways involved in cell survival. MAPK has been shown to be involved in the induction of cell cycle related cyclin Ds in many types of cancer (17). Given that treatment with Huaier extract upregulated the expression of cyclin D1 and cyclin D3, we examined the expression of MAPK related proteins after treatment of hepatoblastoma cells with Huaier extract.…”

The STRIPAK Complex Regulates Response to Chemotherapy Through p21 and p27

“…Over the past few years, extensive functional and mechanistic research has been conducted to resolve the framework of the Striatin Interacting Phosphatase and Kinase (STRIPAK) complex. The accumulated findings have linked specific components of the complex to various biological functions including vesicular trafficking (Zhang et al, 2013;Lant et al, 2015), Golgi assembly (Kean et al, 2011), Hippo signaling (Ribeiro et al, 2010;Zheng et al, 2017), autophagy (Huang et al, 2017), cell migration (Madsen et al, 2015;Bazzi et al, 2017), and cell cycle control (Cornils et al, 2011;Frost et al, 2012;Kazmierczak-Baranska et al, 2015;Pandey et al, 2017). Substantiated by these findings, the STRIPAK complex is supervising embryogenesis and development (Lant et al, 2015;Madsen et al, 2015;Sakuma et al, 2015Sakuma et al, , 2016Bazzi et al, 2017;Pal et al, 2017;Zheng et al, 2017), circadian rhythms (Andreazza et al, 2015), type 2 diabetes (Chursa et al, 2017), and progression of cancer (Wong et al, 2014;Zhang et al, 2014;Madsen et al, 2015;Huang et al, 2017).…”

Anti-tumor effect of Huaier extract against neuroblastoma cells in vitro

“…Since the anti-tumor effect is correlated with down-regulation of cell survival signaling pathways, we hypothesized that Huaier extract may result in the inhibition of the signaling pathways involved in cell survival. MEK has been shown to be involved in the induction of cell cycle related cyclin Ds in many types of cancer [16]. Given that treatment with Huaier extract downregulated the expression of cyclinD3 (Fig.…”