scholarly journals Lithium Stabilizes the CCAAT/Enhancer-binding Protein α (C/EBPα) through a Glycogen Synthase Kinase 3 (GSK3)-independent Pathway Involving Direct Inhibition of Proteasomal Activity

2003 ◽  
Vol 278 (22) ◽  
pp. 19674-19681 ◽  
Author(s):  
Minsub Shim ◽  
Robert C. Smart
Keyword(s):  
Glycogen Synthase ◽  
Binding Protein ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Direct Inhibition ◽  
Proteasomal Activity ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

scholarly journals Natural Functions of PLIN2 Mediating Wnt/LiCl Signaling and Glycogen Synthase Kinase 3 (GSK3)/GSK3 Substrate-Related Effects Are Modulated by Lipid

2015 ◽  
Vol 36 (3) ◽  
pp. 421-437 ◽  
Author(s):  
Xunxian Liu ◽  
Xinyue Lu ◽  
Kaimei Song ◽  
Marc R. Blackman
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Insulin Receptor Substrate ◽  
T Cell Factor ◽  
Mediated Effects ◽  
C Terminus ◽  
High Lipid ◽  
Enhancer Binding Protein ◽  
Interfering Rna

Belonging to the PLIN family, PLIN2 associates with lipid storage droplets (LSDs), but other functions of PLIN2 remain unclear. Here, we suggest that PLIN2 mediates Wnt signaling because PLIN2 small interfering RNA (siRNA) suppresses activation of Wnt/coreceptor pathways. The mediation in the Wnt/Frizzled pathway seems to occur from Dishevelleds to axin/glycogen synthase kinase 3(GSK3)/β-catenin complexes (AGβC) as Wnt decreases Dishevelled/PLIN2 but increases AGβC/PLIN2 associations. Augmenting cellular LSDs that affect PLIN2 associations with these proteins, oleic acid (OA) treatment inhibits Wnt-increased AGβC/PLIN2 associations and β-catenin T-cell factor signaling (β-CTS). Revealing that PLIN2 is a GSK3-associated protein, the study explored PLIN2-mediated effects on GSK3/GSK3 substrates. PLIN2 siRNA reduces inhibitory GSK3 levels and lithium chloride (LiCl)-upregulated β-catenin or CCAAT/enhancer binding protein α (c/EBPα) expression. OA treatment decreases LiCl-increased c/EBPα via PLIN2-c/EBPα dissociation. In addition to PLIN2 overexpression increasing β-CTS, PLIN2 depletion or overexpression drops or adds expression of GSK3 substrates, such as β-catenin, c/EBPα,c-Myc, cyclin D1, and insulin receptor substrate 1, and cell growth/survival. PLIN2 N or C terminus overexpression that is associated with higher levels of the substrates suggests that those substrates bind to specific regions of PLIN2. Mimicking the possible high lipid concentrations in cells in the human body under conditions of hyperlipidemia/obesity, OA-treated cells gain or reduce GSK3 substrate expression in parallel with a decrease (a Wnt-like effect) or increase in GSK3 activity, likely regulated by GSK3/PLIN2/GSK3 substrate associations.

scholarly journals Glycogen Synthase Kinase 3 Is an Insulin-Regulated C/EBPα Kinase

1999 ◽  
Vol 19 (12) ◽  
pp. 8433-8441 ◽  
Author(s):  
Sarah E. Ross ◽  
Robin L. Erickson ◽  
Nahid Hemati ◽  
Ormond A. MacDougald
Keyword(s):  
Conformational Changes ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Phosphatidylinositol 3 Kinase ◽  
Pharmacological Agents ◽  
Enhancer Binding Protein

ABSTRACT CCAAT/enhancer binding protein α (C/EBPα) is a transcription factor involved in creating and maintaining the adipocyte phenotype. We have shown previously that insulin stimulates dephosphorylation of C/EBPα in 3T3-L1 adipocytes. Studies to identify the insulin-sensitive sites of phosphorylation reveal that a C/EBPα peptide (amino acids H215 to K250) is phosphorylated on T222, T226, and S230 in vivo. The context of these phosphoamino acids implicates glycogen synthase kinase 3 (GSK3), whose activity is known to be repressed in response to insulin, as a potential kinase for phosphorylation of T222 and T226. Accordingly, GSK3 phosphorylates the predicted region of C/EBPα on threonine in vitro, and GSK3 uses C/EBPα as a substrate in vivo. In addition, the effect of pharmacological agents on GSK3 activity correlates with regulation of C/EBPα phosphorylation. Treatment of 3T3-L1 adipocytes with the phosphatidylinositol 3-kinase inhibitor wortmannin results in phosphorylation of C/EBPα, whereas treatment with the GSK3 inhibitor lithium results in dephosphorylation of C/EBPα. Collectively, these data indicate that insulin stimulates dephosphorylation of C/EBPα on T222 and T226 through inactivation of GSK3. Since dephosphorylation of C/EBPα in response to lithium is blocked by okadaic acid, strong candidates for the T222 and T226 phosphatase are protein phosphatases 1 and 2a. Treatment of adipocytes with insulin alters the protease accessibility of widespread sites within the N terminus of C/EBPα, consistent with phosphorylation causing profound conformational changes. Finally, phosphorylation of C/EBPα and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes.

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