scholarly journals Glycogen Synthase Kinase-3 and Omi/HtrA2 Induce Annexin A2 Cleavage followed by Cell Cycle Inhibition and Apoptosis

2009 ◽  
Vol 20 (19) ◽  
pp. 4153-4161 ◽  
Author(s):  
Chi-Yun Wang ◽  
Yee-Shin Lin ◽  
Wu-Chou Su ◽  
Chia-Ling Chen ◽  
Chiou-Feng Lin
Keyword(s):  
Cell Cycle ◽  
Serine Proteases ◽  
Glycogen Synthase ◽  
Annexin A2 ◽  
Glycogen Synthase Kinase ◽  
Serum Withdrawal ◽  
Cellular Processes ◽  
Cell Cycle Inhibition ◽  
Necrotic Region ◽  
Induced Apoptosis

Annexin A2 is involved in multiple cellular processes, including cell survival, growth, division, and differentiation. A lack of annexin A2 makes cells more sensitive to apoptotic stimuli. Here, we demonstrate a potential mechanism for apoptotic stimuli-induced annexin A2 cleavage, which contributes to cell cycle inhibition and apoptosis. Annexin A2 was persistently expressed around the proliferative but not the necrotic region in BALB/c nude mice with human lung epithelial carcinoma cell A549-derived tumors. Knockdown expression of annexin A2 made cells susceptible to either serum withdrawal-induced cell cycle inhibition or cisplatin-induced apoptosis. Under apoptotic stimuli, annexin A2 was time-dependently cleaved. Mechanistic studies have shown that protein phosphatase 2A (PP2A)-activated glycogen synthase kinase (GSK)-3 is essential for this process. Therefore, inhibiting GSK-3 reversed serum withdrawal-induced cell cycle inhibition and cisplatin-induced apoptosis. Furthermore, inhibiting serine proteases blocked apoptotic stimuli-induced annexin A2 cleavage. Bax activation and Mcl-1 destabilization, which is regulated by PP2A and GSK-3, caused annexin A2 cleavage via an Omi/HtrA2-dependent pathway. Taking these results together, we conclude that GSK-3 and Omi/HtrA2 synergistically cause annexin A2 cleavage and then cell cycle inhibition or apoptosis.

A novel role for glycogen synthase kinase-3 in Xenopus development: maintenance of oocyte cell cycle arrest by a beta-catenin-independent mechanism

Development ◽  
1999 ◽  
Vol 126 (3) ◽  
pp. 567-576 ◽  
Author(s):  
D.L. Fisher ◽  
N. Morin ◽  
M. Doree
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Glycogen Synthase ◽  
Cyclin B1 ◽  
Dominant Negative ◽  
Glycogen Synthase Kinase ◽  
Beta Catenin ◽  
Xenopus Development ◽  
Cycle Arrest ◽  
Cell Cycle Inhibition

We have examined the expression of glycogen synthase kinase-3beta in oocytes and early embryos of Xenopus and found that the protein is developmentally regulated. In resting oocytes, GSK-3beta is active and it is inactivated on maturation in response to progesterone. GSK-3beta inactivation is necessary and rate limiting for the cell cycle response to this hormone and the subsequent accumulation of beta-catenin. Overexpression of a dominant negative form of the kinase accelerates maturation, as does inactivation by expression of Xenopus Dishevelled or microinjection of an inactivating antibody. Cell cycle inhibition by GSK-3beta is not mediated by the level of beta-catenin or by a direct effect on either the MAP kinase pathway or translation of mos and cyclin B1. These data indicate a novel role for GSK-3beta in Xenopus development: in addition to controlling specification of the dorsoventral axis in embryos, it mediates cell cycle arrest in oocytes.

scholarly journals Glycogen Synthase Kinase-3 Inhibition Sensitizes Pancreatic Cancer Cells to TRAIL-Induced Apoptosis

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e41102 ◽  
Author(s):  
Shadi Mamaghani ◽  
Craig D. Simpson ◽  
Pinjiang M. Cao ◽  
May Cheung ◽  
Sue Chow ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Pancreatic Cancer Cells ◽  
Induced Apoptosis

scholarly journals mTORC1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis via Increased Hexokinase II and GLUT1 Expression, Sustained Mcl-1 Expression, and Glycogen Synthase Kinase 3β Inhibition

2009 ◽  
Vol 29 (18) ◽  
pp. 5136-5147 ◽  
Author(s):  
Prashanth T. Bhaskar ◽  
Veronique Nogueira ◽  
Krushna C. Patra ◽  
Sang-Min Jeon ◽  
Youngkyu Park ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Hypoxia Inducible Factor ◽  
Feedback Mechanism ◽  
Serum Deprivation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Hexokinase Ii ◽  
Negative Feedback Mechanism ◽  
Glut1 Expression ◽  
Induced Apoptosis

ABSTRACT The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1α (HIF1α) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1α abundance in these cells is attributed to both an increased level and the sustained translation of HIF1α mRNA. Sustained glycogen synthase kinase 3β inhibition and Mcl-1 expression also contribute to the apoptotic resistance of Tsc2-deficient cells to serum deprivation. The inhibition of mTORC1 activity by either rapamycin or Raptor knockdown cannot resensitize these cells to serum deprivation-induced apoptosis because of elevated Akt activity that is an indirect consequence of mTORC1 inhibition. However, the increased HIF1α abundance and the maintenance of Mcl-1 protein expression in serum-deprived Tsc2 −/ − cells are dependent largely on the hyperactive eIF4E in these cells. Consistently, the reduction of eIF4E levels abrogates the resistance of Tsc2 −/ − cells to serum deprivation-induced apoptosis.

scholarly journals cAMP-guanine exchange factor protection from bile acid-induced hepatocyte apoptosis involves glycogen synthase kinase regulation of c-Jun NH2-terminal kinase

2011 ◽  
Vol 301 (2) ◽  
pp. G385-G400 ◽  
Author(s):  
A. Johnston ◽  
K. Ponzetti ◽  
M. S. Anwer ◽  
C. R. L. Webster
Keyword(s):  
Bile Acid ◽  
Glycogen Synthase ◽  
Rat Hepatocytes ◽  
Glycogen Synthase Kinase ◽  
Exchange Factor ◽  
Stress Markers ◽  
Guanine Exchange Factor ◽  
Phosphoinositide 3 Kinase ◽  
Induced Apoptosis ◽  
Interfering Rna

Cholestatic liver disorders are accompanied by the hepatic accumulation of cytotoxic bile acids that induce cell death. Increases in cAMP protect hepatocytes from bile acid-induced apoptosis by a cAMP-guanine exchange factor (cAMP-GEF)/phosphoinositide-3-kinase (PI3K)/Akt pathway. The aim of these studies was to identify the downstream substrate in this pathway and to determine at what level in the apoptotic cascade cytoprotection occurs. Since inhibitory phosphorylation of glycogen synthase kinase-3 (GSK) occurs downstream of PI3K/Akt and this phosphorylation has been implicated in cell survival, we conducted studies to determine whether GSK was downstream in cAMP-GEF/PI3K/Akt-mediated cytoprotection. Our results show that treatment of hepatocytes with the cAMP-GEF-specific analog, 4-(4-chlorophenylthio)-2′- O-methyladenosine-3′,5′-cAMP, results in PI3K-dependent phosphorylation of GSK. Direct chemical inhibition of GSK in rat hepatocytes or human HUH7-NTCP cells with several structurally and functionally distinct inhibitors including bromoindirubin-3′-oxime (BIO), maleimides (SB216763, SB415286), thiadiazolidine derivatives, and LiCl attenuates apoptosis induced by glycochenodeoxycholate (GCDC). In addition, genetic silencing of the GSK β isoform with small interfering RNA attenuates GCDC apoptosis in HUH7-NTCP cells. Adenoviral inhibition of the Rap1 blocks both cAMP-GEF-mediated cytoprotection against GCDC-induced apoptosis and Akt/GSK3β phosphorylation. GCDC-induced phosphorylation of the proapoptotic kinase, c-Jun NH2-terminal kinase (JNK) is inhibited by GSK inhibition or cAMP-GEF activation. GCDC-induced apoptosis is accompanied by phosphorylation of the endoplasmic reticulum stress markers pIEF2α and IRE-1, and pretreatment with the cAMP-GEF analog or GSK inhibitors prevents this phosphorylation. Collectively, our results support the presence of a cAMP/cAMP-GEF/Rap1/PI3K/Akt/GSKβ survival pathway in hepatocytes that inhibits bile acid-induced JNK phosphorylation.

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