Glycogen synthase kinase-3 and Omi/HtrA2 induce annexin A2 cleavage followed by cell cycle inhibition and apoptosis

Chi-Yun Wang, Yee-Shin Lin, Wu-Chou Su, Chia-Ling Chen, Chiou Feng Lin

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Abstract

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.

Original languageEnglish
Pages (from-to)4153-4161
Number of pages9
JournalMolecular Biology of the Cell
Volume20
Issue number19
DOIs
Publication statusPublished - Oct 1 2009

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Annexin A2
Glycogen Synthase Kinase 3
Cell Cycle
Apoptosis
Protein Phosphatase 2
Cisplatin
Serine Proteases
Serum
Nude Mice
Cell Survival
Epithelial Cells
Carcinoma

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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Glycogen synthase kinase-3 and Omi/HtrA2 induce annexin A2 cleavage followed by cell cycle inhibition and apoptosis. / Wang, Chi-Yun; Lin, Yee-Shin; Su, Wu-Chou; Chen, Chia-Ling; Lin, Chiou Feng.

In: Molecular Biology of the Cell, Vol. 20, No. 19, 01.10.2009, p. 4153-4161.

Research output: Contribution to journalArticle

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