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

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.

• Authors: Chi-Yun Wang, Yee-Shin Lin, Wu-Chou Su, Chia-Ling Chen, Chiou-Feng Lin
• Journal: Molecular biology of the cell (Mol Biol Cell) Vol. 20 Issue 19 Pg. 4153-61 (Oct 2009) ISSN: 1939-4586 [Electronic] United States
• PMID: 19656851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Annexin A2
• Antineoplastic Agents
• Culture Media, Serum-Free
• Mitochondrial Proteins
• bcl-2-Associated X Protein
• Green Fluorescent Proteins
• Glycogen Synthase Kinase 3
• Protein Phosphatase 2
• Serine Endopeptidases
• HTRA2 protein, human
• High-Temperature Requirement A Serine Peptidase 2
• Htra2 protein, mouse
• Cisplatin

Topics

• Animals
• Annexin A2 (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Blotting, Western
• Cell Cycle (drug effects, physiology)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Culture Media, Serum-Free (pharmacology)
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Green Fluorescent Proteins (genetics, metabolism)
• High-Temperature Requirement A Serine Peptidase 2
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondrial Proteins (genetics, metabolism)
• Mutation
• Neoplasms, Experimental (genetics, metabolism, pathology)
• Protein Phosphatase 2 (metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Serine Endopeptidases (genetics, metabolism)
• Transplantation, Heterologous
• bcl-2-Associated X Protein (metabolism)