Implications of caspase-dependent proteolytic cleavage of cyclin A1 in DNA damage-induced cell death.

Abstract

Cyclin A1 is an A-type cyclin that directly binds to CDK2 to regulate cell-cycle progression. In the present study, we found that doxorubicin decreased the expression of cyclin A1 at the protein level in A549 lung cancer cells, while markedly downregulating its mRNA levels. Interestingly, doxorubicin upregulated caspase-1 in a concentration-dependent manner, and z-YAVD-fmk, a specific inhibitor of caspase-1, reversed the doxorubicin-induced decrease in cyclin A1 in A549 lung cancer and MCF7 breast cancer cells. Active caspase-1 effectively cleaved cyclin A1 at D165 into two fragments, which in vitro cleavage assays showed were further cleaved by caspase-3. Finally, we found that overexpression of cyclin A1 significantly reduced the cytotoxicity of doxorubicin, and knockdown of cyclin A1 by RNA interference enhanced the sensitivity of cells to ionizing radiation. Our data suggest a new mechanism for the downregulation of cyclin A1 by DNA-damaging stimuli that could be intimately involved in the cell death induced by DNA damage-inducing stimuli, including doxorubicin and ionizing radiation.

• Authors: Sang Hyeok Woo, Sung-Keum Seo, Sungkwan An, Tae-Boo Choe, Seok-Il Hong, Yun-Han Lee, In-Chul Park
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 453 Issue 3 Pg. 438-42 (Oct 24 2014) ISSN: 1090-2104 [Electronic] United States
• PMID: 25281537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Cyclin A1
• DNA Primers
• Caspases

Topics

• Base Sequence
• Caspases (metabolism)
• Cell Death (genetics)
• Cell Line, Tumor
• Cyclin A1 (metabolism)
• DNA Damage
• DNA Primers
• Humans
• Proteolysis
• Real-Time Polymerase Chain Reaction