title: 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.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
authors.forename: Sang Hyeok
authors.initials: SH
authors.lastname: Woo
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
authors.forename: Sung-Keum
authors.initials: SK
authors.lastname: Seo
authors.affiliation: Department of Microbiological Engineering, Kon-Kuk University, Gwangjin-gu, Seoul, Republic of Korea.
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.affiliation: Department of Microbiological Engineering, Kon-Kuk University, Gwangjin-gu, Seoul, Republic of Korea.
authors.forename: Tae-Boo
authors.initials: TB
authors.lastname: Choe
authors.affiliation: Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
authors.forename: Seok-Il
authors.initials: SI
authors.lastname: Hong
authors.affiliation: Department of Radiation Oncology, College of Medicine, Yonsei University, 250 Seongsan-no, Seodaemun-gu, Seoul, Republic of Korea. Electronic address: yhlee87@yuhs.ac.
authors.forename: Yun-Han
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea. Electronic address: parkic@kcch.re.kr.
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
mesh_terms: D001483:Base Sequence; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics*; D045744:Cell Line, Tumor; D056750:Cyclin A1 / Q000378:metabolism*; D004249:DNA Damage; D017931:DNA Primers; D006801:Humans; D059748:Proteolysis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D056750:Cyclin A1; D017931:DNA Primers; D020169:Caspases
keywords: Caspase-1; Cyclin A1; Doxorubicin; Ionizing radiation