RASSF1A [Ras association (RalGDS/AF-6) domain family member 1A] and RASSF1C are two ubiquitously expressed isoforms of the RASSF1 gene. The promoter of RASSF1A is frequently hypermethylated, resulting in inactivation in various human cancers. RASSF1A is implicated in the regulation of apoptosis, microtubule stability and cell cycle arrest. However, little is known about the regulation and function of RASSF1C. In the present study we show that exogenously expressed RASSF1C is a very unstable protein that is highly polyubiquitylated and degraded via the proteasome. Furthermore, RASSF1C degradation is enhanced when cells are exposed to stress signals, such as UV irradiation. Mule, a HECT (homologous with E6-associated protein C-terminus) family E3 ligase, but not SCFβ-TrCP [where SCF is Skp1 (S-phase kinase-associated protein 1)/cullin/F-box and β-TrCP is β-bransducin repeat-containing protein] or CUL4 (cullin 4)-DDB1 (damage-specific DNA-binding protein 1), is the E3 ligase for RASSF1C under normal conditions, whereas both Mule and SCFβ-TrCP target RASSF1C degradation in response to UV irradiation. GSK3 (glycogen synthase kinase 3) phosphorylates RASSF1C to promote RASSF1C degradation subsequently, which is negatively regulated by the PI3K (phosphoinositide 3-kinase)/Akt pathway. Thus the present study reveals a novel regulation of RASSF1C and the potentially important role of RASSF1C in DNA damage responses.
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Research Article|
December 14 2011
Targeted polyubiquitylation of RASSF1C by the Mule and SCFβ-TrCP ligases in response to DNA damage
Xin Zhou;
Xin Zhou
*Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Shanghai 200032, China
†Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
‡School of Life Sciences, Fudan University, Shanghai 200032, China
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Ting-Ting Li;
Ting-Ting Li
*Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Shanghai 200032, China
†Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
‡School of Life Sciences, Fudan University, Shanghai 200032, China
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Xu Feng;
Xu Feng
*Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Shanghai 200032, China
†Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
‡School of Life Sciences, Fudan University, Shanghai 200032, China
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Esther Hsiang;
Esther Hsiang
§Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, U.S.A.
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Yue Xiong;
Yue Xiong
†Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
‡School of Life Sciences, Fudan University, Shanghai 200032, China
∥Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, U.S.A.
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Kun-Liang Guan;
Kun-Liang Guan
*Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Shanghai 200032, China
†Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
¶Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093-0815, U.S.A.
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Qun-Ying Lei
Qun-Ying Lei
1
*Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Shanghai 200032, China
†Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
‡School of Life Sciences, Fudan University, Shanghai 200032, China
1To whom correspondence should be addressed (email qlei@fudan.edu.cn).
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Publisher: Portland Press Ltd
Received:
August 18 2011
Revision Received:
September 10 2011
Accepted:
September 12 2011
Accepted Manuscript online:
September 12 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 441 (1): 227–236.
Article history
Received:
August 18 2011
Revision Received:
September 10 2011
Accepted:
September 12 2011
Accepted Manuscript online:
September 12 2011
Citation
Xin Zhou, Ting-Ting Li, Xu Feng, Esther Hsiang, Yue Xiong, Kun-Liang Guan, Qun-Ying Lei; Targeted polyubiquitylation of RASSF1C by the Mule and SCFβ-TrCP ligases in response to DNA damage. Biochem J 1 January 2012; 441 (1): 227–236. doi: https://doi.org/10.1042/BJ20111500
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