DNA damage invokes mismatch repair-dependent cyclin D1 attenuation and retinoblastoma signaling pathways to inhibit CDK2. J Biol Chem 2002 Mar 08;277(10):8372-81
Date
12/01/2001Pubmed ID
11726663DOI
10.1074/jbc.M108906200Scopus ID
2-s2.0-0037041027 (requires institutional sign-in at Scopus site) 56 CitationsAbstract
DNA-damage evokes cell cycle checkpoints, which function to maintain genomic integrity. The retinoblastoma tumor suppressor (RB) and mismatch repair complexes are known to contribute to the appropriate cellular response to specific types of DNA damage. However, the signaling pathways through which these proteins impact the cell cycle machinery have not been explicitly determined. RB-deficient murine embryo fibroblasts continued a high degree of DNA replication following the induction of cisplatin damage, but were inhibited for G(2)/M progression. This damage led to RB dephosphorylation/activation and subsequent RB-dependent attenuation of cyclin A and CDK2 activity. In both Rb+/+ and Rb -/- cells, cyclin D1 expression was attenuated following DNA damage. As cyclin D1 is a critical determinant of RB phosphorylation and cell cycle progression, we probed the pathway through which cyclin D1 degradation occurs in response to DNA damage. We found that attenuation of endogenous cyclin D1 is dependent on multiple mismatch repair proteins. We demonstrate that the mismatch repair-dependent attenuation of endogenous cyclin D1 is critical for attenuation of CDK2 activity and induction of cell cycle checkpoints. Together, these studies couple the activity of the retinoblastoma and mismatch repair tumor suppressor pathways through the degradation of cyclin D1 and dual attenuation of CDK2 activity.
Author List
Lan Z, Sever-Chroneos Z, Strobeck MW, Park CH, Baskaran R, Edelmann W, Leone G, Knudsen ESAuthor
Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBase Pair Mismatch
CDC2-CDC28 Kinases
Cell Cycle
Cell Line
Cisplatin
Cyclin A
Cyclin D1
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases
DNA Damage
DNA Repair
Enzyme Activation
G2 Phase
Immunoblotting
Mice
Microscopy, Fluorescence
Mitosis
Phosphorylation
Precipitin Tests
Protein Binding
Retinoblastoma Protein
Signal Transduction
Time Factors