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DNA damage invokes mismatch repair-dependent cyclin D1 attenuation and retinoblastoma signaling pathways to inhibit CDK2.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2002 Mar 08; Vol. 277 (10), pp. 8372-81. Date of Electronic Publication: 2001 Nov 28. - Publication Year :
- 2002
-
Abstract
- 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.
- Subjects :
- Animals
Base Pair Mismatch
Cell Cycle
Cell Line
Cisplatin pharmacology
Cyclin A metabolism
Cyclin-Dependent Kinase 2
Enzyme Activation
G2 Phase
Immunoblotting
Mice
Microscopy, Fluorescence
Mitosis
Phosphorylation
Precipitin Tests
Protein Binding
Time Factors
CDC2-CDC28 Kinases
Cyclin D1 metabolism
Cyclin-Dependent Kinases metabolism
DNA Damage
DNA Repair
Protein Serine-Threonine Kinases metabolism
Retinoblastoma Protein metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 277
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11726663
- Full Text :
- https://doi.org/10.1074/jbc.M108906200