Ionizing Radiation Induces ATM-independent Degradation of p21Cip1 in Transformed Cells
Copyright policy )Ionizing Radiation Induces ATM-independent Degradation of p21Cip1 in Transformed Cells
The cyclin-dependent kinase inhibitor p21(Cip1) plays an important role in the cellular response to DNA damage. In normal cells, genotoxic stress activates the ATM-p53 pathway that up-regulates the expression of p21(Cip1) leading to cell cycle arrest. However, we have found that in several neoplastic cell lines, ionizing radiation (IR) induces ubiquitin-dependent degradation of p21(Cip1). This process is independent of the ATM pathway as it occurs in immortalized A-T fibroblasts. Knockdown of Skp2, an F-box protein capable of regulating the normal turnover of p21(Cip1), does not prevent the IR-induced degradation. Instead, this process requires the Cul4-DDB1(Cdt2) E3 ligase as knockdown of either DDB1 or Cdt2 rescues p21(Cip1) degradation after IR. Mutating the proliferating cell nuclear antigen-binding site of p21(Cip1) also prevents its IR-induced degradation suggesting that the p21(Cip1)-proliferating cell nuclear antigen interaction is critical for this event. Although ectopic expression of a nondegradable p21(Cip1) did not by itself affect the clonogenic survival of HEK293 cells after IR, the degradation of p21(Cip1) and other targets of the Cul4-DDB1(Cdt2) E3 ligase may collectively contribute to the survival of neoplastic cells after ionizing radiation.
- University of California, San Diego United States
- Moores Cancer Center United States
- University of California, San Diego United States
Cyclin-Dependent Kinase Inhibitor p21, Proteasome Endopeptidase Complex, Ubiquitin, Tumor Suppressor Proteins, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, DNA-Binding Proteins, Proliferating Cell Nuclear Antigen, Radiation, Ionizing, Animals, Humans, Protein Processing, Post-Translational, S-Phase Kinase-Associated Proteins, Cell Line, Transformed, Protein Binding
Cyclin-Dependent Kinase Inhibitor p21, Proteasome Endopeptidase Complex, Ubiquitin, Tumor Suppressor Proteins, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, DNA-Binding Proteins, Proliferating Cell Nuclear Antigen, Radiation, Ionizing, Animals, Humans, Protein Processing, Post-Translational, S-Phase Kinase-Associated Proteins, Cell Line, Transformed, Protein Binding
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