Ionizing Radiation Induces ATM-independent Degradation of p21Cip1 in Transformed Cells*S⃞

AUTOR(ES)

Stuart, Scott A.

FONTE

American Society for Biochemistry and Molecular Biology

RESUMO

The cyclin-dependent kinase inhibitor p21Cip1 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 p21Cip1 leading to cell cycle arrest. However, we have found that in several neoplastic cell lines, ionizing radiation (IR) induces ubiquitin-dependent degradation of p21Cip1. 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 p21Cip1, does not prevent the IR-induced degradation. Instead, this process requires the Cul4-DDB1Cdt2 E3 ligase as knockdown of either DDB1 or Cdt2 rescues p21Cip1 degradation after IR. Mutating the proliferating cell nuclear antigen-binding site of p21Cip1 also prevents its IR-induced degradation suggesting that the p21Cip1-proliferating cell nuclear antigen interaction is critical for this event. Although ectopic expression of a nondegradable p21Cip1 did not by itself affect the clonogenic survival of HEK293 cells after IR, the degradation of p21Cip1 and other targets of the Cul4-DDB1Cdt2 E3 ligase may collectively contribute to the survival of neoplastic cells after ionizing radiation.

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