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J. Biol. Chem., Vol. 277, Issue 41, 38476-38485, October 11, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/41/38476    most recent M206184200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Finkielstein, C. V. Articles by Maller, J. L. Search for Related Content PubMed PubMed Citation Articles by Finkielstein, C. V. Articles by Maller, J. L. Social Bookmarking                      What's this?

A Role for G₁/S Cyclin-dependent Protein Kinases in the Apoptotic Response to Ionizing Radiation^*

Carla V. Finkielstein, Lin G. Chen, and James L. Maller^§

From the Howard Hughes Medical Institute and Department of Pharmacology, University of Colorado School of Medicine, Denver, Colorado 80262

In Xenopus development the mid-blastula transition (MBT) marks a dramatic change in response of the embryo to ionizing radiation. Whereas inhibition of cyclin D1-Cdk4 and cyclin A2-Cdk2 by p27^Xic1 has been linked to cell cycle arrest and prevention of apoptosis in embryos irradiated post-MBT, distinct roles for these complexes during apoptosis are evident in embryos irradiated pre-MBT. Cyclin A2 is cleaved by caspases to generate a truncated complex termed N-cyclin A2-Cdk2, which is kinase active, not inhibited by p27^Xic1, and not sensitive to degradation by the ubiquitin-mediated proteasome pathway. Moreover, N-cyclin A2-Cdk2 has an expanded substrate specificity and can phosphorylate histone H2B at Ser-32, which may facilitate DNA cleavage. Consistent with a role for cyclin A2 in apoptosis, the addition of N-cyclin A2-Cdk2, but not full-length cyclin A2-Cdk2, to Xenopus egg extracts triggers apoptotic DNA fragmentation even when caspases are not activated. Similarly, cyclin D1 is targeted by caspases, and the generated product exhibits higher affinity for p27^Xic1, leading to reduced phosphorylation of the retinoblastoma protein (pRB) during apoptosis. These data suggest that caspase cleavage of both cyclin D1-Cdk4 and cyclin A2-Cdk2 promotes specific apoptotic events in embryos undergoing apoptosis in response to ionizing radiation.

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