Editors' ChoiceCell Cycle

GSK3 Implicated in DNA Damage Response

Science's STKE  18 Jun 2002:
Vol. 2002, Issue 137, pp. tw217-TW217
DOI: 10.1126/stke.2002.137.tw217

Watcharasit et al. propose a role for glycogen synthase kinase-3β (GSK3β) in apoptotic signaling through the tumor suppressor protein p53 in response to DNA damage. Human neuroblastoma cells were treated with the topoisomerase inhibitor camptothecin to induce DNA damage. After such treatment, GSK3β could be immunoprecipitated with p53 from nuclear extracts, and the kinase showed increased catalytic activity. The activation of GSK3β appeared to be directly mediated by p53, because recombinant GSK3β was activated in vitro by incubation with recombinant p53. Treatment of cells with pharmacological inhibitors of GSK3β or expression of a modified form of the inhibitory GSK3-binding protein (GBP) that was targeted to the nucleus inhibited the increased expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and activation of caspase 3 normally observed in response to p53. Thus, in addition to its key roles in other signaling pathway, GSK3β may also mediate effects of 53 that lead to caspase activation and cell death.

P. Watcharasit, G. N. Bijur, J. W. Zmijewski, L. Song, A. Zmijewska, X. Chen, G. V. W. Johnson, R. S. Jope, Direct, activating interaction between glycogen synthase kinase-3β and p53 after DNA damage. Proc. Natl. Acad. Sci. U.S.A. 99, 7951-7955 (2002). [Abstract] [Full Text]