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Pharmacologic Modulation of Glycogen Synthase Kinase-3ß Promotes p53-Dependent Apoptosis through a Direct Bax-Mediated Mitochondrial Pathway in Colorectal Cancer Cells

Laboratory of Molecular Pharmacology, Genome Institute of Singapore, Singapore, Singapore

Requests for reprints: Qiang Yu. Laboratory of Molecular Pharmacology, Genome Institute of Singapore, Genome Building, #02-01, 60 Bipolis Street, Singapore, Singapore 138672. Phone: 65-6478-8127; Fax: 65-6478-9003; E-mail: yuq{at}gis.a-star.edu.sg.

Activation of p53 tumor suppressor induces either cell cycle arrest or apoptosis through transcription-dependent and independent pathways; however, their relative roles in apoptosis induction and how these pathways are regulated remains elusive. Here, we report a unique role for glycogen synthesis kinase-3ß (GSK-3ß) in regulating p53 functions in human colorectal cancer cells. Pharmacologic modulation of GSK-3ß markedly impaired p53-dependent transactivation of targets including p21 and Puma but promoted p53-dependent conformational activation of Bax, resulting in cytochrome c release, loss of mitochondrial membrane potential, and caspase-9 processing. Thus, p53-mediated damage response is converted from cell cycle arrest to apoptosis following exposure to a variety of chemotherapeutic agents. We found that this effect is associated with the modulation of inhibitory Ser⁹ phosphorylation of GSK-3ß but not with the activating tyrosine phosphorylation. We further show that the induction of apoptosis is through a direct mitochondrial pathway that requires Bax but not Puma. Our results underscore the importance of transcription-independent mechanism in p53-induced apoptosis and indicate that GSK-3ß plays distinct dual roles in regulating p53 pathways: promoting p53 transcriptional activity in the nucleus but suppressing p53-mediated direct apoptotic function at the mitochondria. Importantly, our data suggest that small-molecule inhibition of GSK-3ß might represent a novel approach for modulating chemotherapy.

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