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J. Biol. Chem., Vol. 279, Issue 14, 13496-13505, April 2, 2004

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Induction of G₁ Arrest and Apoptosis in Human Jurkat T Cells by Pentagalloylglucose through Inhibiting Proteasome Activity and Elevating p27^Kip1, p21^Cip1/WAF1, and Bax Proteins^*

Wei-Jen Chen and Jen-Kun Lin

From the Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan

Pentagalloylglucose, which is found in many medicinal plants, can arrest the cell cycle at G₁ phase through down-regulation of cyclin-dependent kinases 2 and 4 and up-regulation of the cyclin-dependent kinase inhibitors p27^Kip1 and p21^Cip1/WAF1 in human breast cancer cells. Pentagalloylglucose also induces apoptosis in human leukemic cells. However, the mechanisms by which pentagalloylglucose induces these effects is unclear. We now show that pentagalloylglucose inhibits the activities of purified 20 and 26 S proteasomes in vitro, the 26 S proteasome in Jurkat T cell lysates, and chymotrypsin-like activity of the 26 S proteasome in intact Jurkat T cells. The turnover of p27^Kip1 and p21^Cip1/WAF1, which is necessary for cell cycle progression mediated by proteasome degradation, was disrupted by treatment of human Jurkat T cells with pentagalloylglucose. This was shown by cycloheximide treatment and in vivo pulse-chase labeling experiments, and this effect correlated with the arrest of proliferation of Jurkat T cells at G₁. Inhibition of the proteasome by pentagalloylglucose and by the proteasome inhibitor MG132 caused accumulation of ubiquitin-tagged proteins in Jurkat T cells. The addition of pentagalloylglucose to Jurkat T cells enhanced the stability of the proteasome substrate Bax and increased cytochrome c release and apoptosis. Our findings suggest a mechanism for the effect of pentagalloylglucose on the cell cycle in human leukemic cells: that pentagalloylglucose down-regulates proteasome-mediated pathways because it is a proteasome inhibitor.

Received for publication, December 5, 2002 , and in revised form, January 15, 2004.

^* This work was supported by National Science Council Grants NSC 91-2320-B-002-068 and NSC 91-2311-B-002-037, National Health Research Institute Grant NHRI-EX91-8913BL, and Ministry of Education Grant ME 89-B-FA01-1-4. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Rd., Taipei, Taiwan. Tel.: 886-2-2356-2213; Fax: 886-2-2391-8944; E-mail: jklin{at}ha.mc.ntu.edu.tw.

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