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Research Articles: Therapeutics, Targets, and Development

Gam1-associated alterations of drug responsiveness through activation of apoptosis

¹ Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois; ² European Institute of Oncology, Department of Experimental Oncology, Milan, Italy; and ³ Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois

Requests for reprints: Yin-Yuan Mo, Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, 801 North Rutledge, P.O. Box 19626, Springfield, IL 62794. Phone: 217-545-8508. E-mail: ymo{at}siumed.edu

Abstract

An early gene product, Gam1, encoded by the avian adenovirus CELO, is an inhibitory protein for the sumoylation machinery, which has been implicated in regulating a variety of cellular pathways. In this study, we found that Gam1 effectively suppressed both constitutive and inducible sumoylation and caused significant cell growth inhibition. This Gam1-mediated cell growth inhibition was associated with induction of apoptosis. In particular, Gam1 induced caspase-3 activity as detected by immunostaining and Western blot. Of interest, like the Ubc9 dominant-negative mutant, Gam1 also sensitized cells to DNA-damaging agents such as topotecan and doxorubicin and non–DNA-damaging agents such as paclitaxel and vincristine. Taken together, our findings suggest that activation of the caspase pathways is at least in part responsible for the increased apoptosis in Gam1-expressing cells and, thus, contributes to the growth inhibition and enhanced chemosensitivity. [Mol Cancer Ther 2007;6(6):1823–30]

Grant support: NIH grants CA102630 and CA40570.

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.

Received 12/12/06; revised 4/25/07; accepted 5/ 2/07.