HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 3, 1595-1606, January 19, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/3/1595    most recent M606306200v1 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 Lee, Y.-K. Articles by Ann, D. K. Search for Related Content PubMed PubMed Citation Articles by Lee, Y.-K. Articles by Ann, D. K. Social Bookmarking                      What's this?

Doxorubicin Down-regulates Krüppel-associated Box Domain-associated Protein 1 Sumoylation That Relieves Its Transcription Repression on p21^WAF1/CIP1 in Breast Cancer MCF-7 Cells^*

Yung-Kang Lee, Stefani N. Thomas¹, Austin J. Yang^¶, and David K. Ann^||**2

From the Departments of Molecular Pharmacology and Toxicology, Pharmaceutical Sciences, ^||Medicine, and the ^**Norris Cancer Center, University of Southern California, Los Angeles, California 90033, the Department of Clinical and Molecular Pharmacology, City of Hope Medical Center, Duarte, California 91010, and the ^¶Department of Anatomy and Neurobiology, Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201

The role of post-translational modification, such as sumoylation, in modulating the efficacy of doxorubicin (Dox) treatment remains unclear. Transcriptional cofactor KRAB domain-associated protein 1 (KAP1) has been shown to complex with the KRAB zinc finger protein, ZBRK1, to repress the transcription of target genes. Through a combination of proteomic screening and site-directed mutagenesis approaches, we have identified lysines 554, 779, and 804 as the major sumoylation sites in KAP1. We then present evidence that Dox-mediated induction of cell cycle regulator p21 expression is differentially regulated by KAP1 sumoylation status. Moreover, the KAP1 sumoylation level was transiently decreased upon Dox exposure, and transfection with the KAP1 sumoylation mimetic, SUMO-1-KAP1, desensitizes breast cancer MCF-7 cells to Dox-elicited cell death. The sumoylation-dependent stimulation of KAP1 function is achieved by enhancing the methylation of H3-K9 and attenuating the acetylation of H3-K9 and H3-K14 at the p21 core promoter. We also show that occupancy of ZBRK1 response elements located at the p21 promoter by ZBRK1·KAP1 is independent of KAP1 sumoylation. Hence, sumoylation of KAP1 represses p21 transcription via a chromatin-silencing process without affecting interaction between KAP1·ZBRK1 and DNA, thus providing a novel mechanistic basis for the understanding of Dox-induced de-repression of p21 transcription. Taken together, our results suggest that Dox-induced decrease in KAP1 sumoylation is essential for Dox to induce p21 expression and subsequent cell growth inhibition in MCF-7 cells.

Received for publication, July 3, 2006 , and in revised form, October 23, 2006.

^* This work was supported in part by the National Institutes of Health Research Grants R01 DE 10742 and DE 14183 (to D. K. A.) and MH 59786 and AG 25323 (to A. J. Y.). 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.

¹ Recipient of a pre-doctoral fellowship awarded by the Society of Neuroscience Minority Neuroscience Fellowship Program.

² To whom correspondence should be addressed: City of Hope Medical Center, 1500 East Duarte Road, Duarte, CA 91010. Tel.: 626-359-8111 (ext. 64967); Fax: 626-471-7204; E-mail: dann{at}coh.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Briers, C. Crawford, W. A. Bickmore, and H. G. Sutherland KRAB zinc-finger proteins localise to novel KAP1-containing foci that are adjacent to PML nuclear bodies J. Cell Sci., April 1, 2009; 122(7): 937 - 946. [Abstract] [Full Text] [PDF]

				S. Chupreta, H. Brevig, L. Bai, J. L. Merchant, and J. A. Iniguez-Lluhi Sumoylation-dependent Control of Homotypic and Heterotypic Synergy by the Kruppel-type Zinc Finger Protein ZBP-89 J. Biol. Chem., December 14, 2007; 282(50): 36155 - 36166. [Abstract] [Full Text] [PDF]

				X. Li, Y.-K. Lee, J.-C. Jeng, Y. Yen, D. C. Schultz, H.-M. Shih, and D. K. Ann Role for KAP1 Serine 824 Phosphorylation and Sumoylation/Desumoylation Switch in Regulating KAP1-mediated Transcriptional Repression J. Biol. Chem., December 14, 2007; 282(50): 36177 - 36189. [Abstract] [Full Text] [PDF]