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

J. Biol. Chem., Vol. 279, Issue 37, 38313-38324, September 10, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/37/38313    most recent M401610200v1 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 Pinte, S. Articles by Leprince, D. Search for Related Content PubMed PubMed Citation Articles by Pinte, S. Articles by Leprince, D. Social Bookmarking                      What's this?

The Tumor Suppressor Gene HIC1 (Hypermethylated in Cancer 1) Is a Sequence-specific Transcriptional Repressor

DEFINITION OF ITS CONSENSUS BINDING SEQUENCE AND ANALYSIS OF ITS DNA BINDING AND REPRESSIVE PROPERTIES^*

Sébastien Pinte, Nicolas Stankovic-Valentin, Sophie Deltour, Brian R. Rood¶, Cateline Guérardel, and Dominique Leprince||

From the CNRS UMR 8526, Institut de Biologie de Lille, Institut Pasteur de Lille, 1 Rue Calmette, Lille Cedex 59017, France, and the ^¶Division of Pediatric Hematology/Oncology, Children's National Medical Center, Washington, D. C. 20010

HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene located at chromosome 17p13.3, a region frequently hypermethylated or deleted in human tumors and in a contiguous-gene syndrome, the Miller-Dieker syndrome. HIC1 is a transcriptional repressor containing five Krüppel-like C₂H₂ zinc fingers and an N-terminal dimerization and autonomous repression domain called BTB/POZ. Although some of the HIC1 transcriptional repression mechanisms have been recently deciphered, target genes are still to be discovered. In this study, we determined the consensus binding sequence for HIC1 and investigated its DNA binding properties. Using a selection and amplification of binding sites technique, we identified the sequence 5'-^C/_GNG^C/_GGGGCA^C/_A CC-3' as an optimal binding site. In silico and functional analyses fully validated this consensus and highlighted a GGCA core motif bound by zinc fingers 3 and 4. The BTB/POZ domain inhibits the binding of HIC1 to a single site but mediates cooperative binding to a probe containing five concatemerized binding sites, a property shared by other BTB/POZ proteins. Finally, full-length HIC1 proteins transiently expressed in RK13 cells and more importantly, endogenous HIC1 proteins from the DAOY medulloblastoma cell line, repress the transcription of a reporter gene through their direct binding to these sites, as confirmed by chromatin immunoprecipitation experiments. The definition of the HIC1-specific DNA binding sequence as well as the requirement for multiple sites for optimal binding of the full-length protein are mandatory prerequisites for the identification and analyses of bona fide HIC1 target genes.

Received for publication, February 13, 2004 , and in revised form, June 8, 2004.

^* This work was supported by funds from CNRS, the Pasteur Institute, and the Association pour la Recherche contre le Cancer. 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.

Present address: Welcome Trust, University of Cambridge, Cambridge, United Kingdom.

^|| To whom correspondence should be addressed. Tel.: 33-3-2087-1119; Fax: 33-3-2087-1111; E-mail: dominique.leprince{at}ibl.fr.

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

This article has been cited by other articles:

				K. J. Briggs, I. M. Corcoran-Schwartz, W. Zhang, T. Harcke, W. L. Devereux, S. B. Baylin, C. G. Eberhart, and D. N. Watkins Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma Genes & Dev., March 15, 2008; 22(6): 770 - 785. [Abstract] [Full Text] [PDF]

				N. Stankovic-Valentin, S. Deltour, J. Seeler, S. Pinte, G. Vergoten, C. Guerardel, A. Dejean, and D. Leprince An Acetylation/Deacetylation-SUMOylation Switch through a Phylogenetically Conserved {psi}KXEP Motif in the Tumor Suppressor HIC1 Regulates Transcriptional Repression Activity Mol. Cell. Biol., April 1, 2007; 27(7): 2661 - 2675. [Abstract] [Full Text] [PDF]

				C. Hellerbrand, E. Bumes, F. Bataille, W. Dietmaier, R. Massoumi, and A. K. Bosserhoff Reduced expression of CYLD in human colon and hepatocellular carcinomas Carcinogenesis, January 1, 2007; 28(1): 21 - 27. [Abstract] [Full Text] [PDF]

				D. Arlt, W. Huber, U. Liebel, C. Schmidt, M. Majety, M. Sauermann, H. Rosenfelder, S. Bechtel, A. Mehrle, D. Bannasch, et al. Functional Profiling: From Microarrays via Cell-Based Assays to Novel Tumor Relevant Modulators of the Cell Cycle Cancer Res., September 1, 2005; 65(17): 7733 - 7742. [Abstract] [Full Text] [PDF]

				T. Morinaga, A. Enomoto, Y. Shimono, F. Hirose, N. Fukuda, A. Dambara, M. Jijiwa, K. Kawai, K. Hashimoto, M. Ichihara, et al. GDNF-inducible zinc finger protein 1 is a sequence-specific transcriptional repressor that binds to the HOXA10 gene regulatory region Nucleic Acids Res., July 26, 2005; 33(13): 4191 - 4201. [Abstract] [Full Text] [PDF]

				K. F. Kelly, A. A. Otchere, M. Graham, and J. M. Daniel Nuclear import of the BTB/POZ transcriptional regulator Kaiso J. Cell Sci., December 1, 2004; 117(25): 6143 - 6152. [Abstract] [Full Text] [PDF]