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Published 29 March 2004. doi:10.1083/jcb.200301106
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 7, 985-996
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Article

The p75NTR-interacting protein SC1 inhibits cell cycle progression by transcriptional repression of cyclin E

Alexandra Chittka1, Juan Carlos Arevalo2, Maria Rodriguez-Guzman1, Pilar Pérez3, Moses V. Chao2, and Michael Sendtner1

1 Institute for Clinical Neurobiology, University of Würzburg, 97080 Würzburg, Germany
2 Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016
3 Instituto de Microbiologia Bioquimica, CSIC/Departamento de Microbiologia y Genetica, Universidad de Salamanca, 37007 Salamanca, Spain

Address correspondence to Alexandra Chittka at her present address, Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Tel.: (44) 20-7679-3365. Fax: (44) 20-7679-2091. email: a.chittka{at}ich.ucl.ac.uk

Schwann cell factor 1 (SC1), a p75 neurotrophin receptor–interacting protein, is a member of the positive regulatory/suppressor of variegation, enhancer of zeste, trithorax (PR/SET) domain-containing zinc finger protein family, and it has been shown to be regulated by serum and neurotrophins. SC1 shows a differential cytoplasmic and nuclear distribution, and its presence in the nucleus correlates strongly with the absence of bromodeoxyuridine (BrdU) in these nuclei. Here, we investigated potential transcriptional activities of SC1 and analyzed the function of its various domains. We show that SC1 acts as a transcriptional repressor when it is tethered to Gal4 DNA-binding domain. The repressive activity requires a trichostatin A–sensitive histone deacetylase (HDAC) activity, and SC1 is found in a complex with HDACs 1, 2, and 3. Transcriptional repression exerted by SC1 requires the presence of its zinc finger domains and the PR domain. Additionally, these two domains are involved in the efficient block of BrdU incorporation by SC1. The zinc finger domains are also necessary to direct SC1's nuclear localization. Lastly, SC1 represses the promoter of a promitotic gene, cyclin E, suggesting a mechanism for how growth arrest is regulated by SC1.

Key Words: p75NTR; cell cycle; HDAC; transcriptional repressor; PR/SET domains


Abbreviations used in this paper: DBD, DNA-binding domain; HDAC, histone deacetylase; NTR, neurotrophin receptor; PR/SET, positive regulatory/suppressor of variegation, enhancer of zeste, trithorax; RIZ, retinoblastoma-interacting zinc finger; SC1, Schwann cell factor 1; siRNA, small interfering RNA; TSA, trichostatin A.


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