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Molecular and Cellular Biology, August 2001, p. 5041-5049, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5041-5049.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

A Conserved alpha -Helical Motif Mediates the Interaction of Sp1-Like Transcriptional Repressors with the Corepressor mSin3A

Jin-San Zhang,1 Martin C. Moncrieffe,2 Joanna Kaczynski,1 Volker Ellenrieder,1 Franklyn G. Prendergast,2 and Raul Urrutia1,2,3,*

Gastroenterology Research Unit,1 Tumor Biology Program,3 and Department of Biochemistry and Molecular Biology,2 Mayo Clinic, Rochester, Minnesota 55901

Received 26 February 2000/Returned for modification 30 March 2001/Accepted 9 May 2001

Sp1-like proteins are defined by three highly homologous C2H2 zinc finger motifs that bind GC-rich sequences found in the promoters of a large number of genes essential for mammalian cell homeostasis. Here we report that TIEG2, a transforming growth factor beta -inducible Sp1-like protein with antiproliferative functions, represses transcription through recruitment of the mSin3A-histone deacetylase complex. The interaction of TIEG2 with mSin3A is mediated by an alpha-helical repression motif (alpha -HRM) located within the repression domain (R1) of TIEG2. This alpha -HRM specifically associates with the second paired amphipathic helix (PAH2) domain of mSin3A. Mutations in the TIEG2 alpha -HRM domain that disrupt its helical structure abolish its ability to both bind mSin3A and repress transcription. Interestingly, the alpha -HRM is conserved in both the TIEG (TIEG1 and TIEG2) and BTEB (BTEB1, BTEB3, and BTEB4) subfamilies of Sp1-like proteins. The alpha -HRM from these proteins also mediates direct interaction with mSin3A and represses transcription. Surprisingly, we found that the alpha -HRM of the Sp1-like proteins characterized here exhibits structural and functional resemblance to the Sin3A-interacting domain previously described for the basic helix-loop-helix protein Mad1. Thus, our study defines a mechanism of transcriptional repression via the interactions of the alpha -HRM with the Sin3-histone deacetylase complex that is utilized by at least five Sp1-like transcriptional factors. More importantly, we demonstrate that a helical repression motif which mediates Sin3 interaction is not an exclusive structural and functional characteristic of the Mad1 subfamily but rather has a wider functional impact on transcriptional repression than previously demonstrated.

* Corresponding author. Mailing address: GI Research Unit, Alfred 2-435, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Phone: (507) 284-7500. Fax: (507) 255-6318. E-mail: urrutia.raul{at}mayo.edu.

Molecular and Cellular Biology, August 2001, p. 5041-5049, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5041-5049.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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