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

doi:10.1128/MCB.21.15.5041-5049.2001

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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 thepromoters of a large number of genes essential for mammalian cellhomeostasis. Here we report that TIEG2, a transforming growthfactor $beta$ -inducible Sp1-like protein with antiproliferative functions,represses transcription through recruitment of the mSin3A-histonedeacetylase complex. The interaction of TIEG2 with mSin3A is mediatedby an alpha-helical repression motif ( $alpha$ -HRM) located within therepression domain (R1) of TIEG2. This $alpha$ -HRM specifically associateswith the second paired amphipathic helix (PAH2) domain of mSin3A.Mutations in the TIEG2 $alpha$ -HRM domain that disrupt its helical structureabolish its ability to both bind mSin3A and repress transcription.Interestingly, the $alpha$ -HRM is conserved in both the TIEG (TIEG1and TIEG2) and BTEB (BTEB1, BTEB3, and BTEB4) subfamilies of Sp1-likeproteins. The $alpha$ -HRM from these proteins also mediates direct interactionwith mSin3A and represses transcription. Surprisingly, we foundthat the $alpha$ -HRM of the Sp1-like proteins characterized here exhibitsstructural and functional resemblance to the Sin3A-interactingdomain previously described for the basic helix-loop-helix proteinMad1. Thus, our study defines a mechanism of transcriptional repressionvia the interactions of the $alpha$ -HRM with the Sin3-histone deacetylasecomplex that is utilized by at least five Sp1-like transcriptionalfactors. More importantly, we demonstrate that a helical repressionmotif which mediates Sin3 interaction is not an exclusive structuraland functional characteristic of the Mad1 subfamily but ratherhas a wider functional impact on transcriptional repression thanpreviouslydemonstrated.

^* 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.

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

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