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Molecular and Cellular Biology, October 2008, p. 6358-6372, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00333-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Effects of the SANT Domain of Tension-Induced/Inhibited Proteins (TIPs), Novel Partners of the Histone Acetyltransferase p300, on p300 Activity and TIP-6-Induced Adipogenesis {triangledown}

Kameswara Rao Badri, Yuanxiang Zhou, Urmil Dhru, Sreelatha Aramgam, and Lucia Schuger*

Department of Pathology, Wayne State University, School of Medicine, Detroit, Michigan 48201

Received 27 February 2008/ Returned for modification 8 May 2008/ Accepted 4 August 2008

We previously identified a set of transcription regulators, referred to as TIPs (tension-induced/inhibited proteins), with a role in myogenic versus adipogenic differentiation. Here we report that the TIP family comprises eight isoforms, all bearing a SANT (switching-defective protein 3, adaptor 2, nuclear receptor corepressor, and transcription factor IIIB) domain and some of them presenting S-adenosyl-L-methionine (SAM) and nuclear receptor box (NRB) motifs, all characteristic of histone-modifying enzymatic complexes. TIPs have SANT-dependent, p300-mediated histone acetyltransferase (HAT) activity. Ectopic TIP-6 (SANT+ SAM– NRB–) but not TIP-6{Delta}SANT induced de novo PPAR{gamma}2-mediated adipogenic gene expression in NIH 3T3 cells and promoted preadipocyte differentiation into fat cells. TIP-6 was also involved in mediating hormonally/biochemically induced adipogenic differentiation of 3T3-L1 cells. Furthermore, TIP-6 was identified in adipose tissue in vivo. TIP-6 bound directly and indirectly to p300 and histone H4 (H4). Deletion of the SANT domain did not abolish TIP-6 interaction with p300 and H4 but eliminated direct TIP-6 binding to p300. Chromatin immunoprecipitation assays showed the recruitment of TIP-6, TIP-6{Delta}SANT, and p300 to the PPAR{gamma}2 promoter, but H3/H4 acetylation occurred only when p300 was directly associated with TIP-6. These studies demonstrated the importance of TIPs in the recruitment of p300 to specific promoters and in the regulation of p300 HAT activity through the involvement of the SANT domain. Furthermore, we identified TIP-6 as a new member of the adipogenic cascade.

* Corresponding author. Mailing address: Department of Pathology, Wayne State University, School of Medicine, 540 E. Canfield Street, Detroit, MI 48201. Phone: (313) 577-5651. Fax: (313) 577-0057. E-mail: lschuger{at}med.wayne.edu

{triangledown} Published ahead of print on 18 August 2008.

Molecular and Cellular Biology, October 2008, p. 6358-6372, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00333-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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