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Molecular and Cellular Biology, September 2003, p. 6373-6384, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6373-6384.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Human I-mfa Domain-Containing Protein, HIC, Interacts with Cyclin T1 and Modulates P-TEFb-Dependent Transcription

Tara M. Young,1,2 Qi Wang,1,2 Tsafi Pe'ery,1,2,3 and Michael B. Mathews1,2*

Departments of Biochemistry and Molecular Biology,1 Medicine, New Jersey Medical School,3 Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07013-27142

Received 22 November 2002/ Returned for modification 21 January 2003/ Accepted 27 May 2003

Positive transcription elongation factor b (P-TEFb) hyperphosphorylates the carboxy-terminal domain of RNA polymerase II, permitting productive transcriptional elongation. The cyclin T1 subunit of P-TEFb engages cellular transcription factors as well as the human immunodeficiency virus type 1 (HIV-1) transactivator Tat. To identify potential P-TEFb regulators, we conducted a yeast two-hybrid screen with cyclin T1 as bait. Among the proteins isolated was the human I-mfa domain-containing protein (HIC). HIC has been reported to modulate expression from both cellular and viral promoters via its C-terminal cysteine-rich domain, which is similar to the inhibitor of MyoD family a (I-mfa) protein. We show that HIC binds cyclin T1 in yeast and mammalian cells and that it interacts with intact P-TEFb in mammalian cell extracts. The interaction involves the I-mfa domain of HIC and the regulatory histidine-rich region of cyclin T1. HIC also binds Tat via its I-mfa domain, although the sequence requirements are different. HIC colocalizes with cyclin T1 in nuclear speckle regions and with Tat in the nucleolus. Expression of the HIC cDNA modulates Tat transactivation of the HIV-1 long terminal repeat (LTR) in a cell type-specific fashion. It is mildly inhibitory in CEM cells but stimulates gene expression in HeLa, COS, and NIH 3T3 cells. The isolated I-mfa domain acts as a dominant negative inhibitor. Activation of the HIV-1 LTR by HIC in NIH 3T3 cells occurs at the RNA level and is mediated by direct interactions with P-TEFb.

* Corresponding author. Mailing address: UMDNJ-New Jersey Medical School, 185 South Orange Ave., P.O. Box 1709, Newark, NJ 07101-1709. Phone: (973) 972-4411. Fax: (973) 972-5594. E-mail: mathews{at}umdnj.edu.

Molecular and Cellular Biology, September 2003, p. 6373-6384, Vol. 23, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.18.6373-6384.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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