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Molecular and Cellular Biology, June 2002, p. 4334-4345, Vol. 22, No. 12
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.12.4334-4345.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

RGS12TS-S Localizes at Nuclear Matrix-Associated Subnuclear Structures and Represses Transcription: Structural Requirements for Subnuclear Targeting and Transcriptional Repression

Tapan K. Chatterjee and Rory A. Fisher*

Department of Pharmacology, University of Iowa College of Medicine, Iowa City, Iowa 52242

Received 24 May 2001/ Returned for modification 30 July 2001/ Accepted 12 March 2002

RGS12TS-S, an 1,157-amino-acid RGS protein (regulator of G protein signaling), is a nuclear protein that exhibits a unique pattern of subnuclear organization into nuclear foci or dots when expressed endogenously or ectopically. We now report that RGS12TS-S is a nuclear matrix protein and identify structural determinants that target this protein to the nuclear matrix and to discrete subnuclear sites. We also determine the relationship between RGS12TS-S-decorated nuclear dots and known subnuclear domains involved in control of gene expression and provide the first evidence that RGS12TS-S is functionally involved in the regulation of transcription and cell cycle events. A novel nuclear matrix-targeting sequence was identified that is distinct from a second novel motif needed for targeting RGS12TS-S to nuclear dots. RGS12TS-S nuclear dots were distinct from Cajal bodies, SC-35 domains, promyelocytic leukemia protein nuclear bodies, Polycomb group domains, and DNA replication sites. However, RGS12TS-S inhibited S-phase DNA synthesis in various tumor cell lines independently of Rb and p53 proteins, and its prolonged expression promoted formation of multinucleated cells. Expression of RGS12TS-S dramatically reduced bromo-UTP incorporation into sites of transcription. RGS12TS-S, when tethered to a Gal4 DNA binding domain, dramatically inhibited basal transcription from a Gal4-E1b TATA promoter in a histone deacetylase-independent manner. Structural analysis revealed a role for the unique N-terminal domain of RGS12TS-S in its transcriptional repressor and cell cycle-regulating activities and showed that the RGS domain was dispensable for these functions. These results provide novel insights into the structure and function of RGS12TS-S in the nucleus and demonstrate that RGS12TS-S possesses biological activities distinct from those of other members of the RGS protein family.

* Corresponding author. Mailing address: Department of Pharmacology, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 335-8330. Fax: (319) 335-8930. E-mail: rory-fisher{at}uiowa.edu.

Molecular and Cellular Biology, June 2002, p. 4334-4345, Vol. 22, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.12.4334-4345.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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