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Genes & Dev. 14 (13): 1605-1616

Copyright © 2000 by Cold Spring Harbor Laboratory Press.

Vol. 14, No. 13, pp. 1605-1616, July 1, 2000

A novel Smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction

Richard H. Kim,1 David Wang,1 Michael Tsang,2 Jennifer Martin,3,5 Carla Huff,1 Mark P. de Caestecker,1 W. Tony Parks,2 Xianwang Meng,3,5 Robert J. Lechleider,4 Tongwen Wang,3,5 and Anita B. Roberts2,6

1 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892 USA; 2 Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, Bethesda, Maryland 20892 USA; 3 Department of Surgery, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114 USA

Members of the transforming growth factor-beta superfamily play critical roles in controlling cell growth and differentiation. Effects of TGF-beta family ligands are mediated by Smad proteins. To understand the mechanism of Smad function, we sought to identify novel interactors of Smads by use of a yeast two-hybrid system. A 396-amino acid nuclear protein termed SNIP1 was cloned and shown to harbor a nuclear localization signal (NLS) and a Forkhead-associated (FHA) domain. The carboxyl terminus of SNIP1 interacts with Smad1 and Smad2 in yeast two-hybrid as well as in mammalian overexpression systems. However, the amino terminus of SNIP1 harbors binding sites for both Smad4 and the coactivator CBP/p300. Interaction between endogenous levels of SNIP1 and Smad4 or CBP/p300 is detected in NMuMg cells as well as in vitro. Overexpression of full-length SNIP1 or its amino terminus is sufficient to inhibit multiple gene responses to TGF-beta and CBP/p300, as well as the formation of a Smad4/p300 complex. Studies in Xenopus laevis further suggest that SNIP1 plays a role in regulating dorsomedial mesoderm formation by the TGF-beta family member nodal. Thus, SNIP1 is a nuclear inhibitor of CBP/p300 and its level of expression in specific cell types has important physiological consequences by setting a threshold for TGF-beta -induced transcriptional activation involving CBP/p300.

[Key Words: TGF-beta ; Smad; CBP/p300; signal transduction; transcriptional suppression]

Present addresses: 4Department of Pharmacology, Uniformed Services University of Health Sciences, Bethesda, MD 20814-4799 USA; 5Virginia Mason Research Center, Seattle, WA 98101 USA.

6 Corresponding author.

GENES & DEVELOPMENT 14:1605-1616 © 2000 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/00 $5.00

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