A novel Smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-β signal transduction
- Richard H. Kim1,
- David Wang1,
- Michael Tsang2,
- Jennifer Martin3,5,
- Carla Huff1,
- Mark P. de Caestecker1,
- W. Tony Parks2,
- Xianwang Meng3,5,
- Robert J. Lechleider4,
- Tongwen Wang3,5, and
- Anita B. Roberts2,6
- 1Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892 USA; 2Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, Bethesda, Maryland 20892 USA; 3Department of Surgery, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114 USA
Abstract
Members of the transforming growth factor-β superfamily play critical roles in controlling cell growth and differentiation. Effects of TGF-β 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-β and CBP/p300, as well as the formation of a Smad4/p300 complex. Studies in Xenopus laevisfurther suggest that SNIP1 plays a role in regulating dorsomedial mesoderm formation by the TGF-β 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-β-induced transcriptional activation involving CBP/p300.
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Footnotes
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Present addresses: 4Department of Pharmacology, Uniformed Services University of Health Sciences, Bethesda, MD 20814-4799 USA; 5Virginia Mason Research Center, Seattle, WA 98101 USA.
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↵6 Corresponding author.
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E-MAIL Robertsa{at}dce41.nci.nih.gov; FAX (301) 496-8395.
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- Received March 28, 2000.
- Accepted May 15, 2000.
- Cold Spring Harbor Laboratory Press
