A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction.
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.
Kim
R H
RH
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892, USA.
Wang
D
D
Tsang
M
M
Martin
J
J
Huff
C
C
de Caestecker
M P
MP
Parks
W T
WT
Meng
X
X
Lechleider
R J
RJ
Wang
T
T
Roberts
A B
AB
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D003001:Cloning, Molecular; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D014982:Xenopus laevis
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C411545:SNIP1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta