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Cited by 287TGF-β signaling in diseasesGenomics and Chromatin DynamicsDevelopmental Biology and Gene Regulation

Direct Binding of Smad1 and Smad4 to Two Distinct Motifs Mediates Bone Morphogenetic Protein-specific Transcriptional Activation ofId1 Gene

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López-Rovira, Teresa, Chalaux, Elisabet, Massagué, Joan, Rosa, Jose Luis, Ventura, Francesc·2002·Journal of Biological Chemistry
DOI 10.1074/jbc.m106826200
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Abstract

Bone morphogenetic proteins (BMPs) are potent inhibitors of myoblast differentiation and inducers of bone formation both in vivo and in vitro. Expression of Id1, a negative regulator of basic helix-loop-helix transcription factors, is up-regulated by BMPs and contributes to the antimyogenic effects of this family of cytokines. In this report, we have identified a specific BMP-2 immediate early response enhancer in the human Id1 gene. Transcriptional activation of the enhancer was increased by overexpression of BMP-responsive Smads, and Smad4 and was completely abrogated in Smad4-deficient cells. Deletion analysis demonstrates that the responsive region is composed of two separate DNA binding elements, a set of overlapping GC boxes, which bind BMP-regulated Smads upon BMP stimulation, and three repeats of CAGAC boxes. Gel shift and oligonucleotide pull-down assays demonstrated that these two types of motifs were capable of binding their corresponding Smads. However, deletion or mutation of either DNA binding element was nonadditive, since disruption of either GC or CAGAC boxes resulted in complete or severe loss of BMP-2 responsiveness. These data suggest the simultaneous requirement of two independent DNA binding elements to allow functional cooperativity of BMP-regulated Smads and Smad4 in BMP-activated gene promoters.

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  • SMAD1 has been reported to repress Lgr5+ stem cell signature genes, thereby limiting stem cell expansion and maintaining intestinal homeostasis.

    “As a major receptor-activated SMADs (R-SMADs) downstream of BMP pathway, SMAD1 has been reported to repress Lgr5+ stem cell signature genes, thereby limiting stem cell expansion and maintaining intestinal homeostasis.50–52”

    From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [51]

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Authors
López-Rovira, T., Chalaux, E., Massagué, J., Rosa, J. L., & Ventura, F.
Affiliations
  • Universitat de Barcelona (ES)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Ventura, Francesc
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2002-02
Volume
277
Issue
5
Pages
3176-3185
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m106826200
OpenAlex
W1994377715
Cited by
285
References
59
Citations by year
2026: 3 · 2025: 5 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 10 · 2019: 12 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 11 · 2014: 15 · 2013: 16 · 2012: 15
FWCI
7.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
Smad1, SMAD4, bone morphogenetic proteins, BMP-2, transcriptional activation, enhancers, Sp1 binding site, DNA-binding motifs, myogenesis, bHLH transcription factors, gene expression regulation
MeSH terms
Animals, Binding Sites, Cell Line, Cloning, Molecular, DNA-Binding Proteins, Gene Expression Regulation, Kinetics, Luciferases, Promoter Regions, Genetic, Recombinant Proteins, Repressor Proteins, Transcription Factors, Transfection, Signal Transduction, Transcriptional Activation, Trans-Activators, Transforming Growth Factor beta, Genes, Reporter, Helix-Loop-Helix Motifs, Bone Morphogenetic Proteins, Smad Proteins, Inhibitor of Differentiation Protein 1, Bone Morphogenetic Protein 2

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