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Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.
EMBO J. 1998 Jun 01; 17(11):3091-100.EJ

Abstract

Smad proteins play a key role in the intracellular signalling of transforming growth factor beta (TGF beta), which elicits a large variety of cellular responses. Upon TGF beta receptor activation, Smad2 and Smad3 become phosphorylated and form heteromeric complexes with Smad4. These complexes translocate to the nucleus where they control expression of target genes. However, the mechanism by which Smads mediate transcriptional regulation is largely unknown. Human plasminogen activator inhibitor-1 (PAI-1) is a gene that is potently induced by TGF beta. Here we report the identification of Smad3/Smad4 binding sequences, termed CAGA boxes, within the promoter of the human PAI-1 gene. The CAGA boxes confer TGF beta and activin, but not bone morphogenetic protein (BMP) stimulation to a heterologous promoter reporter construct. Importantly, mutation of the three CAGA boxes present in the PAI-1 promoter was found to abolish TGF beta responsiveness. Thus, CAGA elements are essential and sufficient for the induction by TGF beta. In addition, TGFbeta induces the binding of a Smad3/Smad4-containing nuclear complex to CAGA boxes. Furthermore, bacterially expressed Smad3 and Smad4 proteins, but not Smad1 nor Smad2 protein, bind directly to this sequence in vitro. The presence of this box in TGF beta-responsive regions of several other genes suggests that this may be a widely used motif in TGF beta-regulated transcription.

Authors+Show Affiliations

Laboratoire Glaxo Wellcome, 25 avenue de Québec, 91951 Les Ulis Cedex, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9606191

Citation

Dennler, S, et al. "Direct Binding of Smad3 and Smad4 to Critical TGF Beta-inducible Elements in the Promoter of Human Plasminogen Activator Inhibitor-type 1 Gene." The EMBO Journal, vol. 17, no. 11, 1998, pp. 3091-100.
Dennler S, Itoh S, Vivien D, et al. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J. 1998;17(11):3091-100.
Dennler, S., Itoh, S., Vivien, D., ten Dijke, P., Huet, S., & Gauthier, J. M. (1998). Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. The EMBO Journal, 17(11), 3091-100.
Dennler S, et al. Direct Binding of Smad3 and Smad4 to Critical TGF Beta-inducible Elements in the Promoter of Human Plasminogen Activator Inhibitor-type 1 Gene. EMBO J. 1998 Jun 1;17(11):3091-100. PubMed PMID: 9606191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. AU - Dennler,S, AU - Itoh,S, AU - Vivien,D, AU - ten Dijke,P, AU - Huet,S, AU - Gauthier,J M, PY - 1998/6/26/pubmed PY - 1998/6/26/medline PY - 1998/6/26/entrez SP - 3091 EP - 100 JF - The EMBO journal JO - EMBO J VL - 17 IS - 11 N2 - Smad proteins play a key role in the intracellular signalling of transforming growth factor beta (TGF beta), which elicits a large variety of cellular responses. Upon TGF beta receptor activation, Smad2 and Smad3 become phosphorylated and form heteromeric complexes with Smad4. These complexes translocate to the nucleus where they control expression of target genes. However, the mechanism by which Smads mediate transcriptional regulation is largely unknown. Human plasminogen activator inhibitor-1 (PAI-1) is a gene that is potently induced by TGF beta. Here we report the identification of Smad3/Smad4 binding sequences, termed CAGA boxes, within the promoter of the human PAI-1 gene. The CAGA boxes confer TGF beta and activin, but not bone morphogenetic protein (BMP) stimulation to a heterologous promoter reporter construct. Importantly, mutation of the three CAGA boxes present in the PAI-1 promoter was found to abolish TGF beta responsiveness. Thus, CAGA elements are essential and sufficient for the induction by TGF beta. In addition, TGFbeta induces the binding of a Smad3/Smad4-containing nuclear complex to CAGA boxes. Furthermore, bacterially expressed Smad3 and Smad4 proteins, but not Smad1 nor Smad2 protein, bind directly to this sequence in vitro. The presence of this box in TGF beta-responsive regions of several other genes suggests that this may be a widely used motif in TGF beta-regulated transcription. SN - 0261-4189 UR - https://www.unboundmedicine.com/medline/citation/9606191/Direct_binding_of_Smad3_and_Smad4_to_critical_TGF_beta_inducible_elements_in_the_promoter_of_human_plasminogen_activator_inhibitor_type_1_gene_ L2 - https://doi.org/10.1093/emboj/17.11.3091 DB - PRIME DP - Unbound Medicine ER -