These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: TGF-beta 1-induced PAI-1 expression is E box/USF-dependent and requires EGFR signaling.
    Author: Kutz SM, Higgins CE, Samarakoon R, Higgins SP, Allen RR, Qi L, Higgins PJ.
    Journal: Exp Cell Res; 2006 Apr 15; 312(7):1093-105. PubMed ID: 16457817.
    Abstract:
    Transforming growth factor-beta1 (TGF-beta1) transcriptionally regulates the expression of genes that encode specific proteins (e.g., plasminogen activator inhibitor-1; PAI-1) important in stromal remodeling and cellular invasion. Definition of molecular events underlying TGF-beta1-initiated PAI-1 transcription, therefore, may lead to the identification of new therapeutic targets for diseases associated with elevated PAI-1 synthesis (e.g., tissue fibrosis, vascular disorders, tumor progression). An intact upstream stimulatory factor (USF)-binding E box motif (5'-(-165)CACGTG(-160)-3') at the HRE-2 site in the rat PAI-1 gene was required for PAI-1 transcription in TGF-beta1-treated cells. Mutation of the CA dinucleotide to TC at position -165/-164 in a reporter construct driven by 764 bp of PAI-1 promoter sequence decreased TGF-beta1-dependent CAT activity by >80% indicating the necessity for a consensus hexanucleotide E box motif in induced expression. The same CA --> TC substitution eliminated USF binding to an 18-bp HRE-2 DNA target highlighting the importance of site occupancy to transcriptional activation. Transfection of a dominant-negative USF construct, moreover, completely inhibited formation of USF/HRE-2 probe complexes, attenuated PAI-1 promoter-driven luciferase activity and reduced the response of the endogenous PAI-1 gene to TGF-beta1 (to that approximating quiescent controls). Maximal immediate-early PAI-1 induction upon exposure to TGF-beta1 required EGFR, p21ras, MEK and pp60(c-src) signaling as pharmacologic or dominant-negative inhibition of any of the four intermediates (EGFR, p21ras, MEK, pp60(c-src)) virtually eliminated TGF-beta1-augmented PAI-1 levels. U0126 titering experiments, furthermore, revealed that the same MEK inhibitor concentration that blocked the TGF-beta1 increase in ERK1/2 phosphorylation (20 microM) also effectively attenuated the PAI-1 inductive response suggesting a requirement for stimulated ERK signaling in TGF-beta1-mediated PAI-1 expression. These data suggest a model whereby TGF-beta1 activates a complex signaling cascade to affect PAI-1 gene control and involves USF occupancy of a critical E box motif at the HRE-2 site in the PAI-1 gene.
    [Abstract] [Full Text] [Related] [New Search]