Overlapping pathways mediate the opposing actions of tumor necrosis factor-alpha and transforming growth factor-beta on alpha 2(I) collagen gene transcription.

TitleOverlapping pathways mediate the opposing actions of tumor necrosis factor-alpha and transforming growth factor-beta on alpha 2(I) collagen gene transcription.
Publication TypeJournal Article
Year of Publication1995
AuthorsInagaki Y, Truter S, Tanaka S, Di Liberto M, Ramirez F
JournalJ Biol Chem
Volume270
Issue7
Pagination3353-8
Date Published1995 Feb 17
ISSN0021-9258
KeywordsBase Sequence, Binding Sites, Cell Line, Chloramphenicol O-Acetyltransferase, Collagen, Gene Expression, Humans, Molecular Sequence Data, Oligonucleotide Probes, Regulatory Sequences, Nucleic Acid, Restriction Mapping, Skin, Sp1 Transcription Factor, Transcription, Genetic, Transfection, Transforming Growth Factor beta, Tumor Necrosis Factor-alpha
Abstract

Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) are multifunctional peptides intimately involved in the process of extracellular matrix remodeling. We recently showed that TGF-beta stimulates the human alpha 2(I) collagen gene by increasing the affinity of an Sp1-containing transcriptional complex bound to an upstream sequence termed the TbRE (Inagaki, Y., Truter, S. and Ramirez, F. (1994) J. Biol. Chem. 269, 14828-14834). Here, we report that the TbRE-bound complex also mediates the inhibitory signal of TNF-alpha. Nuclear proteins from cells treated with TNF-alpha bind to the TbRE sequence substantially more strongly than those from untreated cells. Additionally, TNF-alpha increases binding of a second protein complex that recognizes the negatively cis-acting element located immediately next to the TbRE. Thus, we postulate that TNF-alpha counteracts the TGF-beta-elicited stimulation of collagen gene expression through overlapping nuclear signaling pathways. One modifies the TGF-beta-targeted transcriptional complex, probably by reducing its stimulatory effect on collagen transcription. The other acts on the binding of the adjacent factor, presumably by increasing its effectiveness in repressing the activity of the collagen promoter. The convergence of the TGF-beta and TNF-alpha pathways on the same sequence of the alpha 2(I) collagen promoter is yet another example of combinatorial gene regulation achieved through composite response elements.

DOI10.1074/jbc.270.7.3353
Alternate JournalJ Biol Chem
PubMed ID7852421
Grant ListAR-38648 / AR / NIAMS NIH HHS / United States
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Maurizio DiLiberto, Ph.D.

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