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Volume 271, Number 47, Issue of November 22, 1996 pp. 29672-29681
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Antagonistic Regulation of a Proline-rich Transcription Factor by Transforming Growth Factor  and Tumor Necrosis Factor

(Received for publication, January 29, 1996, and in revised form, September 10, 1996)

From the Institute of Animal Biology, University of Lausanne, CH-1015 Lausanne, Switzerland

Transforming growth factor  (TGF-) and tumor necrosis factor  (TNF-) often exhibit antagonistic actions on the regulation of various activities such as immune responses, cell growth, and gene expression. However, the molecular mechanisms involved in the mutually opposing effects of TGF- and TNF- are unknown. Here, we report that binding sites for the transcription factor CTF/NF-I mediate antagonistic TGF- and TNF- transcriptional regulation in NIH3T3 fibroblasts. TGF- induces the proline-rich transactivation domain of specific CTF/NF-I family members, such as CTF-1, whereas TNF- represses both the uninduced as well as the TGF--induced CTF-1 transcriptional activity. CTF-1 is thus the first transcription factor reported to be repressed by TNF-. The previously identified TGF--responsive domain in the proline-rich transcriptional activation sequence of CTF-1 mediates both transcriptional induction and repression by the two growth factors. Analysis of potential signal transduction intermediates does not support a role for known mediators of TNF- action, such as arachidonic acid, in CTF-1 regulation. However, overexpression of oncogenic forms of the small GTPase Ras or of the Raf-1 kinase represses CTF-1 transcriptional activity, as does TNF-. Furthermore, TNF- is unable to repress CTF-1 activity in NIH3T3 cells overexpressing ras or raf, suggesting that TNF- regulates CTF-1 by a Ras-Raf kinase-dependent pathway. Mutagenesis studies demonstrated that the CTF-1 TGF--responsive domain is not the primary target of regulatory phosphorylations. Interestingly, however, the domain mediating TGF- and TNF- antagonistic regulation overlapped precisely the previously identified histone H3 interaction domain of CTF-1. These results identify CTF-1 as a molecular target of mutually antagonistic TGF- and TNF- regulation, and they further suggest a molecular mechanism for the opposing effects of these growth factors on gene expression.

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