Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.
TGF-BETA: ALTERED TRANSCRIPTIONAL CONTROL AND RESPONSE PATTERNS ASSOCIATED WITH CARCINOGENESIS (MEETING ABSTRACT)
Proc Annu Meet Am Assoc Cancer Res; 32:454-5 1991. Unique Identifier : AIDSLINE ICDB/91676639 Roberts AB; Kim SJ; Wakefield LM; Glick AB; Sporn MB; Lab. of Chemoprevention, NCI, Bethesda, MD 20892
Abstract:
Transforming growth factor beta (TGF beta) can inhibit epithelial and lymphoid cell proliferation, stimulate chemotaxis and regulate synthesis and degradation of extracellular matrix. Many transformed cell lines do not respond to TGF beta although they may express higher levels of the mRNA and protein product than their normal counterparts. Inhibitory effects of retinoic acid on cell growth may be mediated through TGF beta whose expression it is able to induce in epithelial tissues. This induction is at a post-transcriptional level. Studies have suggested that there is a mechanistic link between TGF beta and the product of the retinoblastoma susceptibility gene (RB-1), which is inactivated in many human cancers. The gene product Rb has properties of a cell cycle regulatory factor, and TGF beta might control the phosphorylation state of Rb which itself might mediate the downregulation of c-myc resulting from TGF beta action. Since TGF beta can act on cells lacking RB, the latter is not an obligatory intermediate. The c-fos gene contains an Rb responsive element (RCE) in its promoter, and it has been found that several RCE-like elements occur in the 5' regulatory regions of each of three TGF-beta genes. A portion of the TGF beta promoter containing two RCE-like elements can mediate Rb action. Cotransfection of cells with an Rb-expression vector either upregulates or downregulates the activity of the TGF beta 1 promoter constructs depending on the cell type. Autoregulation of the promoter by TGF beta 1 or induction of activity by phorbol ester is mediated through binding sites for the AP-1 Jun/Fos complex and is dependent on levels of both these proto-oncogenes. Both TGF beta and Jun also activate the jun promoter via AP-1 sites. Aberrant expression of either could lead to amplification of both. In transformed mesenchymal and myeloid cells, the ras, and abl and src oncogenes, respectively, equally upregulate TGF beta first and second promoters. In human adult T-cell leukemia, the tax transactivator protein of the causative HTLV-1 virus activates TGF beta 1 promoter, leading to increase in TGF beta 1 mRNA. Similar findings are obtained in transgenic mice, and TGF beta 1 also markedly stimulates expression of the tax gene; these processes may play a role in development of neurofibroma-like tumors in these mice. (19 Refs)
Keywords: Animal Cell Line, Transformed Cell Transformation, Neoplastic/*GENETICS *Cloning, Molecular Genes, pX/GENETICS Human Leukemia-Lymphoma, T-Cell, Acute, HTLV-I-Associated/GENETICS Mice Mice, Transgenic Promoter Regions (Genetics)/GENETICS Transcription, Genetic/*GENETICS Transforming Growth Factor beta/*GENETICS/PHYSIOLOGY ABSTRACT 911030
M91A1118
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Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.
