Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
TGF-BETA: MULTIFUNCTIONAL EFFECTOR AND RESPONSE PATTERNS ASSOCIATED WITH CARCINOGENESIS (MEETING ABSTRACT)
Proc Annu Meet Am Assoc Cancer Res; 33:A580-1 1992. Unique Identifier : AIDSLINE ICDB/92687914 Roberts AB; Kim SJ; Sporn MB; Lab. of Chemoprevention, NCI, Bethesda, MD 20892
Abstract:
The ability of TGF-beta to inhibit the growth of most epithelial and lymphoid cells suggests that one of the mechanisms whereby these cells undergo carcinogenic transformation and escape from normal growth control might involve an altered response to this negative regulator. Characterization of the response pattern to TGF-beta might be important both in staging cancers and in determination of an effective clinical approach. TGF-beta can act as an endogenous negative regulator of tumor cell growth and that loss of response to TGF-beta may contribute to tumor progression. Conversely, in transformed cells that have escaped from the negative growth regulatory effects of TGF-beta, studies show that the ability of the cells to synthesize and secrete elevated levels of TGF-beta may be a critical determinant of the ability of the tumor to grow progressively. The data suggest that expression of elevated levels of TGF-beta mRNA and protein by transformed cells which have become insensitive to growth regulation by TGF-beta, might serve to augment tumor growth indirectly by paracrine mechanisms targeted to stromal elements including fibroblasts, endothelial cells, and immune cells. TGF-beta secreted by tumor cells could also contribute to the desmoplastic response by stimulating formation of extracellular matrix by fibroblasts and enhance angiogenesis in the local environment of the tumor. Studies show that a variety of oncogenes including jun, fos, src, abl, and ras selectively enhance the activity of the TGF-beta 1 promoter. These oncogenes act both indirectly and directly to enhance promoter activity through binding sites for the AP-1 Jun/Fos complex located in both the first and second promoters of the TGF-beta 1 gene. Autoregulation of the promoter by TGF-beta 1 or induction of activity by phorbol esters is also mediated through these same sites. TGF-beta 1 expression is also transcriptionally activated in the lymphocytes of patients with adult T-cell leukemia. Studies using TGF-beta 1 promoter constructs have shown that the Tax transactivator protein of the HTLV-1 virus activates the TGF-beta 1 promoter, thus correlating with the observed increases in TGF-beta 1 mRNA. Attempts to identify intracellular mediators of inhibition of growth by TGF-beta have recently focused on possible mechanistic links between TGF-beta and the product (RB) of the retinoblastoma-susceptibility gene. We have shown that RB can regulate the activity of the promoter of the TGF-beta 1 gene negatively or positively, depending on the cell type, suggesting that the TGF-beta 1 gene might be one of the target genes controlled by RB. Moreover, the data have important implications for the mechanism of action of RB in suppression of cell growth, suggesting that its actions may, in part, be mediated by secretion of a negative regulator of growth. Recent data suggest that RB may also control expression of TGF-beta 2 and 3, possibly through different transcription factor binding sites. Investigations into links between the TGF-betas and the retinoid/steroid superfamily of nuclear receptors demonstrate that certain of the effects of these agents on inhibition of growth are mediated by the TGF-betas. Studies now ongoing in our laboratory are focussed at identifying specific translational control elements in the 5' untranslated regions of the TGF-beta 1 and 2 mRNAs that might be responsive to members of the retinoid/steroid superfamily. Since many epithelial and lymphoid cells remain sensitive to the growth suppressive effects of TGF-beta at early stages of carcinogenic progression, and since certain well differentiated tumor cells retain sensitivity to inhibition by TGF-beta, these observations have immediate implications for combination chemoprevention regimens to control the development of neoplasms and suggest that identification of new pharmacological agents that enhance the synthesis or activity of TGF-beta might be important in development of novel chemopreventive approaches. (14 Refs)
Keywords: Animal Breast Neoplasms/DRUG THERAPY Cell Differentiation/*DRUG EFFECTS Cell Division/*DRUG EFFECTS Fibroblasts/CYTOLOGY Gene Expression Gene Products, tax/GENETICS Genes, Retinoblastoma/PHYSIOLOGY HTLV-I/METABOLISM Keratinocytes/CYTOLOGY Leukemia, T-Cell/METABOLISM Lymphocytes/CYTOLOGY/DRUG EFFECTS Mice Mice, Nude Neoplasms/PATHOLOGY/*THERAPY Oncogene Proteins/GENETICS Promoter Regions (Genetics) Receptors, Cell Surface/METABOLISM RNA, Messenger/METABOLISM Tamoxifen/THERAPEUTIC USE Transcription, Genetic Transforming Growth Factor beta/GENETICS/METABOLISM/*PHARMACOLOGY Tretinoin/PHARMACOLOGY ABSTRACT 921230
M92C5370
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
