A novel growth inhibitor of the TGF-beta-family has been cloned and sequenced from human placental cDNA; the new form is designated TGF-beta-3. TGF-betas are secreted as inactive precursor molecules, that are subsequently proteolytically cleaved to yield biologically active mature dimers of 25 KDa. The precursor regions of TGF-beta-1 and TGF-beta-3 contain an RGD sequence. TGF-betas influence the proliferation and differentiation processes of cells, and specifically demonstrate potent growth inhibitory activity on many cell types, especially carcinomas. Preliminary experiments showed that TGF-beta-3 exhibited at least 10 fold greater growth inhibitory activity on cells, including a human lung carcinoma. Recently, different functions, partially mediated through specific receptors have been demonstrated for TGF-beta-1 and TGF-beta-2. Since TGF-beta-3 is a newly discovered protein its distribution, functions, and receptor binding characteristics are unknown. Anti- sera will be raised to synthetic peptides of both the precursor and mature forms of TGF-beta-3. Non-cross-reacting anti-peptide IgG will be used analytically to screen normal and neoplastic cells and tissues for TGF-beta-3 by immunofluorescence. Immunoprecipitation and immunoaffinity chromatographic techniques will be employed to quantitate and purify mature TGF-beta-3 and the precursor form of TGF-beta-1 and TGF-beta-3 from cells and tissues. Purified TGF- beta-3 will be used to quantitate its specific activity in various TGF-beta specific functions and to identify and characterize its receptor binding entities on the cell surface. By stimulating the production of certain components of the extracellular matrix (ECM) such as fibronectin (Fn) and collagen, and by preventing ECM breakdown through the synthesis of anticatalytic proteins such as plasminogen activator inhibitor (PAI), TGF-beta appears to have an important effect on maintaining the integrity of the ECM. The influence of TGF-beta-3 on Fn, collagen, and PAI production will be assessed. The possibility that the inactive TGF-beta-3 precursor molecule binds to the Fn receptor through its RGD sequence, creating a negative feedback mechanism, will be examined. Blocking the binding of fibronectin to its receptor would cause decreased adherence of cells to the ECM. The Fn receptor is phosphorylated on tyrosines in transformed but not normal cells. The ability of TGF-beta-3 to ameliorate transformation related properties by preventing tyrosine phosphorylation of the Fn receptor will be evaluated. The significance of these studies in understanding control mechanisms of tumor cell proliferation and metastasis may elucidate concepts for future therapeutics in two important areas of cancer research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA049507-04
Application #
3193653
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1989-06-15
Project End
1994-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Parekh, Trilok V; Gama, Patricia; Wen, Xie et al. (2002) Transforming growth factor beta signaling is disabled early in human endometrial carcinogenesis concomitant with loss of growth inhibition. Cancer Res 62:2778-90
Khalil, Nasreen; Parekh, Trilok V; O'Connor, Robert N et al. (2002) Differential expression of transforming growth factor-beta type I and II receptors by pulmonary cells in bleomycin-induced lung injury: correlation with repair and fibrosis. Exp Lung Res 28:233-50
Gold, L I; Jussila, T; Fusenig, N E et al. (2000) TGF-beta isoforms are differentially expressed in increasing malignant grades of HaCaT keratinocytes, suggesting separate roles in skin carcinogenesis. J Pathol 190:579-88
Gold, L I (1999) The role for transforming growth factor-beta (TGF-beta) in human cancer. Crit Rev Oncog 10:303-60
Picon, A; Gold, L I; Wang, J et al. (1998) A subset of metastatic human colon cancers expresses elevated levels of transforming growth factor beta1. Cancer Epidemiol Biomarkers Prev 7:497-504
Friess, H; Lu, Z; Riesle, E et al. (1998) Enhanced expression of TGF-betas and their receptors in human acute pancreatitis. Ann Surg 227:95-104
Gold, L I; Sung, J J; Siebert, J W et al. (1997) Type I (RI) and type II (RII) receptors for transforming growth factor-beta isoforms are expressed subsequent to transforming growth factor-beta ligands during excisional wound repair. Am J Pathol 150:209-22
Roth, D A; Longaker, M T; McCarthy, J G et al. (1997) Studies in cranial suture biology: Part I. Increased immunoreactivity for TGF-beta isoforms (beta 1, beta 2, and beta 3) during rat cranial suture fusion. J Bone Miner Res 12:311-21
Friess, H; Cantero, D; Graber, H et al. (1997) Enhanced urokinase plasminogen activation in chronic pancreatitis suggests a role in its pathogenesis. Gastroenterology 113:904-13
Riesle, E; Friess, H; Zhao, L et al. (1997) Increased expression of transforming growth factor beta s after acute oedematous pancreatitis in rats suggests a role in pancreatic repair. Gut 40:73-9

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