Abstract
Transforming growth factor beta (TGF-beta) has been extensively studied as an exogenous agent that stimulates the expression of extracellular matrix proteins and their cell-surface integrin receptors in a variety of cell types. However, the recent demonstration of autocrine TGF-beta growth effects in a number of cell types suggests that the steady-state expression of extracellular matrix and integrin proteins and their biological activity may also be under autocrine TGF-beta control. Previously, we reported that repression of autocrine TGF-beta 1 activity by constitutive expression of a full-length TGF-beta 1 antisense cDNA led to abrogation of autocrine negative TGF-beta and, as a result, increased tumorigenicity and anchorage-independent growth of a poorly tumorigenic, well-differentiated colon carcinoma cell line designated FET (Wu, S., Theodorescu, D., Kerbel, R. S., Willson, J. K. V., Mulder, K. M., Humphrey, L. E., and Brattain, M. G. (1992) J. Cell Biol. 116, 187-196). Consequently, we have used this model system to study the effects of repression of autocrine TGF-beta 1 activity on the expression of integrin alpha 5 beta 1 and integrin alpha 5 beta 1-mediated cell adhesion to fibronectin. The expression of the integrin alpha 5 subunit was reduced in TGF-beta 1 antisense transfected FET cells at both mRNA and protein levels as determined by RNase protection assays and immunoprecipitation, respectively. Autocrine TGF-beta 1 had no effect on the transcription of integrin alpha 5 and beta 1 subunits, indicating that autocrine TGF-beta 1 may regulate integrin alpha 5 beta 1 expression at the post-transcriptional level. The diminished expression of integrin alpha 5 beta 1 on the cell surface led to the reduced adhesion of TGF-beta 1 antisense transfected cells to fibronectin. This phenomenon could be reversed by treatment with exogenous TGF-beta 1.
Highlights
From the Wepartment of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43699-0008, the lIDepartment of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, and the HDepartment of Internal Medicine, Washington University School of Medicine, St
Transforming growth factor fJ (TGF-(J) has been extensively studied as an exogenous agent that stimulates the expression of extracellular matrix proteins and their cell-surface integrin receptors in a variety of cell types
The recent demonstration of autocrine TGF-fJ growth effects in a number ofcell types suggests that the steady-state expression of extracellular matrix and integrin proteins and their biological activity may be under autocrine TGF-fJ control
Summary
§ Performed this work to fulfill partial requirements for a Ph.D. degree at the Medical College of Ohio. Characterization of transfeeted FET cells with constitutively repressed TGF-/31 expression showed high cloning efficiency in anchorage-independent assays and enhanced tumorigenicity in athymic nude mice These studies suggested that loss of autocrine TGF-/3 activity may be an important step in progression of malignancy. Given the effects of exogenous TGF-/3 treatment on the expression of integrins in a wide variety of model systems, we hypothesized that autocrine TGF-/31 may control biological function by regulating steadystate integrin receptor expression and cellular interactions with the ECM We have tested this hypothesis using the FET model system, described above, in which autocrine TGF-/3 activity was constitutively repressed [21]
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