Extracellular matrix regulates expression of the TGF-beta 1 gene.

Abstract

Transforming growth factor-beta (TGF-beta) is a potent regulator of cell proliferation and modulates the interactions of cells with their extracellular matrix (ECM), in part by inducing the synthesis of various ECM proteins. Three different isoforms of TGF-beta are synthesized in a defined pattern in specific cell populations in vivo. In the specific case of TGF-beta 1, this well-defined and limited expression stands in sharp contrast to its synthesis by virtually all cells in culture. Using mammary epithelial cells as a model system, we evaluated the substratum dependence of the expression of TGF-beta 1. The level of TGF-beta 1 expression is high in cells on plastic, but is strongly downregulated when cells are cultured on a reconstituted basement membrane matrix. In contrast, TGF-beta 2 mRNA levels in cells on either substratum remain unchanged. Using the chloramphenicol acetyl transferase gene as reporter gene under the control of the TGF-beta 1 promoter, we show that transcription from this promoter is suppressed when the cells are in contact with either endogenously synthesized or exogenously administered basement membrane. TGF-beta 1 promoter activity is strongly induced by the absence of basement membrane, i.e., by direct contact of the cells with plastic. This modulation of transcription from the TGF-beta 1 promoter occurs in the absence of lactogenic hormones which allow full differentiation. Our results thus indicate that basement membrane is an important regulator of TGF-beta 1 synthesis, and explain why most cells in culture on plastic express TGF-beta 1 in contrast with the more restricted TGF-beta 1 synthesis in vivo. We propose that there is a feedback loop whereby TGF-beta 1-induced synthesis of basement membrane components is repressed once a functional basement membrane is present. Finally, these results together with our current knowledge of regulation of TGF-beta 1 and TGF-beta 2 synthesis, suggest that, in vivo, TGF-beta 1 may play a major role in regulating the ECM synthesis and the cell-ECM interactions, whereas TGF-beta 2 may be more important in morphogenetic processes.

Tumor cell invasiveness correlates with changes in integrin expression and localization

“…Rather, integrins like a5b1 become expressed in certain 'emergency' situations, such as wounding or tumor development, during which basement membranes are destroyed and epithelial cells have to survive and migrate within or in close contact to a stromal environment (Saulnier et al, 1996). Basement membrane disruption, per se, induces TGFb1 expression (Streuli et al, 1993) leading to increased production of ECM proteins, reformation of the basement membrane and downregulation of TGFb1 synthesis. However, in malignant tumors this feedback regulation between TGFb1 production and ECM protein deposition is disturbed.…”

A hierarchy of ECM-mediated signalling regulates tissue-specific gene expression

“…Instead, changes in cell shape and polarity lead to the deposition of a laminin-containing basement membrane that in turn induces β-casein expression [79•,98]. This deposition also results in decreased ECM gene expression, an event that is regulated by the 'matrix modifier' transforming growth factor-β (TGF-β) [99]. Interestingly, basement membrane-second tier signal processing itself leads to the downregulation of TGF-β.…”

Involvement of extracellular matrix constituents in breast cancer

“…60 For example, it has been shown that TGF-β synthesis is down-regulated in mammary epithelial cells when they are exposed to EHS matrix or allowed to make their own basement membrane. 62 When mammary epithelial cells are plated in a malleable matrix gel, they remain rounded and stop proliferating; on a substrate permissive for cell spreading, they continue to grow. 9 Similarly, type V collagen, a non-permissive substrate for cell spreading, inhibits proliferation of a mammary cancer cell line.…”