Transforming growth factor-beta system and its regulation by members of the steroid-thyroid hormone superfamily

This chapter focuses on the transforming growth factor-β system and its regulation by members of the steroid-thyroid hormone superfamily. Transforming growth factor-βs (TGF- β s) are potent regulators of cellular proliferation, differentiation, and morphogenesis as well as extracellular matrix formation, extracellular proteolysis, and inflammation. A major effect of TGF-β is its ability to inhibit cell proliferation. Three different mammalian TGF-β isoforms and many related peptides have been identified. The diverse activities of the members of the TGF-β family are regulated at the levels of TGF-β expression, secretion, and activity; TGF-β receptor expression; and cellular responsiveness. At later stages of tumor development, cells often become refractory to the antiproliferative action of TGF-β. A role for TGF-β in the progression and escape from hormone dependence has also been suggested. The mechanisms of the regulation of TGF-β expression and activation, in addition to TGF- β signaling pathways, are important in understanding neoplastic transformation and escape from normal growth control. TGF- β participates in a variety of cell differentiation processes. Members of the steroid hormone superfamily are potent regulators of the expression of TGF-β isoforms. TGF-βs might have a role as local mediators of the various actions of steroid hormones. Plasmin is a wide-spectrum serine protease that can dissolve fibrin clots and cleave various extracellular and basement membrane proteins. In addition, plasmin activates metalloproteinases and latent elastase, which further contribute to the degradation of matrices. TGF-βs and their receptors are expressed ubiquitously, and they act as key regulators of many aspects of cell growth, differentiation, and function. Steroid action on target tissues is often associated with increase in TGF-β isoforms. Regulation of TGF-β expression and activation is crucial for normal development and growth control. © 1996 Academic Press Inc.