TGF-β expression during the oestrous or menstrual cycle: the role of ovarian steroids

The transforming growth factor βs (TGF-β) belong a family of structurally related, dimeric, disulfide-linked polypeptides that includes five TGF-β isoforms, activins, inhibins, Müllerian inhibiting substance, bone morphogenic proteins, and products of the Xenopus Vg1 and Drosophila decapentaplegic (dpp) genes (reviewed in Rizzino, 1988; Massagué, 1990; Roberts and Sporn, 1990). In mammals, three isoforms of TGF-β (TGF-β1,-β2, and β3) have been identified. TGF-βs are multifunctional cytokines that influence numerous cellular processes. They can regulate cell proliferation and differentiation positively or negatively depending on cell type and have been implicated in such diverse physiological events as angiogenesis, immune function, steroidogenesis, and tissue remodelling and repair. Since all of these events take place in the uterine endometrium during the oestrous or menstrual cycle and during the establishment of pregnancy, TGF-βs are likely candidates to regulate some of these reproductive functions. Biological effects of TGF-β are mediated through interactions with cell surface receptors, designated type I, II and III (reviewed in Massagué and Weis-Garcia, 1996). Type I and II receptors are transmembrane proteins containing cytoplasmic serine/threonine kinase domains. TGF-β binds the type II but not type I receptor. The type I receptor recognizes the ligand bound type II receptor with which it forms a heteromeric complex. The type I receptor then undergoes phosphorylation, which is probably catalysed by the type II kinase. Signalling downstream of the type I receptor involves the phosphorylation of one or more cytoplasmic proteins referred to as Smads, complex formation of Smad-2, -3 and -4, and their translocation to the nucleus and association with transcription factors. The type III receptor is a proteoglycan with no cytoplasmic kinase domain and may be involved in presentation of TGF-β to the type II receptor. TGF-β expression during the oestrous or menstrual cycle: the role of ovarian steroids