Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix.

Transforming growth factor-β (TGF-β) is generally acknowledged to be the cytokine with the broadest range of activities in repair of injured tissue, based both on the variety of cell types that produce and/or respond to it and on the spectrum of its cellular responses (Roberts and Sporn, 1990). TGF-β is released from degranulating platelets and secreted by all of the major cell types participating in the repair process, including lymphocytes, macrophages, endothelial cells, smooth muscle cells, epithelial cells, and fibroblasts (see Fig. 1). A unique feature of this molecule is that its autoinduction results in sustained expression at the site of a wound and extends the effectiveness of both the initial burst of endogenous TGF-β released upon injury and exogenous TGF-β that might be applied to a wound. The ability of TGF-β to improve and/or accelerate tissue repair has been studied extensively in a variety of animal models of both normal and impaired healing. A limited number of clinical trials are in progress, but it is anticipated that many new applications for TGF-β will ultimately be found, once problems with appropriate timing and formulation can be solved.

Transforming Growth Factor-β

Alveolar macrophages activated with concanavalin A and peripheral blood monocytes activated with lipopolysaccharide secrete type beta transforming growth factor (TGF-beta). There is minimal TGF-beta secretion in unactivated monocytes, even though TGF-beta mRNA is expressed in these cells at a level similar to that in activated, lipopolysaccharide-treated cultures. U937 lymphoma cells, which have monocytic characteristics, also express mRNA for TGF-beta. Freshly isolated monocytes, both control and lipopolysaccharide-treated, secrete an acid-labile binding protein that inhibits TGF-beta action. We conclude the following: (i) that expression of TGF-beta mRNA is unrelated to monocyte activation, (ii) that secretion of TGF-beta is induced by monocyte activation, and (iii) that cosecretion of TGF-beta and its monocyte/macrophage-derived binding protein may modulate growth factor action. In contrast, monocytic expression of other growth factor genes, such as the B chain of platelet-derived growth factor, is not constitutive and requires activation.

https://www.pnas.org/content/pnas/84/17/6020.full.pdf

Expression and secretion of type beta transforming growth factor by activated human macrophages

Following the initial purification and characterization of transforming growth factor-β (TGF-β) as a homodimeric, 25-kDa peptide (Frolik et al. 1983; Assoian et al. 1983; Roberts et al. 1983a), there has been an exponential increase in knowledge relating to this molecule. The cloning of TGF-β1 and the resultant elucidation of its precursor structure (Derynck et al. 1985) have led to the identification of at least four other forms of TGF-β and the definition of a larger gene family comprising many other structurally related, but functionally distinct, regulatory proteins. The original narrow definition of TGF-β, in terms of induction of a transformed phenotype in mesenchymal cells (Moses et al. 1981; Roberts et al. 1981, 1983 b), has now been supplanted by the knowledge that this peptide affects many functions in nearly all cells. Immunohistochemical and in situ hybridization studies have identified in vivo sites of TGF-β action; its broad spectrum of cellular targets as well as its multifunctional actions suggest that it has a pivotal control function in many physiological and pathological processes. Elucidation of physiological mechanisms of activation of the latent forms of the TGF-βs and of regulation of expression of the TGF-βs and their receptors are important problems that must still be solved for better understanding of the action of the TGF-βs. In this chapter we summarize current knowledge of the chemistry and complex biology of the growing family of TGF-βs.

The Transforming Growth Factor-βs

Oncogene-induced cellular senescence constitutes a strong anti-proliferative response, which can be set in motion following either oncogene activation or loss of tumour suppressor signalling. It serves to limit the expansion of early neoplastic cells and as such is a potent cancer-protective response to oncogenic events. Recently emerging evidence points to a crucial role in oncogene-induced cellular senescence for the 'senescence-messaging secretome' or SMS, setting the stage for cross-talk between senescent cells and their environment. How are such signals integrated into a coordinated response and what are the implications of this unexpected finding?

Senescence-messaging secretome: SMS-ing cellular stress

Stimulation by insulin-like growth factors is required for cellular transformation by type beta transforming growth factor.

Retrovirus-transformed rat cells that actively express transforming growth factor type alpha (TGF-alpha) release into the medium a soluble protein of 17-19 kDa that has been identified as a precursor for TGF-alpha. The identification of this protein as a TGF-alpha precursor is based on its recognition by specific antibodies and by the ability of elastase to convert this protein into a 6-kDa polypeptide with the properties of mature TGF-alpha. This TGF-alpha precursor binds to epidermal growth factor/TGF-alpha receptors and activates the receptor-associated tyrosine kinase activity in intact cells. The biological potency of this precursor is not markedly increased by conversion into mature TGF-alpha in vitro. These studies demonstrate the ability of transformed cells to release a TGF-alpha precursor capable of strong mitogenic action in vivo.

Biologically active precursor for transforming growth factor type alpha, released by retrovirally transformed cells

The fate of 125I-labeled transforming growth factor-beta (125I-TGF beta) after binding to its cells surface receptor has been investigated in BALB/c 3T3 mouse fibroblasts. Binding of 125I-TGF beta to cellular receptors at 4 degrees C is pH-sensitive, being markedly decreased at pH less than 6. Most (approximately 90%) of the 125I-TGF beta bound to cells at 4 degrees C can be removed by a brief treatment with acidic medium but is converted into an acid-resistant state rapidly after shifting the cells to 37 degrees C. Cell-bound 125I-TGF beta is degraded at 37 degrees C and the degradation products are released into the medium. The lysosomotropic bases chloroquine, methylamine, and ammonium and the carboxylic ionophore monensin inhibit the degradation and release of 125I-TGF beta from the cells. Cells allowed to accumulate 125I-TGF beta intracellularly by the action of chloroquine or monensin were treated with the bifunctional agent disuccinimidyl suberate in the presence of detergent Triton X-100; this treatment caused the cross-linking of internalized 125I-TGF beta with the 280-kilodalton TGF beta receptor component. Under conditions in which sustained binding and degradation of saturating 125I-TGF beta concentrations occurs, there is no marked decrease in the binding capacity of the cells even when protein synthesis is blocked with cycloheximide. These results indicate that after TGF beta binding the TGF beta:receptor complex becomes rapidly internalized and that TGF beta is directed towards lysosomes where it is degraded and released. However, the cell surface is replenished with TGF beta receptors recycled after internalization or supplied by a large intracellular pool.

Brenda Kelly

Papers

Stimulation by insulin-like growth factors is required for cellular transformation by type beta transforming growth factor.

Biologically active precursor for transforming growth factor type alpha, released by retrovirally transformed cells

Internalization of transforming growth factor‐β and its receptor in BALB/c 3T3 fibroblasts