Transforming growth factor beta (TGF‐β) inhibits hepatocyte DNA synthesis independently of EGF binding and egf receptor autophosphorylation

Abstract

Subpicomolar concentrations of human platelet-derived transforming growth factor beta (TGF-beta) inhibited growth factor-stimulated DNA synthesis in primary cultures of adult rat hepatocytes. This inhibition was not the result of changes in the size of intracellular pools of 3H-thymidine and was not dependent on the state of confluence of the cells. A 24-hr exposure to TGF-beta either before or after insulin/EGF stimulation was as inhibitory on DNA synthesis between 48 and 72 hr of culture as was TGF-beta present throughout 72 hr of culture. From 12 hr in culture to 24 hr, hepatocyte EGF binding sites dropped from about 230,000 to 85,000 per cell with no significant change in Kd, but with a loss in capacity for EGF-induced receptor down-regulation. Maximally inhibitory concentrations of TGF-beta did not compete with EGF for the EGF receptor, and a 4- to 24-hr exposure to TGF-beta did not alter subsequent EGF binding. Coincubation of hepatocytes with TGF-beta and EGF did not influence the 60% reduction in EGF binding sites produced by EGF alone. In addition, TGF-beta did not prevent EGF-induced autophosphorylation of the 170,000 dalton EGF receptor in membranes from whole liver. Our studies suggest that TGF-beta regulates hepatocyte growth independently of changes in EGF receptor number, ligand affinity, or postbinding autophosphorylation.

Transforming growth factor‐β1 rapidly activates phosphorylase in a calcium‐dependent manner in rat hepatocytes

“…1), and the concentration range over which such activation occurs (Fig. 2), is similar to the concentration range over which TGF-]~I inhibits epidermal growth factor-induced DNA synthesis in rat hepatocytes [10]. The change in phosphorylase activity is rapid (maximal by 30 s) and is one of the earliest observed changes in a cellular response to TGF-]~I.…”

“…The prototype, now designated TGF-/~1, was initially purified from human platelets [4] and exists in the biologically active form as a homodimeric peptide of 25 kDa. Although originally identified by its ability to induce anchorage-independent growth in fibroblasts [5,6], TGF-]~I has subsequently been shown to be a potent inhibitor of the growth of epithelial cells, including hepatocytes [7][8][9][10]. The mechanisms whereby TGF-,81 and other TGF-,B family members regulate cell growth are presently unknown, but appear to be mediated by specific cell surface receptors.…”

Inactivation of TGF-β signaling in hepatocytes results in an increased proliferative response after partial hepatectomy

“…Indeed, recent studies have shown important differences in TGF-b signaling between whole animal studies and in vitro studies, which has led to our development and use of an in vivo model system (Ewen et al, 1993;Sandhu et al, 1997;Tang et al, 1998). In the liver, TGF-b signaling through the TGFBR1-TGFBR2 receptor complex has been implicated in the regulation of biological processes to appropriately suppress the regenerative response after partial hepatectomy, after CCl 4 exposure, and after mitogen exposure (GraslKraupp et al, 1998;Nagoshi et al, 1998;Russell, 1988b). For instance, Nagoshi et al (1998) observed massive increases in TGF-b during involution of hyperplastic rat liver, suggesting that TGF-b helps restore the liver to its appropriate mass after mitogenic stimulation.…”

SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration

“…Control of liver regeneration requires both stimulatory and inhibitory factors (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Although it might be expected that stimulatory factors are induced and inhibitory factors repressed after partial hepatectomy, in fact, for certain genes, the reverse occurs.…”