Growth Hormone Preferentially Induces the Rapid, Transient Expression of SOCS-3, a Novel Inhibitor of Cytokine Receptor Signaling

Abstract

Four members (SOCS-1, SOCS-2, SOCS-3, and CIS) of a family of cytokine-inducible, negative regulators of cytokine receptor signaling have recently been identified. To address whether any of these genes are induced in response to growth hormone (GH), serum-starved 3T3-F442A fibroblasts were incubated with GH for various time points, and the expression of the SOCS gene family was analyzed by Northern blotting. GH stimulated the rapid, transient induction of SOCS-3 mRNA, peaking 30 min after the initiation of GH exposure and declining to basal levels by 2 h. Expression of the other SOCS genes (SOCS-1, SOCS-2, CIS) was also up-regulated by GH, although to a lesser extent than SOCS-3 and with differing kinetics. SOCS-3 expression was also strongly induced in 3T3-F442A cells treated with leukemia-inhibitory factor (LIF), with weaker induction of SOCS-1 and CIS being observed. The preferential induction of SOCS-3 mRNA was also observed in hepatic RNA isolated from the livers of mice that had received a single supraphysiological dose of GH intraperitoneally. Co-transfection studies revealed that constitutive expression of SOCS-1 and SOCS-3, but not SOCS-2 or CIS, blocked GH-induced transactivation of the GH-responsive serine protease inhibitor 2.1 gene promoter.The elucidation of the pivotal role played by the tyrosine kinase Jak2 in initiating signal transduction from the GH 1 receptor has led to the identification of a number of intracellular pathways that mediate the cellular response to GH (1). However, the mechanism(s) by which signaling from GH receptor-activated Jak2 is attenuated is unclear. Ligand-induced tyrosine phosphorylation/activation of Jak2 by the erythropoietin (EPO) receptor, a member of the cytokine receptor superfamily that includes the GH receptor, is followed by the binding of the protein-tyrosine phosphatase SHP-1 to the cytoplasmic domain of the receptor (2). The recruitment of SHP-1 is accompanied by the dephosphorylation/inactivation of Jak2 and subsequent termination of EPO-induced cellular proliferation.A similar role for SHP-1 in mediating the down-regulation of Jak2 following stimulation of cells with GH has been proposed (3), although whether SHP-1 can directly associate with the GH receptor remains to be established. Recently, a novel family of cytokine-inducible genes has been identified that appear to function as negative regulators of the JAK signaling pathway (4 -7). Constitutive expression of one member, SOCS-1 (also referred to as SSI-1 and JAB) in the murine myeloid leukemia M1 cell line blocked growth factor-induced differentiation and apoptosis and inhibited interleukin-6 (IL-6)-mediated tyrosine phosphorylation of the cell-surface receptor component, gp130, and the transcription factor, Stat3 (5, 6). SOCS-1 can interact with all four members of the JAK family of tyrosine kinases (6, 7), suppressing kinase activity and the subsequent tyrosine phosphorylation/activation of STAT factors (7). As a diverse array of cytokines appears to be able to induce expression of one or more mem...

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

“…Treatment with human rG-CSF resulted in a dramatic increase of SOCS-3 mRNA within 45 min. This rapid induction of SOCS-3 was similar to that observed with other cytokines (47)(48)(49) and this indicates that SOCS-3 is an immediate early gene induced by G-CSF to rapidly modulate G-CSFR-mediated signaling. The strong and rapid induction of SOCS-3 mRNA in myeloid cells by G-CSF reported in this study, together with the previously reported potent induction of SOCS-3 by G-CSF, GM-CSF, and IL-3 in bone marrow cells (22), is a strong indication for SOCS-3 being an important regulator of signal transduction in immune cells.…”

Cloning of common carp SOCS-3 gene and its expression during embryogenesis, GH-transgene and viral infection

“…GH was previously shown to induce strong transient expression of SOCS-3 in mouse liver [32]. Regulation of the GH intracellular signalization pathway occurs through a complex mechanism involving the coordinated action of various negative regulators, whose main targets apparently are JAKs and STATs phosphorylated by activated GHR [33].…”

SOCS-3 Is an Insulin-induced Negative Regulator of Insulin Signaling

“…For instance, tumor necrosis factor ␣, a molecule thought to be involved in insulin resistance, has been shown independently to induce SOCS-3 (4) and to inhibit insulin-induced STAT5 activation (47). GH, a molecule known to lead to a state of insulin resistance (48), is also a recognized SOCS-3 inducer (49). Although this is still a matter of debate, leptin, an adipocyte-produced hormone, has been proposed to hamper insulin signaling (50,51) and is a recognized inducer of SOCS-3.…”