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. 1999 Jun 8;96(12):6964–6969. doi: 10.1073/pnas.96.12.6964

Figure 7.

Figure 7

Model of interaction and negative autoregulatory feedback of SOCS-3 protein on POMC and SOCS-3 gene expression. The LIF-induced signaling cascade in the corticotroph cell envolves tyrosine phosphorylation of gp130, STAT-3, and STAT-1 (15, 23, 26, 27). LIF induces gene expression of POMC (28) and SOCS-3 in the corticotroph cell in a STAT-3 dependent manner. Although the region from nucleotides −173 to −160 in the rat POMC promoter is important for synergy of LIF and corticotropin-releasing hormone, it does not involve STAT protein binding (25); the putative STAT binding element in the POMC promoter has not yet been characterized. The murine SOCS-3 promoter has a functionally critical STAT-1/STAT-3 binding region at −72 to −64. SOCS-3 inhibits Jak2 activity by binding to its JH1 domain (9) and thus inhibits LIF-induced tyrosine phosphorylation of gp130 and STAT-3 in the corticotroph cell (15). By inhibiting Jak-STAT signaling, SOCS-3 negatively regulates LIF-induced POMC gene expression and ACTH secretion and also exerts a negative autoregulatory feedback on its own gene expression. This negative autoregulatory feedback of SOCS-3 on its own gene expression limits the accumulation of SOCS-3 protein in the corticotroph cell.