Corticotroph SOCS-3 as an intracellular suppressor of cytokine signaling. Corticotroph SOCS-3 inhibits STAT-dependent POMC gene expression by negatively interfering with LIF-induced activation of the JAK-STAT cascade. In contrast, CRH-induced POMC gene expression is not affected by SOCS-3. LIF stimulation of the corticotroph results in rapid upregulation of SOCS-3 by a STAT-dependent mechanism. Thus, LIF-induced activation of corticotroph POMC gene activation is limited by parallel induction of SOCS-3 expression, rendering the cell resistant to further JAK-STAT activation. On the other hand, autoregulation of STAT-dependent SOCS-3 gene expression and rapid degradation of SOCS-3 protein by the proteasome pathway enable the cell to restore its functional status. LIF and CRH synergistically induce POMC promoter activity. LIF activates POMC promoter activity not only by direct binding of activated STATs, but also indirectly by inducing STAT-dependent expression of transcription factors c-fos and JunB. CRH also induces SOCS3 promoter activity by binding of c-fos and JunB. Thus, CRH indirectly inhibits LIF-induced POMC promoter activation and downregulates the synergistic cross-talk of CRH and LIF on POMC promoter activity. Adapted from ref. 34 and ref. 47 with permission.