EGF activation of POMC gene transcription is mediated by STAT3

Classical activation of the hypothalamic-pituitary-adrenal axis is exerted by the stimulation of pituitary POMC gene transcription and ACTH release by the hypothalamic hormone CRH. In parallel, inflammatory cytokines such as IL6 and LIF also stimulate ACTH release and POMC transcription through the JAK/STAT pathway. In recent years, a particular interest in the role of the EGF pathway for POMC activation was sparked by the identification of causative mutations in the USP8 gene that have been implicated in the formation of pituitary corticotroph adenomas that are the hallmark of Cushing's disease. These mutations were associated with the persistent upregulation of the EGF/EGFR pathway and its putative role in ACTH hypersecretion. In the present work, we reassessed the signaling pathways that are activated in response to EGF in pituitary corticotroph cells using the AtT20 cell model. We confirmed the activation of the MAP kinase pathway by EGF and also showed the activation of the AKT/mTOR and JAK/STAT pathways. Whereas activation of all three pathways appears essential for the stimulation of cell proliferation, only the JAK/STAT pathway, and more specifically STAT3, enhances POMC gene transcription. This action is mapped to a single STAT-binding element of the POMC promoter in contrast to the activation by the other STAT-activating cytokines LIF and IL6. Furthermore, EGF signaling is specifically enhanced by STAT3 but not STAT1 in contrast to LIF-dependent activation. All together, the data identified a unique STAT3-dependent target on the POMC promoter that mediates EGF activation of POMC gene transcription.