Gam Ryhem, Sochodolsky Kevin, Balsalobre Aurélio, Gauthier Yves, Drouin Jacques
J Mol Endocrinol. 2025 Jul 26;75(2). doi: 10.1530/JME-25-0037. Print 2025 Aug 1.
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.
下丘脑-垂体-肾上腺轴的经典激活是通过下丘脑激素促肾上腺皮质激素释放激素（CRH）刺激垂体阿黑皮素原（POMC）基因转录和促肾上腺皮质激素（ACTH）释放来实现的。同时，白细胞介素6（IL6）和白血病抑制因子（LIF）等炎性细胞因子也通过JAK/STAT途径刺激ACTH释放和POMC转录。近年来，由于在USP8基因中发现了致病突变，这些突变与垂体促肾上腺皮质激素腺瘤的形成有关，而垂体促肾上腺皮质激素腺瘤是库欣病的标志，因此人们对表皮生长因子（EGF）途径在POMC激活中的作用产生了特别的兴趣。这些突变与EGF/表皮生长因子受体（EGFR）途径的持续上调及其在ACTH分泌过多中的假定作用有关。在本研究中，我们使用AtT20细胞模型重新评估了垂体促肾上腺皮质激素细胞中响应EGF而激活的信号通路。我们证实了EGF激活丝裂原活化蛋白激酶（MAP）激酶途径，并且还显示了AKT/哺乳动物雷帕霉素靶蛋白（mTOR）和JAK/STAT途径的激活。虽然所有这三种途径的激活似乎对细胞增殖的刺激至关重要，但只有JAK/STAT途径，更具体地说是信号转导和转录激活因子3（STAT3），增强POMC基因转录。与其他STAT激活细胞因子LIF和IL6的激活相反，这种作用定位于POMC启动子的单个STAT结合元件。此外，与LIF依赖性激活相反，EGF信号传导被STAT3特异性增强而不是STAT1。总之，这些数据确定了POMC启动子上一个独特的依赖于STAT3的靶点，该靶点介导EGF对POMC基因转录的激活。
