Synergistic Signaling by Corticotropin-Releasing Hormone and Leukemia Inhibitory Factor Bridged by Phosphorylated 3′,5′-Cyclic Adenosine Monophosphate Response Element Binding Protein at the Nur Response Element (NurRE)-Signal Transducers and Activators of Transcription (STAT) Element of the Proopiomelanocortin Promoter

Leukemia inhibitory factor (LIF) cooperates with CRH at the pituitary level to induce POMC gene transcription, resulting in activation of the pituitary-adrenal axis. However, the underlying molecular mechanisms remain elusive. Here, we show that the NurRE-signal transducers and activators of transcription (STAT) composite element of the POMC promoter was the predominant target of the LIF-CRH synergy. Whereas NurRE or STAT sites alone conferred synergy, the maximal response was found with the NurRE-STAT reporter, suggesting that direct DNA binding of both transcription factors is required for an optimal synergy. During LIF-CRH stimulation, Nur77 and activated STAT1–3 were bound to the composite element, and the binding of each factor was abolished by appropriate mutations. CREB was also detected in this complex in a stimulation-dependent and DNA binding-independent manner. Nur77 and STAT1–3 bound to the NurRE-STAT site were each sufficient for CREB recruitment. Recombinant CREB directly interacted with rec...