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Submitted on October 24, 2003
Accepted on August 12, 2004
Département d'Endocrinologie, Institut Cochin, INSERM U567, CNRS UMR8104, Université René Descartes; 24, rue du Faubourg Saint Jacques, 75014 Paris, France; Clinique des Maladies Endocriniennes et Métaboliques, Hôpital Cochin; 27, rue du Faubourg Saint Jacques, 75014 Paris, France; INSERM U564, Centre Hospitalier Universitaire, 4 ru e Larrey, 49033 Angers cedex, France; INSERM U478, 16, rue Henri Huchard, 75018 Paris, France
* To whom correspondence should be addressed. E-mail: catelli{at}cochin.inserm.fr.
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-STAT composite element of the POMC promoter was the predominant target of the LIF-CRH synergy. While 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 recombinant Nur77 or STAT1-3. Moreover, CREB-Nur77 interaction was increased by CREB phosphorylation at Ser-133 and the dominant negative mutant CREB-M1 efficiently inhibited the synergistic LIF-CRH response. This synergism was also inhibited after transfection of CREB-siRNA. We conclude that both CREB phosphorylation at Ser-133 and level of CREB expression are crucial in LIF-CRH synergism where CREB, without direct DNA binding, could improve the stability of Nur77 and STAT1-3 binding to POMC promoter and facilitate the recruitment of coactivators. This novel intrapituitary signaling mechanism may have more general implications in cross talks between cAMP-PKA and Jak-STAT pathways.
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