title: Transcriptional control of adrenal steroidogenesis: novel connection between Janus kinase (JAK) 2 protein and protein kinase A (PKA) through stabilization of cAMP response element-binding protein (CREB) transcription factor.
abstract: In the adrenal gland, adrenocorticotropin (ACTH) acting through the cAMP protein kinase (PKA) transduction pathway is the main regulator of genes involved in glucocorticoid synthesis. The prolactin (PRL) receptor is expressed in the adrenal cortex of most mammals, but experimental proof that PRL ensures direct control on glucocorticoid synthesis in rodents remains elusive. To unravel the physiological importance of PRL in adrenocortical functions, we measured steroidogenic capacity of Prlr-deficient mice (Prlr(-/-)) and explored the influence of JAK/STAT signaling, the major PRL transduction pathway, on the steroidogenic activity of adrenocortical cell cultures. We demonstrate that lack of Prlr does not affect basal (nor stress-induced) corticosterone levels in mice. PRL triggers JAK2/STAT5-dependent transcription in adrenal cells, but this does not influence corticosterone release. In contrast, pharmacological or siRNA-mediated inhibition of JAK2 reveals its essential role in both basal and ACTH/cAMP-induced steroidogenesis. We demonstrate that nuclear JAK2 regulates the amount of active transcription factor CREB (cAMP response element-binding protein) through tyrosine phosphorylation and prevention of proteasomal degradation, which in turn leads to transcriptional activation of the rate-limiting steroidogenic Star gene. Hence, we describe a novel link between PKA and JAK2 by which nuclear JAK2 signaling controls adrenal steroidogenesis by increasing the stability of CREB.
authors.affiliation: CNRS UMR6247, Génétique Reproduction et Développement, Clermont Université, 63171 Aubière, France. a-marie.lefrancois-martinez@univ-bpclermont.fr
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lefrancois-Martinez
authors.forename: Antonine
authors.initials: A
authors.lastname: Blondet-Trichard
authors.forename: Nadine
authors.initials: N
authors.lastname: Binart
authors.forename: Pierre
authors.initials: P
authors.lastname: Val
authors.forename: Céline
authors.initials: C
authors.lastname: Chambon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sahut-Barnola
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Pointud
authors.forename: Antoine
authors.initials: A
authors.lastname: Martinez
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D003345:Corticosterone / Q000096:biosynthesis; D000242:Cyclic AMP / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011388:Prolactin / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D051381:Rats; D012756:Sheep; D013256:Steroids / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D046912:Multiprotein Complexes; D013256:Steroids; D011388:Prolactin; D000242:Cyclic AMP; D053614:Janus Kinase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D003345:Corticosterone