Transcriptional Control of Adrenal Steroidogenesis

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 ens...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-09, Vol.286 (38), p.32976-32985
Main Authors: Lefrancois-Martinez, Anne-Marie, Blondet-Trichard, Antonine, Binart, Nadine, Val, Pierre, Chambon, Céline, Sahut-Barnola, Isabelle, Pointud, Jean-Christophe, Martinez, Antoine
Format: Article
Language:English
Subjects:
ACTH
Adrenal Gland
Cellular Biology
CREB
Gene Transcription
Hormone Receptors
JAK Kinase
Life Sciences
Prolactin
Protein Kinase A (PKA)
STAT Transcription Factor
Steroid Hormone
Subcellular Processes
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.218016