Hormone receptor regulated proopiomelanocortin gene expression

Abstract

The activity of the POMC gene is regulated by both stimulatory and inhibitory hormones. Presumably, some balance exists in the influence of these hormones in order to maintain a steady-state level of activity of this gene. Physiological insults, such as stress, may upset this balance and change the rate of production of POMC and its biologically active peptides. The relative strength of these different hormones may therefore determine the long-term expression of this gene. Chronic administration of CRF to rats, primates and humans produces prolonged increases in plasma ACTH levels. This long-term effect is most likely due to an activation of the POMC gene. Interestingly, chronic treatment of anterior pituitary cells with CRF desensitizes CRF receptors. Thus, despite the corticotrophs becoming refractory to the acute stimulatory actions of CRF, the POMC gene remains stimulated. These findings suggest that corticotrophs do not have to be continuously activated by CRF to maintain a long-term increase in POMC gene expression. This contrasts with the actions of glucocorticoids whose effects are abruptly terminated following their removal from the target tissue. The molecular basis of this form of cellular memory to the actions of CRF may involve cAMP regulatory phosphoproteins binding to and activating the POMC gene. If this phenomenon is shown to occur and the phosphorylation state of these nuclear proteins is found to govern their level of interaction with POMC gene, then it would represent a novel mechanism of gene regulation. Proof for this mechanism and the elucidation of how other second messengers such as protein kinase C and calcium regulate the POMC gene will greatly aid our understanding of the precise molecular mechanisms controlling opioid peptide expression.