1351 - O-GlcNAcylation regulates the gene expression of melanocortin hormones.

Objectives: The rapid cyclic addition and removal of single O-linked N-acetylglucosamine residues (O-GlcNAc) to intracellular proteins is important for functional regulation of gene expression. O-GlcNAcylation and O-GlcNAc-associated enzyme activity are found throughout the body but enriched in the brain. Therefore, O-GlcNAc may be an attractive target for correcting dysregulated gene expression associated with abnormal hormone secretion in the pituitary. Adenomatous growth within the pituitary can disrupt the coordinated release of several hormones crucial for maintaining bodily homeostasis. Pituitary corticotroph adenomas exhibiting dysregulated expression of the melanocortin hormone pro-opiomelanocortin (POMC) and increased secretion of POMC-cleavage product, adrenocorticotropic hormone (ACTH), may elevate a patient’s risk for developing cardiovascular morbidities. These tumors are commonly resistant to medical intervention and treated via surgical resection. In this study we explore how O-GlcNAcylation contributes to the dysregulation of POMC in adenomatous corticotropic cells.

Design: We use a combination of models to explore how O-GlcNAcylation contributes to the dysregulation of POMC, including the well-established murine corticotroph adenoma cell line, AtT-20, and primary human pituitary tissue cultures derived from patient surgical resections.

Results: We show increasing protein O-GlcNAcylation levels are critical for increasing Pomc mRNA levels and provide a stabilizing effect on the Pomc mRNA transcript. Follow up studies show this mRNA stability may be due to the O-GlcNAcylation of mRNA binding and processing proteins and/or by the inclusion of intronic sequences into the Pomc mRNA transcript.

Conclusions: From these results we work to unravel the cellular mechanism of how O-GlcNAc affects POMC gene expression, potentially expanding intervention strategies in managing the morbidities associated with dysregulated melanocortin hormones.