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Endocrine. 2018 Sep;61(3):511-517. doi: 10.1007/s12020-018-1573-9. Epub 2018 Mar 13.

Role of the ubiquitin/proteasome system on ACTH turnover in rat corticotropes.

Author information

1
Neuroendocrinology Research Laboratory, Istituto Auxologico Italiano IRCCS, Cusano Milanino (Milan), Milan, Italy.
2
Neuroendocrinology Research Laboratory, Istituto Auxologico Italiano IRCCS, Cusano Milanino (Milan), Milan, Italy. fpg@auxologico.it.
3
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. fpg@auxologico.it.

Abstract

PURPOSE:

A large number of studies has investigated proopiomelanocortin processing in anterior pituitary corticotropes but little is known on proopiomelanocortin/ACTH degradation within these cells. The ubiquitin-proteasome system is an intracellular protein degradation pathway which has garnered considerable interest in recent times, given its role in maintenance of protein homeostasis. Aim of the present study was to evaluate the role of the ubiquitin-proteasome system in proopiomelanocortin/ACTH turnover in pituitary corticotropes.

METHODS:

Rat anterior pituitary primary cultures were treated with 0.01-100 nM MG132, a proteasome inhibitor, or 0.1-100 nM K48R, an inhibitor of polyubiquitylation, for 4 and 24 h and ACTH concentrations in medium and cell lysates estimated by immunometric assay. Co-immunoprecipitation for ubiquitin and ACTH was carried out to establish ubiquitin-tagged protein products.

RESULTS:

Inhibition of proteasome-mediated degradation with MG132 lead to an increase in ACTH concentrations, both as regards secretion and cell content. Likewise, inhibition of polyubiquitylation was associated with increased ACTH secretion and cell content. Ubiquitin/ACTH co-immunoprecipitation revealed that proopiomelanocortin was a target of ubiquitylation.

CONCLUSIONS:

We provide the first evidence that the ubiquitin-proteasome system is involved in proopiomelanocortin/ACTH degradation in corticotropes. Indeed, proopiomelanocortin is a target of ubiquitylation and modulation of ubiquitin-proteasome system affects ACTH turnover. This study shows that regulation of ACTH proteolytic degradation may represent a means to control ACTH secretion.

KEYWORDS:

ACTH; Proopiomelanocortin; Ubiquitin-proteasome; Ubiquitylation

PMID:
29536250
PMCID:
PMC6105253
DOI:
10.1007/s12020-018-1573-9
[Indexed for MEDLINE]
Free PMC Article

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