Rapid proteasomal degradation of mutant proteins is the primary mechanism leading to tumorigenesis in patients with missense AIP mutations

CONTEXT The pathogenic effect of AIP mutations (AIPmuts) in pituitary adenomas is incompletely understood. We have identified the primary mechanism of loss of function for missense AIPmuts. OBJECTIVE To analyze the mechanism/speed of protein turnover of wild-type (WT) and missense AIP variants, correlating protein half-life with clinical parameters. DESIGN Half-life and protein-protein interaction experiments and cross-sectional analysis of AIPmut positive patients' data were performed. SETTING Clinical academic research institution. PATIENTS Data was obtained from our cohort of pituitary adenoma patients and literature-reported cases. INTERVENTIONS Protein turnover of endogenous AIP in two cell lines and fifteen AIP variants overexpressed in HEK293 cells was analyzed via cycloheximide chase and proteasome inhibition. GST pull-down and quantitative mass spectrometry identified proteins involved in AIP degradation; results were confirmed by co-immunoprecipitation and gene knockdown. Relevant clinical data was collected. MAIN OUTCOME MEASURES Half-life of WT and mutant AIP proteins and its correlation with clinical parameters. RESULTS Endogenous AIP half-life was similar in HEK293 and lymphoblastoid cells (43.5 and 32.7h). AIP variants were divided in stable proteins (median 77.7h [IQR 60.7-92.9]), and those with short (27h [21.6-28.7]) or very short (7.7h [5.6-10.5]) half-life; proteasomal inhibition rescued the rapid degradation of mutant proteins. The experimental half-life significantly correlated with age at diagnosis of acromegaly/gigantism (r=0.411, P=0.002). The FBXO3-containing SCF complex was identified as the E3 ubiquitin-ligase recognizing AIP. CONCLUSIONS AIP is a stable protein, driven to ubiquitination by the SCF complex. Enhanced proteasomal degradation is a novel pathogenic mechanism for AIPmuts, with direct implications for the phenotype

Rockport Comprehensive Plan

This document was developed and prepared by Texas Target Communities (TxTC) at Texas A&M University in partnership with the City of Rockport, Texas Sea Grant, Texas A&M University - Corpus Christi, Texas A&M University - School of Law and Texas Tech University.Founded in 1871, the City of Rockport aims to continue growing economically and sustainably. Rockport is a resilient community dedicated to sustainable growth and attracting businesses to the area. Rockport is a charming town that offers a close-knit community feel and is a popular tourist destination for marine recreation, fairs, and exhibitions throughout the year. The Comprehensive Plan 2020-2040 is designed to guide the city of Rockport for its future growth. The guiding principles for this planning process were Rockport's vision statement and its corresponding goals, which were crafted by the task force. The goals focus on factors of growth and development including public participation, development considerations, transportation, community facilities, economic development, parks, and housing and social vulnerability