cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors.
PDE4 cyclic nucleotide phosphodiesterases regulate cAMP abundance in cells and therefore regulate numerous processes, including cell growth and differentiation. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein (also called XAP2 or ARA-9). Germline mutations in AIP occur in approximately 20% of patients with Familial Isolated Pituitary Adenoma (FIPA) and 20% of childhood-onset simplex somatotroph adenomas. We therefore examined the protein expression of PDE4A4 and the closely related isoform PDE4A8 in normal human pituitary tissue and in pituitary adenomas. PDE4A4 had low expression in normal pituitary but was significantly overexpressed in somatotroph, lactotroph, corticotroph and clinically nonfunctioning gonadotroph adenomas (P<0.0001 for all subtypes). Likewise, PDE4A8 was expressed in normal pituitary and was also significantly overexpressed in the adenoma subtypes (P<0.0001 for all). Among the different adenoma subtypes, corticotroph and lactotroph adenomas were the highest and lowest expressed for PDE4A4, respectively, whereas the opposite was observed for PDE4A8. Naturally occurring oncogenic variants in AIP were shown by a two-hybrid assay to disrupt the ability of AIP to interact with PDE4A5. A reverse two-hybrid screen identified numerous additional variants in the tetratricopeptide repeat (TPR) region of AIP that also disrupted its ability to interact with PDE4A5. The expression of PDE4A4 and PDE4A8 in normal pituitary, their increased expression in adenomatous pituitary cells where AIP is meant to participate, and the disruption of the PDE4A4-AIP interaction by AIP mutants may play a role in pituitary tumorigenesis.
Department of MedicineUniversity of Alabama at Birmingham, Birmingham, Alabama, USA Department of PharmacologyUniversity of Alabama at Birmingham, Birmingham, Alabama, USA gbbolger@uab.edu.
Graeme B
GB
Bolger
Department of Internal MedicineFederal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Mariana F
MF
Bizzi
Department of PediatricsFederal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Sergio V
SV
Pinheiro
Center for EndocrinologyWilliam Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
Giampaolo
G
Trivellin
Department of MedicineUniversity of Alabama at Birmingham, Birmingham, Alabama, USA.
Lisa
L
Smoot
Department of Microbiology and ImmunologyUniversity of Alabama at Birmingham, Birmingham, Alabama, USA.
Mary-Ann
MA
Accavitti
Center for EndocrinologyWilliam Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
Márta
M
Korbonits
Department of Internal MedicineFederal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Antonio
A
Ribeiro-Oliveira
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010902:Pituitary Gland / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517355:PDE4A protein, human
AIP; FIPA; PDE4A4; PDE4A5; PDE4A8; PKA; cAMP; phosphodiesterases; pituitary adenomas