{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T21:03:23Z","timestamp":1789592603793,"version":"build-2803163510"},"reference-count":55,"publisher":"Bioscientifica","issue":"5","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>AIP<\/jats:italic>\n                    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 (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.0001 for all subtypes). Likewise, PDE4A8 was expressed in normal pituitary and was also significantly overexpressed in the adenoma subtypes (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;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\u2013AIP interaction by\n                    <jats:italic>AIP<\/jats:italic>\n                    mutants may play a role in pituitary tumorigenesis.\n                  <\/jats:p>","DOI":"10.1530\/erc-15-0205","type":"journal-article","created":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T22:02:04Z","timestamp":1465336924000},"page":"419-431","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":39,"title":["cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors"],"prefix":"10.1530","volume":"23","author":[{"given":"Graeme B","family":"Bolger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana F","family":"Bizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio V","family":"Pinheiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giampaolo","family":"Trivellin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Smoot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary-Ann","family":"Accavitti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rta","family":"Korbonits","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Ribeiro-Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"2016060718483194000_23.5.419.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11632"},{"key":"2016060718483194000_23.5.419.2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2012-1013"},{"key":"2016060718483194000_23.5.419.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1310359"},{"key":"2016060718483194000_23.5.419.4","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.13.10.6558"},{"key":"2016060718483194000_23.5.419.5","first-page":"101","article-title":"Molecular genetic approaches. I. Two-hybrid systems","volume":"88","author":"Bolger","year":"1998","journal-title":"Methods in Molecular Biology"},{"key":"2016060718483194000_23.5.419.6","doi-asserted-by":"crossref","unstructured":"Bolger GB 2007 Phosphodiesterase isoforms \u2013 an annotated list. In Cyclic Nucleotide Phosphodiesterases in Health and Disease, pp 19\u201331. Eds Beavo JA Francis SH Houslay MD Boca Raton, FL, USA: CRC Press.","DOI":"10.1201\/9781420020847-2"},{"key":"2016060718483194000_23.5.419.7","doi-asserted-by":"crossref","unstructured":"Bolger GB Conti M Houslay MD 2007 Cellular functions of PDE4 enzymes. In Cyclic Nucleotide Phosphodiesterases in Health and Disease, pp. 99\u2013129. Eds Beavo JA Francis SH Houslay MD Boca Raton, FL, USA: Taylor & Francis.","DOI":"10.1201\/9781420020847.ch6"},{"key":"2016060718483194000_23.5.419.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303772200"},{"key":"2016060718483194000_23.5.419.9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.2.1065"},{"key":"2016060718483194000_23.5.419.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303269200"},{"key":"2016060718483194000_23.5.419.11","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(94)90155-4"},{"key":"2016060718483194000_23.5.419.12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.17.11452"},{"key":"2016060718483194000_23.5.419.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2010.06.003"},{"key":"2016060718483194000_23.5.419.14","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.76.060305.150444"},{"key":"2016060718483194000_23.5.419.15","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-2513"},{"key":"2016060718483194000_23.5.419.16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M610942200"},{"key":"2016060718483194000_23.5.419.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2008.08.027"},{"key":"2016060718483194000_23.5.419.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1309730"},{"key":"2016060718483194000_23.5.419.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2014.05.004"},{"key":"2016060718483194000_23.5.419.20","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-13-0043"},{"key":"2016060718483194000_23.5.419.21","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00030.2010"},{"key":"2016060718483194000_23.5.419.22","doi-asserted-by":"publisher","DOI":"10.1159\/000345673"},{"key":"2016060718483194000_23.5.419.23","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(83)01013-7"},{"key":"2016060718483194000_23.5.419.24","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.081131"},{"key":"2016060718483194000_23.5.419.25","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1869"},{"key":"2016060718483194000_23.5.419.26","unstructured":"Hernandez-Ramirez LC Martucci F Morgan RM Ferrau F Trivellin G Begum F Tilley D Ramos-Guajardo N Iacovazzo D Prodromou C 2015 b The enhanced proteasomal degradation of AIP mutant proteins is a mechanism for AIP deficiency in AIP mutation-associated pituitary adenomas. Endocrine Reviews OR35\u201333."},{"key":"2016060718483194000_23.5.419.27","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21178"},{"key":"2016060718483194000_23.5.419.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2009.09.007"},{"key":"2016060718483194000_23.5.419.29","unstructured":"Iacovazzo D Jose D Bunce B Caswell R ez-Ramirez LC Caimari F Ferrau F Kapur S Gabrovska P Dang MN 2015 X-linked acrogigantism (X-LAG): results from a large cohort of patients with pituitary gigantism. Abstract presented at the ENEA Acromegaly Workshop , Marseilles, France."},{"key":"2016060718483194000_23.5.419.30","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21292"},{"key":"2016060718483194000_23.5.419.31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.210120"},{"key":"2016060718483194000_23.5.419.32","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90173-C"},{"key":"2016060718483194000_23.5.419.33","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1002\/j.1460-2075.1986.tb04306.x","article-title":"Microinjected antibodies against the cytoplasmic domain of vesicular stomatitis virus glycoprotein block its transport to the cell surface","volume":"5","author":"Kreis","year":"1986","journal-title":"EMBO Journal"},{"key":"2016060718483194000_23.5.419.34","doi-asserted-by":"publisher","DOI":"10.1038\/340692a0"},{"key":"2016060718483194000_23.5.419.35","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-2611"},{"key":"2016060718483194000_23.5.419.36","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20071251"},{"key":"2016060718483194000_23.5.419.37","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4228"},{"key":"2016060718483194000_23.5.419.38","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.17.11796"},{"key":"2016060718483194000_23.5.419.39","doi-asserted-by":"crossref","unstructured":"Morgan RM Hernandez-Ramirez LC Trivellin G Zhou L Roe SM Korbonits M Prodromou C 2012 Structure of the TPR domain of AIP: lack of client protein interaction with the C-terminal alpha-7 helix of the TPR domain of AIP is sufficient for pituitary adenoma predisposition. PLoS ONE 7 e53339. (doi:10.1371\/journal.pone.0053339)","DOI":"10.1371\/journal.pone.0053339"},{"key":"2016060718483194000_23.5.419.40","doi-asserted-by":"publisher","DOI":"10.1126\/science.1074683"},{"key":"2016060718483194000_23.5.419.41","doi-asserted-by":"publisher","DOI":"10.1210\/jc.86.8.3795"},{"key":"2016060718483194000_23.5.419.42","doi-asserted-by":"crossref","unstructured":"Peverelli E Mantovani G Lania AG Spada A 2014 cAMP in the pituitary: an old messenger for multiple signals. Journal of Molecular Endocrinology 52 R67\u2013R77. (doi:10.1530\/JME-13-0172)","DOI":"10.1530\/JME-13-0172"},{"key":"2016060718483194000_23.5.419.43","doi-asserted-by":"publisher","DOI":"10.1677\/ERC-08-0003"},{"key":"2016060718483194000_23.5.419.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2013.08.022"},{"key":"2016060718483194000_23.5.419.45","first-page":"PP09","article-title":"Interaction of AIP with the cAMP-dependent protein kinase (PKA) pathway and its role in pituitary tumor formation","volume":"35","author":"Schemthaner-Reiter","year":"2014","journal-title":"Endocrine Reviews"},{"key":"2016060718483194000_23.5.419.46","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90745-Z"},{"key":"2016060718483194000_23.5.419.47","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(01)00167-X"},{"key":"2016060718483194000_23.5.419.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2013.01.015"},{"key":"2016060718483194000_23.5.419.49","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408028"},{"key":"2016060718483194000_23.5.419.50","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.50"},{"key":"2016060718483194000_23.5.419.51","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-1980"},{"key":"2016060718483194000_23.5.419.52","doi-asserted-by":"publisher","DOI":"10.1126\/science.1126100"},{"key":"2016060718483194000_23.5.419.53","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(94)90641-6"},{"key":"2016060718483194000_23.5.419.54","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00049.2006"},{"key":"2016060718483194000_23.5.419.55","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.21.14909"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/23\/5\/419.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/23\/5\/419.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:53:09Z","timestamp":1784555589000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/erc\/article\/23\/5\/419-431\/34089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5]]},"references-count":55,"journal-issue":{"issue":"5"},"URL":"https:\/\/doi.org\/10.1530\/erc-15-0205","relation":{},"ISSN":["1351-0088","1479-6821"],"issn-type":[{"value":"1351-0088","type":"print"},{"value":"1479-6821","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5]]}}}