AIP (aryl hydrocarbon receptor interacting protein)

2012-11-01   Sayka Barry , Márta Korbonits 

Molecular Oncology Centre, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom (SB); Department of Endocrinology, Barts, the London School of Medicine, Queen Mary University of London, London, United Kingdom (MK)

Identity

HGNC
LOCATION
11q13.2
LOCUSID
ALIAS
ARA9,FKBP16,FKBP37,PITA1,SMTPHN,XAP-2,XAP2

DNA/RNA

Description

The AIP gene is located on Chromosome 11 at 67250505-67258579 (GRCh37/hg19). The AIP gene is composed of 6 exons and spans approximately 8.07 kb of genomic DNA.

Transcription

AIP gene encodes a 1250bp mRNA transcript. No splice variants have been identified.

Pseudogene

No pseudogene reported.

Proteins

Description

AIP protein consists of 330 amino acids with a molecular weight of 37 kDa.
AIP belongs to the family of tetratricopeptide repeat (TPR) domain-containing proteins. It has three TPR-domains which are important for protein-protein interactions and an α helix at the C-terminal region and a PPIase-like domain (FKBP-type) in the N-terminus.

Expression

AIP is expressed ubiquitously and found in various human tissues such as: heart, brain, lung, placenta, kidney, skeletal muscle, mouth mucosa, exocrine pancreas, salivary gland, stomach, parathyroid, tonsil, nerve, ovary, connective adipose tissue, spleen, thymus, prostate, testis, colon, leucocytes and pituitary (Kuzhandaivelu et al., 1996; Leontiou et al., 2008).

Localisation

Cytoplasm and nucleus.

Function

To date, several AIP interacting partners have been identified including HBV-X, EBNA-3, AhR, Hsp90, Hsc70, PDE4A5, PDE2A3, PPARα, TRβ1, Gα13, Gαq, TOMM20, RET, survivin and ERα, which may indicate that AIP is involved in various cellular pathways, however, the consequenses ot these interactions are not fully understood (Cai et al., 2011; Trivellin and Korbonits, 2011).
Clinical and functional data supports its role as a tumour suppressor gene. Loss of heterozygosity (LOH) is found in AIP mutation positive tumours. Our lab has previously shown that over-expression of wild-type AIP in human fibroblast and pituitary cell lines reduced cell proliferation compared with the empty vector control in vitro whereas the mutant AIP loses this ability compared to the wild-type AIP (Leontiou et al., 2008). AIP knockdown with siRNA also supports the tumour-suppressor role for AIP as it results in increased cell proliferation in GH3 cells (Heliovaara et al., 2009; Leontiou et al., 2008).
Homozygous deletion of AIP is embryonically lethal due to cardiovascular developmental abnormalities and erythropoetic failure (Kang et al., 2011; Lin et al., 2007), suggesting that AIP has a crucial role for cardiac development and for maintaining erythropoiesis in mice. Heterozygote deletion of the AIP gene lead to the development of growth hormone- and prolactin-secreting pituitary adenomas (Raitila et al., 2010).
AIP is a molecular co-chaperone protein. The most studied partner is the nuclear xenobiotic receptor AhR (aryl hydrocarbon receptor). AIP regulates its sub-cellular localization and degradation. AhR, also known as dioxin receptor is a ligand activated transcription factor found in the cytoplasm as part of a multiprotein complex with Hsp90 (Perdew, 1988), AIP (Carver and Bradfield, 1997; Meyer et al., 1998) and p23 (Kazlauskas et al., 1999). After binding to its ligand it is transported to the nucleus where it heterodimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT). This complex then binds to DNA recognition sequences known as xenobiotic inducible response elements (XREs/DREs/AHREs) within the promoter region of specific genes, leading to the transcription of xenobiotic-metabolizing enzymes. However, there is conflicting data regarding the role of AIP on AhR function. Some findings suggested that AIP has a role in stabilising unliganded AhR in the cytoplasm (LaPres et al., 2000; Meyer and Perdew, 1999; Nukaya et al., 2010), therefore AIP may play a positive role in AhR-mediated signalling. In contrast, other studies have suggested that AIP has a negative effect on AhR transcriptional activity (Hollingshead et al., 2004; Pollenz et al., 2006; Pollenz and Dougherty, 2005). AIP has other functions related to the other interacting partners but it is currently not known how lack of AIP leads to pituitary tumorigenesis.

Homology

AIP shares 94% and 93% sequence identity with mouse and rat AIP respectively.

Mutations

Germinal

Germline mutations of AIP are associated with familial isolated pituitary adenoma (FIPA). Approximately 20% of FIPA families and 13% of sporadic young (

Somatic

Somatic mutations in AIP have not been found to date in sporadic pituitary adenomas. Somatic mutations in AIP have been investigated in colorectal cancers, breast cancers, prostate tumours (Georgitsi et al., 2007) as well as endocrine tumours (thyroid lesions, adrenal lesions, carcinoids, parathyroid lesions, paragangliomas, pancreatic endocrine tumours and adenocarcinoids) but no somatic mutations were found (Raitila et al., 2007; Tichomirowa et al., 2011).

Implicated in

Entity name
Familial isolated pituitary adenoma (FIPA) and simplex pituitary adenoma cases with germline AIP mutation
Note
Familial isolated pituitary adenoma (FIPA) is an autosomal dominant disease with incomplete penetrance. Heterozygote germline mutations have been identified in the aryl hydrocarbon receptor interacting protein (AIP) gene in 20% of FIPA families. FIPA has been characterised in >200 families. Most of the FIPA families with AIP mutations presented somatotropinomas or somatomammotropinomas followed by prolactinomas as well as non-functioning adenomas and very rarely corticotroph or thyrotropinomas. Approximately, eighty five percent of AIP mutation positive FIPA patients have acromegaly and around fifty percent with AIP mutation positive somatotropinomas are associated with gigantism (Daly et al., 2010). Pituitary tumours in AIP mutation positive patients have larger, more aggressive, invasive tumours, most commonly sparsely granulated subtype which show a poor response to somatostatin analogues (Daly et al., 2010) and also have a younger age at disease onset (18-24 years) (Korbonits and Kumar, 2012).
Prognosis
AIP mutation positive patients show younger mean age at diagnosis than sporadic pituitary cases. Decreased level of AIP has been correlated with tumour invassiveness in somatotropinomas (Kasuki Jomori de Pinho et al., 2011). Genetic screening is now able to stratify carrier subjects and help to diagnose the presymptomatic patients (Chahal et al., 2011).

Bibliography

Pubmed IDLast YearTitleAuthors
219849052011The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α.Cai W et al
91110571997Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo.Carver LA et al
223190332012Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients.Cazabat L et al
176093952007Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas.Cazabat L et al
205701742010Clinical, genetic and molecular characterization of patients with familial isolated pituitary adenomas (FIPA).Chahal HS et al
212081072011AIP mutation in pituitary adenomas in the 18th century and today.Chahal HS et al
206858572010Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.Daly AF et al
172447802007Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.Daly AF et al
172427032007Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers.Georgitsi M et al
198508932009The expression of AIP-related molecules in elucidation of cellular pathways in pituitary adenomas.Heliövaara E et al
153221222004The aryl hydrocarbon (Ah) receptor transcriptional regulator hepatitis B virus X-associated protein 2 antagonizes p23 binding to Ah receptor-Hsp90 complexes and is dispensable for receptor function.Hollingshead BD et al
214545732011Developmental control of apoptosis by the immunophilin aryl hydrocarbon receptor-interacting protein (AIP) involves mitochondrial import of the survivin protein.Kang BH et al
211783322011Low aryl hydrocarbon receptor-interacting protein expression is a better marker of invasiveness in somatotropinomas than Ki-67 and p53.Kasuki Jomori de Pinho L et al
102241201999Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor.Kazlauskas A et al
227203331993AIP Familial Isolated Pituitary AdenomasKorbonits M et al
89728611996XAP2, a novel hepatitis B virus X-associated protein that inhibits X transactivation.Kuzhandaivelu N et al
106924062000ARA9 modifies agonist signaling through an increase in cytosolic aryl hydrocarbon receptor.LaPres JJ et al
183815722008The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas.Leontiou CA et al
179165582007Deletion of the aryl hydrocarbon receptor-associated protein 9 leads to cardiac malformation and embryonic lethality.Lin BC et al
104134641999Characterization of the AhR-hsp90-XAP2 core complex and the role of the immunophilin-related protein XAP2 in AhR stabilization.Meyer BK et al
94479951998Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity.Meyer BK et al
208293552010The aryl hydrocarbon receptor-interacting protein (AIP) is required for dioxin-induced hepatotoxicity but not for the induction of the Cyp1a1 and Cyp1a2 genes.Nukaya M et al
204572152010AIP gene and familial isolated pituitary adenomas.Ozfirat Z et al
28435371988Association of the Ah receptor with the 90-kDa heat shock protein.Perdew GH et al
168353542006Role of endogenous XAP2 protein on the localization and nucleocytoplasmic shuttling of the endogenous mouse Ahb-1 receptor in the presence and absence of ligand.Pollenz RS et al
179141182007No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia.Raitila A et al
207097962010Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression.Raitila A et al
217530722011High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas.Tichomirowa MA et al
214544412011AIP and its interacting partners.Trivellin G et al
167286432006Pituitary adenoma predisposition caused by germline mutations in the AIP gene.Vierimaa O et al

Other Information

Locus ID:

NCBI: 9049
MIM: 605555
HGNC: 358
Ensembl: ENSG00000110711

Variants:

dbSNP: 9049
ClinVar: 9049
TCGA: ENSG00000110711
COSMIC: AIP

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000110711ENST00000279146O00170
ENSG00000110711ENST00000279146G9I2H4
ENSG00000110711ENST00000525341V9GYQ3
ENSG00000110711ENST00000528641E9PMH2

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
MetabolismREACTOMER-HSA-1430728
Biological oxidationsREACTOMER-HSA-211859
Phase 1 - Functionalization of compoundsREACTOMER-HSA-211945
Aryl hydrocarbon receptor signallingREACTOMER-HSA-8937144

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
167286432006Pituitary adenoma predisposition caused by germline mutations in the AIP gene.109
167286432006Pituitary adenoma predisposition caused by germline mutations in the AIP gene.109
183815722008The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas.57
206858572010Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.57
172447802007Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.56
233719672013Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene.53
205073462010The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes.48
212081072011AIP mutation in pituitary adenomas in the 18th century and today.35
223190332012Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients.32
195562872009Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications.31

Citation

Sayka Barry ; Márta Korbonits

AIP (aryl hydrocarbon receptor interacting protein)

Atlas Genet Cytogenet Oncol Haematol. 2012-11-01

Online version: http://atlasgeneticsoncology.org/gene/604/aip-(aryl-hydrocarbon-receptor-interacting-protein)