Description | Two isoforms: - Isoform alfa (614 aa, mass around 70kD) - Isoform beta: missing of aa 239-565 (mass around 32kD) |
Expression | NCOA4 is widely expressed in several tissues, including testis, adrenal and thyroid glands, thymus, prostate. A truncated NCOA4 corresponding to the beta isoform is fused to RET exon 12 and is aberrantly expressed in papillary thyroid carcinoma as a consequence of intrachromosomal rearrangements at 10q11.2 (RET/NCOA4). |
Function | NCOA4 is involved in the androgen receptor signaling pathway and in the development of the male gonade. It is a ligand-dependent associated protein for the androgen receptor (AR), that functions as coactivator to enhance AR transcriptional activity (7-10 fold in human prostate cancer cells) and protein stability. NCOA4 also enhances the agonist activity of anti-androgens in human prostate cancer cells (3-30 fold in the prostate cancer cell line DU145), with relevant implications for hormonal treatment of prostate cancer. Albeit to a lesser degree (up to 2-fold), NCO4 also enhances transcription activity of other steroid receptors, such as glucocorticoid receptor (GR), progesterone receptor (PR) and oestrogen receptor (ER). In addition to the interaction with steroid hormone receptors, NCOA4 functions as coactivator of peroxisome proliferator-activated receptor gamma (PPARG). PPARG is a peroxisome proliferator-activated receptor and as such belongs to the nuclear hormone receptor superfamily. PPARG is highly expressed in adipose tissue (were it is involved in adipogenesis and in the regulation of adipocyte-specific genes), as well as in other human tissues. Interestingly, PPARG is rearranged with PAX8 in a subset of follicular thyroid tumors. Unlike the AR-NCOA4 interaction, which requires the presence of androgen, the PPARG-NCOA4 interaction can occur in the absence of exogenous ligand. However, the presence of the ligand enhances PPARG-NCOA4 transactivation and NCOA4 is thus regarded as a ligand-enhanced coactivator of PPARG. |
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| Ligand-specific interaction between AR (Androgen receptor), NCOA4, and the androgen receptor ligand DHT (dihydrotestosterone). |
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Entity | inv(10)(q11q11) with RET/NCOA4 rearrangement in thyroid cancer |
Disease | Papillary thyroid carcinoma. RET/NCOA4 may occur in non radiation-associated carcinomas but it is particularly common in radiation-associated tumors like those linked to the Chernobyl nuclear accident (1986). |
Prognosis | RET/NCOA4 may be associated with aggressive behaviour. Among post-Chernobyl papillary carcinomas, RET/NCOA4 has been associated with tumors that were of shorter latency after radiation exposure, of larger size, with extrathyroidal extension, and that were classified as solid variant papillary carcinomas. |
Cytogenetics | Simple karyotypes with balanced chromosomal inversions due to structural rearrangement of NCOA4 and RET gene on chromosome 10 [inv(10)(q11.2-q21)], resulting in RET/NCOA4. |
Hybrid/Mutated Gene | RET/NCOA4 |
Abnormal Protein | NCOA4/RET (RP3) |
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| Diagram of RET/NCOA4 oncogene. The red arrow indicates the breakpoint region. |
Oncogenesis | RET/PTC oncogenes are generated by chromosomal rearrangements resulting in the fusion of the RET tyrosine-kinase (RET-TK) domain to the 5'-terminal region of heterologous genes (e.g. H4, RIa, RFG5, hTIF1, RFG7, ELKS). All are balanced inversions or translocations which involve the 3.0 kb intron 11 of RET. RET-fused genes are widely expressed in human tissues, including thyroid follicular cells, and have putative dimerization domains. As the chimeric forms of RET-TK are translated into fusion proteins, these domains of the translocated amino terminal regions allow dimerization and thus ligand independent activation of RET-TK, which is considered essential for the transformation of thyroid cells. To date, at least 16 chimeric mRNAs involving 10 different genes have been reported, of which RET/PTC1 (consisting in the fusion of RET with H4) and RET/NCOA4 (consisting in the fusion of RET with NCOA4) are by far the most common. ANIMAL MODELS RET/NCOA4 transgenic mice have been generated by Powell and coworkers using a construct with the RET/NCOA4 fusion gene downstream and under the control of the bovine thyroglobulin gene regulatory region; they express RET/NCOA4 selectively in the thyroid gland and develop thyroid hyperplasia and solid tumor variants of papillary carcinomas. |
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Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an Internally deleted ELE1 beta isoform. |
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PMID 15663989 |
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Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. |
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PMID 10347167 |
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PMID 16762319 |
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Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells. |
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Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7379-84. |
PMID 9636157 |
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Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70. |
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The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. |
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PMID 9850089 |
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Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. |
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Clin Cancer Res. 2000 Mar;6(3):1093-103. |
PMID 10741739 |
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Molecular characterization of RET/PTC3: a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma. |
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PMID 8290261 |
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Direct regulation of androgen receptor-associated protein 70 by thyroid hormone and its receptors. |
Tai PJ, Huang YH, Shih CH, Chen RN, Chen CD, Chen WJ, Wang CS, Lin KH. |
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PMID 17412801 |
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RET oncogene activation in papillary thyroid carcinoma. |
Tallini G, Asa S L. |
Adv Anat Pathol. 2001 Nov;8(6):345-54. |
PMID 11707626 |
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Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. |
Yeh S, Chang C. |
Proc Natl Acad Sci U S A. 1996 May 28;93(11):5517-21. |
PMID 8643607 |
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