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GT198

From Wikipedia, the free encyclopedia

PSMC3IP
Identifiers
AliasesPSMC3IP, GT198, HOP2, HUMGT198A, ODG3, TBPIP, PSMC3 interacting protein
External IDsOMIM: 608665; MGI: 1098610; HomoloGene: 5940; GeneCards: PSMC3IP; OMA:PSMC3IP - orthologs
Available structures
PDBOrtholog search: PDBe RCSB
Orthologs
SpeciesHumanMouse
Entrez

29893

19183

Ensembl

ENSG00000131470

ENSMUSG00000019303

UniProt

Q9P2W1

O35047

RefSeq (mRNA)

NM_001256014
NM_001256015
NM_001256016
NM_013290
NM_016556

NM_008949

RefSeq (protein)

NP_001242943
NP_001242944
NP_001242945
NP_037422
NP_057640

NP_032975

Location (UCSC)Chr 17: 42.57 – 42.58 MbChr 11: 100.98 – 100.99 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Homologous-pairing protein 2 homolog is a protein which in humans is encoded by the gene PSMC3IP (aliases include GT198, TBPIP, and HOP2).[5] The gene is located within the BRCA1 locus at chromosome 17q21.[6][7] The PSMC3IP gene is often found mutated and overexpressed in certain human cancers including breast and ovarian cancers.[8][9]

GT198 acts as a DNA repair factor responsible for error-free repair of DNA double-strand breaks.[10][11][12] GT198 also controls gene regulation, including steroid hormone-mediated gene activation as a steroid hormone receptor coactivator.[7]

Similar to BRCA1, GT198 is a breast and ovarian cancer susceptibility gene with germline mutations found in a small percentage of early-onset breast and ovarian cancer families.[13]

Gene

[edit]

GT198 is located at the long arm of human chromosome 17 (17q21). GT198 spans 5.5 kilobase pairs (Kb) and contains eight exons. GT198 is located 470 Kb proximal to BRCA1 and 2.9 megabase pairs (Mb) distal to Her2/neu between the two cancer genes. It is currently unknown if genetic instability of each gene could affect neighboring cancer genes. GT198 is found to have mutation, amplification, recombination and distance translocation in germline DNA of one case of human breast cancer.[13]

Protein structure

[edit]

GT198 is a small protein with its monomer contains 217 amino acids. It comprises a DNA-binding domain and forms a protein homodimer[7] or heterodimer.[10]

Function and mechanism

[edit]

GT198 protein binds to single-stranded and double-stranded DNA.[14][15] Its DNA-binding function explains its multiple roles found in transcriptional activation,[7] DNA repair,[12] and meiosis[16] where the strands of DNA helix are regulated. GT198 protein is likely associated with a nuclear protein complex that specializes functions in transcription and DNA repair. Consistent with other DNA repair factors, the defect of GT198 activity would be a risk in these fundamental cellular functions that leads to apoptosis[15] and cancer.

Transcription

[edit]

GT198 has been shown to be a nuclear receptor coactivator, regulating gene activation controlled by steroid hormone receptors.[7][17] These include estrogen, progesterone, glucocorticoid, thyroid, and androgen receptors. GT198 also regulates VEGF and CYP17 gene promoters and several adipogenic or angiogenic factors.[9][8] GT198 can both activate and suppress genes, in part because GT198 has truncated protein isoforms, called splice variants, to compete or counterbalance its wildtype activity.[15]

DNA repair

[edit]

The DNA repair functions of GT198 are mostly published under the name of Hop2 and TBPIP. GT198 has been extensively shown to regulate DNA repair, to stimulate Rad51-induced DNA strand exchange.[10][11][12][14][18] GT198 may act similarly to DNA recombinase, an activity present in Rad51 homologs.[11] GT198 forms heterodimer with MND1 and their complex stimulate DMC1 and RAD51-mediated DNA strand exchange.[19] GT198 is also required for meiosis.[16] Knockout GT198 mice, the genetically modified mice with the GT198 gene inactivated, showed sterile phenotype with defects in testis and ovary without able to reproduce.[16]

Cancer-testis antigen

[edit]

GT198 protein expression pattern is similar to the cancer-testis antigens.[7] In human tumor tissues, however, GT198 overexpression is mostly found in tumor microenvironment, also called tumor stroma.[9][8] Low level of GT198 is present in normal ovary,[8] bone marrow,[citation needed] spleen, and thymus.[7] In human breast cancer, GT198 is a marker for mutant tumor stroma where breast cancer develops.[9] When mutated or activated, GT198 protein expresses in cell cytoplasm rather than nucleus, permitting cytoplasmic expression as a marker of altered GT198.[9]

Discovery

[edit]

After the breast cancer susceptibility gene locus was identified at chromosome 17q21 by Dr. Mary-Claire King's laboratory in 1990, a number of research laboratories competed for screening the locus using various genetic approaches. Once BRCA1 was found in 1994, the continued screening ended while GT198 was published in 1995 as one of the partial cDNA clones resulted from the genetic screening.[20] GT198 stands for "genomic transcript number 198." This name was later chosen in honor of the first discovery of the GT198 gene. The mouse,[21] and human GT198 gene,[6][7] were subsequently described.

Isoforms

[edit]

GT198 has protein isoforms as splice variants encoded by at least six alternative spliced transcripts.[15] The splice variants (GT198a, GT198-1, GT198-2, GT198-3, GT198-4, GT198a-4) encode a truncated version of GT198 protein containing the DNA-binding domain at its C-terminal half. When mutations are present in cancer, isoforms are often overly produced causing abnormal or unregulated GT198 activity.[15]

Gene mutations in disease and cancer

[edit]

Germline mutations

[edit]

GT198 germline deletion and mutation have been linked to primary ovarian insufficiency, when female members were affected in families with XX-female gonadal dysgenesis.[22][23] However, GT198 may not be a common cause of primary ovarian insufficiency.[24]

In breast and ovarian cancer families, pathogenic germline mutations or variants in GT198 were identified at a low frequency (4-5%) in patients mostly with early cancer onset (age younger than 36).[13] The causative effect of GT198 mutations in cancer was supported by segregating mutations in cancer families.

Somatic mutations

[edit]

Deleterious somatic mutations, which often cluster in the 5´-UTR and at the exon 4/intron 4 border of GT198, are abundantly detected in breast and ovarian cancers and in fallopian tube tumors.[15][8][9] Many somatic mutations were interpreted as splicing mutations since alternative splicing was affected.[15] The frequency of GT198 somatic mutations in cancer is unusually high.

Cancer detection biomarker

[edit]

GT198 expression is specific to reactive or angiogenic tumor stromal cells which occur at the early stage of tumor.[8][9] GT198 expression in tumor tissues can be a biomarker for early cancer detection.[25] These include human solid tumors in breast, ovary, uterus, fallopian tube, prostate, bladder, testis, lung, brain, melanoma, kidney, oral cavity, thyroid, and colon.[26][27]

Therapeutic target

[edit]

It has been shown that cancer chemotherapy drug paclitaxel directly inhibits GT198 protein with a high affinity, so that GT198 protein may be a new protein target of paclitaxel.[28] Paclitaxel, sold under the brand name Taxol, is a clinical successful chemotherapy medication widely used to treat many types of solid tumors. In addition, GT198 peptide vaccine reduced tumor growth in mice suggesting that GT198 is a potential drug target in immunotherapy.[29] This is due to GT198 expression in tumor angiogenesis that may give rise tumor cells.[30]

A new study has found that GT198 is a direct target of many oncology drugs and several anticancer herbs.[31] Over a hundred of clinical oncology drugs were tested, and a panel of well-known oncology drugs directly inhibit GT198 DNA-binding activity in vitro. These include mitoxantrone, doxorubicin, paclitaxel, docetaxel, etoposide, dactinomycin, carfilzomib, sirolimus (rapamycin), imatinib (Gleevec), sunitinib, trifluridine, and aminolevulinic acid. GT198 has protein sequence homology with DNA topoisomerase, so that DNA topoisomerase inhibitors are also GT198 inhibitors.[31] Interestingly, several clinical successful anticancer herbs also inhibit GT198. These include a common spice called Allspice from Jamaica, a tree product Gleditsia sinensis L (ZaoJiaoCi in Chinese) from China, and an online health supplement BIRM (Biological Immune Response Modulator) from Ecuador.[31] GT198 is a multi-drug target in human cancer therapy.

References

[edit]
  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000131470 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000019303 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "PSMC3-Interacting Protein; PSMC3IP". omim.org.
  6. 1 2 Ijichi H, Tanaka T, Nakamura T, Yagi H, Hakuba A, Sato M (May 2000). "Molecular cloning and characterization of a human homologue of TBPIP, a BRCA1 locus-related gene". Gene. 248 (1–2): 99–107. doi:10.1016/s0378-1119(00)00141-4. PMID 10806355.
  7. 1 2 3 4 5 6 7 8 Ko L, Cardona GR, Henrion-Caude A, Chin WW (January 2002). "Identification and characterization of a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors". Molecular and Cellular Biology. 22 (1): 357–369. doi:10.1128/mcb.22.1.357-369.2002. PMC 134202. PMID 11739747.
  8. 1 2 3 4 5 6 Peng M, Zhang H, Jaafar L, Risinger JI, Huang S, Mivechi NF, et al. (November 2013). "Human ovarian cancer stroma contains luteinized theca cells harboring tumor suppressor gene GT198 mutations". The Journal of Biological Chemistry. 288 (46): 33387–33397. doi:10.1074/jbc.M113.485581. PMC 3829185. PMID 24097974.
  9. 1 2 3 4 5 6 7 Yang Z, Peng M, Cheng L, Jones K, Maihle NJ, Mivechi NF, et al. (May 2016). "GT198 Expression Defines Mutant Tumor Stroma in Human Breast Cancer". The American Journal of Pathology. 186 (5): 1340–1350. doi:10.1016/j.ajpath.2016.01.006. PMC 4861764. PMID 27001628.
  10. 1 2 3 Enomoto R, Kinebuchi T, Sato M, Yagi H, Shibata T, Kurumizaka H, et al. (August 2004). "Positive role of the mammalian TBPIP/HOP2 protein in DMC1-mediated homologous pairing". The Journal of Biological Chemistry. 279 (34): 35263–35272. doi:10.1074/jbc.M402481200. PMID 15192114.
  11. 1 2 3 Petukhova GV, Pezza RJ, Vanevski F, Ploquin M, Masson JY, Camerini-Otero RD (May 2005). "The Hop2 and Mnd1 proteins act in concert with Rad51 and Dmc1 in meiotic recombination". Nature Structural & Molecular Biology. 12 (5): 449–453. doi:10.1038/nsmb923. PMID 15834424. S2CID 23815248.
  12. 1 2 3 Pezza RJ, Voloshin ON, Vanevski F, Camerini-Otero RD (July 2007). "Hop2/Mnd1 acts on two critical steps in Dmc1-promoted homologous pairing". Genes & Development. 21 (14): 1758–1766. doi:10.1101/gad.1562907. PMC 1920170. PMID 17639081.
  13. 1 2 3 Peng M, Bakker JL, Dicioccio RA, Gille JJ, Zhao H, Odunsi K, et al. (January 2013). "Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers". Genes & Cancer. 4 (1–2): 15–25. doi:10.1177/1947601913486344. PMC 3743154. PMID 23946868.
  14. 1 2 Chi P, San Filippo J, Sehorn MG, Petukhova GV, Sung P (July 2007). "Bipartite stimulatory action of the Hop2-Mnd1 complex on the Rad51 recombinase". Genes & Development. 21 (14): 1747–1757. doi:10.1101/gad.1563007. PMC 1920169. PMID 17639080.
  15. 1 2 3 4 5 6 7 Peng M, Yang Z, Zhang H, Jaafar L, Wang G, Liu M, et al. (January 2013). "GT198 Splice Variants Display Dominant-Negative Activities and Are Induced by Inactivating Mutations". Genes & Cancer. 4 (1–2): 26–38. doi:10.1177/1947601913486345. PMC 3743156. PMID 23946869.
  16. 1 2 3 Petukhova GV, Romanienko PJ, Camerini-Otero RD (December 2003). "The Hop2 protein has a direct role in promoting interhomolog interactions during mouse meiosis". Developmental Cell. 5 (6): 927–936. doi:10.1016/s1534-5807(03)00369-1. PMID 14667414.
  17. ↑ Satoh T, Ishizuka T, Tomaru T, Yoshino S, Nakajima Y, Hashimoto K, et al. (July 2009). "Tat-binding protein-1 (TBP-1), an ATPase of 19S regulatory particles of the 26S proteasome, enhances androgen receptor function in cooperation with TBP-1-interacting protein/Hop2". Endocrinology. 150 (7): 3283–3290. doi:10.1210/en.2008-1122. PMC 2703560. PMID 19325002.
  18. ↑ Cho NW, Dilley RL, Lampson MA, Greenberg RA (September 2014). "Interchromosomal homology searches drive directional ALT telomere movement and synapsis". Cell. 159 (1): 108–121. doi:10.1016/j.cell.2014.08.030. PMC 4177039. PMID 25259924.
  19. ↑ Enomoto R, Kinebuchi T, Sato M, Yagi H, Kurumizaka H, Yokoyama S (March 2006). "Stimulation of DNA strand exchange by the human TBPIP/Hop2-Mnd1 complex". The Journal of Biological Chemistry. 281 (9): 5575–5581. doi:10.1074/jbc.M506506200. PMID 16407260.
  20. ↑ Rommens JM, Durocher F, McArthur J, Tonin P, LeBlanc JF, Allen T, et al. (August 1995). "Generation of a transcription map at the HSD17B locus centromeric to BRCA1 at 17q21". Genomics. 28 (3): 530–542. doi:10.1006/geno.1995.1185. PMID 7490091.
  21. ↑ Tanaka T, Nakamura T, Takagi H, Sato M (October 1997). "Molecular cloning and characterization of a novel TBP-1 interacting protein (TBPIP):enhancement of TBP-1 action on Tat by TBPIP". Biochemical and Biophysical Research Communications. 239 (1): 176–181. Bibcode:1997BBRC..239..176T. doi:10.1006/bbrc.1997.7447. PMID 9345291.
  22. ↑ Zangen D, Kaufman Y, Zeligson S, Perlberg S, Fridman H, Kanaan M, et al. (October 2011). "XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription". American Journal of Human Genetics. 89 (4): 572–579. doi:10.1016/j.ajhg.2011.09.006. PMC 3188834. PMID 21963259.
  23. ↑ Al-Agha AE, Ahmed IA, Nuebel E, Moriwaki M, Moore B, Peacock KA, et al. (February 2018). "Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation". The Journal of Clinical Endocrinology and Metabolism. 103 (2): 555–563. doi:10.1210/jc.2017-01966. PMC 5800840. PMID 29240891.
  24. ↑ Norling A, Hirschberg AL, Karlsson L, Rodriguez-Wallberg KA, Iwarsson E, Wedell A, et al. (2014). "No mutations in the PSMC3IP gene identified in a Swedish cohort of women with primary ovarian insufficiency". Sexual Development. 8 (4): 146–150. doi:10.1159/000357605. PMID 24481226.
  25. ↑ Staff GE (2016-03-21). "New Biomarker Identified as Cause of Breast Cancer and Early Indicator. March 2016". GEN - Genetic Engineering and Biotechnology News. GEN - Genetic Engineering and Biotechnology News.
  26. ↑ Zhang L, Wang Y, Rashid MH, Liu M, Angara K, Mivechi NF, et al. (August 2017). "Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis". Oncotarget. 8 (31): 51591–51607. doi:10.18632/oncotarget.18196. PMC 5584272. PMID 28881671.
  27. ↑ Zhang L, Liu Y, Cheng L, Zhao C, Ko L (2019-08-06). "Mutant GT198 in angiogenesis as a common origin of human prostate and bladder cancers". bioRxiv 10.1101/726679.
  28. ↑ Yang Z, Gurvich VJ, Gupta ML, Mivechi NF, Ko L (2019-06-19). "Oncoprotein GT198 is a direct target of taxol". bioRxiv 10.1101/675579.
  29. ↑ Achyut BR, Zhang H, Angara K, Mivechi NF, Arbab AS, Ko L (April 2020). "Oncoprotein GT198 vaccination delays tumor growth in MMTV-PyMT mice". Cancer Letters. 476: 57–66. doi:10.1016/j.canlet.2020.02.005. PMC 7067666. PMID 32061755.
  30. ↑ "Cells that make blood vessels can also make tumors and enable their spread". Jagwire. 2017-06-19.
  31. 1 2 3 Pang J, Gao J, Zhang L, Mivechi NF, Ko L (June 2021). "GT198 Is a Target of Oncology Drugs and Anticancer Herbs". Frontiers in Oral Health. 2 679460. doi:10.3389/froh.2021.679460. PMC 8409151. PMID 34476412.
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