Biology:GT198

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GT198 is a human oncogene (gene symbol PSMC3IP, alias TBPIP or Hop2)[1] located within the BRCA1 locus at chromosome 17q21.[2][3] It encodes protein product named GT198, Hop2 or TBPIP. The GT198 gene is found to be mutated with its protein overexpressed in human cancers including breast and ovarian cancers.[4][5]

GT198 acts as a DNA repair factor responsible for error-free repair of DNA double-strand breaks.[6][7][8] GT198 also controls gene regulation, including steroid hormone-mediated gene activation as a steroid hormone receptor coactivator.[3]

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.[9]

Gene

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.[9]

Protein structure

GT198 is a small protein with its monomer contains 217 amino acids. It comprises a DNA-binding domain and forms a protein homodimer[3] or heterodimer.[6]

Function and mechanism

GT198 protein binds to single-stranded and double-stranded DNA.[10][11] Its DNA-binding function explains its multiple roles found in transcriptional activation,[3] DNA repair,[8] and meiosis[12] 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[11] and cancer.

Transcription

GT198 has been shown to be a nuclear receptor coactivator, regulating gene activation controlled by steroid hormone receptors.[3][13] These include estrogen, progesterone, glucocorticoid, thyroid, and androgen receptors. GT198 also regulates VEGF and CYP17 gene promoters and several adipogenic or angiogenic factors.[5][4] 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.[11]

DNA repair

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.[6][7][8][10][14] GT198 may act similarly to DNA recombinase, an activity present in Rad51 homologs.[7] GT198 forms heterodimer with MND1 and their complex stimulate DMC1 and RAD51-mediated DNA strand exchange.[15] GT198 is also required for meiosis.[12] 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.[12]

Cancer-testis antigen

GT198 protein expression pattern is similar to the cancer-testis antigens.[3] In human tumor tissues, however, GT198 overexpression is mostly found in tumor microenvironment, also called tumor stroma.[5][4] Low level of GT198 is present in normal ovary,[4] bone marrow,[citation needed] spleen, and thymus.[3] In human breast cancer, GT198 is a marker for mutant tumor stroma where breast cancer develops.[5] When mutated or activated, GT198 protein expresses in cell cytoplasm rather than nucleus, permitting cytoplasmic expression as a marker of altered GT198.[5]

Discovery

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.[16] GT198 stands for “genomic transcript number 198.” This name was later chosen in honor of the first discovery of the GT198 gene. The mouse,[17] and human GT198 gene,[2][3] were subsequently described.

Isoforms

GT198 has protein isoforms as splice variants encoded by at least six alternative spliced transcripts.[11] 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.[11]

Gene mutations in disease and cancer

Germline mutations

GT198 germline deletion and mutation have been linked to primary ovarian insufficiency, when female members were affected in families with XX-female gonadal dysgenesis.[18][19] However, GT198 may not be a common cause of primary ovarian insufficiency.[20]

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).[9] The causative effect of GT198 mutations in cancer was supported by segregating mutations in cancer families.

Somatic mutations

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.[11][4][5] Many somatic mutations were interpreted as splicing mutations since alternative splicing was affected.[11] The frequency of GT198 somatic mutations in cancer is unusually high.

Cancer detection biomarker

GT198 expression is specific to reactive or angiogenic tumor stromal cells which occur at the early stage of tumor.[4][5] GT198 expression in tumor tissues can be a biomarker for early cancer detection.[21] These include human solid tumors in breast, ovary, uterus, fallopian tube, prostate, bladder, testis, lung, brain, melanoma, kidney, oral cavity, thyroid, and colon.[22][23]

Therapeutic target

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.[24] 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.[25] This is due to GT198 expression in tumor angiogenesis that may give rise tumor cells.[26]

A new study has found that GT198 is a direct target of many oncology drugs and several anticancer herbs.[27] 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.[27] 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.[27] GT198 is a multi-drug target in human cancer therapy.

References

  1. ↑ PSMC3-INTERACTING PROTEIN; PSMC3IP
  2. ↑ 2.0 2.1 Ijichi, H.; Tanaka, T.; Nakamura, T.; Yagi, H.; Hakuba, A.; Sato, M. (2000-05-02). "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. ISSN 0378-1119. PMID 10806355. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Ko, Lan; Cardona, Guemalli R.; Henrion-Caude, Alexandra; Chin, William W. (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. ISSN 0270-7306. PMID 11739747. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Peng, Min; Zhang, Hao; Jaafar, Lahcen; Risinger, John I.; Huang, Shuang; Mivechi, Nahid F.; Ko, Lan (2013-11-15). "Human Ovarian Cancer Stroma Contains Luteinized Theca Cells Harboring Tumor Suppressor Gene GT198 Mutations". Journal of Biological Chemistry 288 (46): 33387–33397. doi:10.1074/jbc.M113.485581. ISSN 0021-9258. PMID 24097974. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Yang, Zheqiong; Peng, Min; Cheng, Liang; Jones, Kimya; Maihle, Nita J.; Mivechi, Nahid F.; Ko, Lan (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. ISSN 0002-9440. PMID 27001628. 
  6. ↑ 6.0 6.1 6.2 Enomoto, Rima; Kinebuchi, Takashi; Sato, Makoto; Yagi, Hideshi; Shibata, Takehiko; Kurumizaka, Hitoshi; Yokoyama, Shigeyuki (2004-08-20). "Positive Role of the Mammalian TBPIP/HOP2 Protein in DMC1-mediated Homologous Pairing". Journal of Biological Chemistry 279 (34): 35263–35272. doi:10.1074/jbc.M402481200. ISSN 0021-9258. PMID 15192114. 
  7. ↑ 7.0 7.1 7.2 Petukhova, Galina V; Pezza, Roberto J; Vanevski, Filip; Ploquin, Mickael; Masson, Jean-Yves; Camerini-Otero, R Daniel (2005-04-17). "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. ISSN 1545-9993. PMID 15834424. 
  8. ↑ 8.0 8.1 8.2 Pezza, Roberto J.; Voloshin, Oleg N.; Vanevski, Filip; Camerini-Otero, R. Daniel (2007-07-15). "Hop2/Mnd1 acts on two critical steps in Dmc1-promoted homologous pairing". Genes & Development 21 (14): 1758–1766. doi:10.1101/gad.1562907. ISSN 0890-9369. PMID 17639081. 
  9. ↑ 9.0 9.1 9.2 Peng, Min; Bakker, Janine L.; Dicioccio, Richard A.; Gille, Johan J. P.; Zhao, Hua; Odunsi, Kunle; Sucheston, Lara; Jaafar, Lahcen 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. ISSN 1947-6019. PMID 23946868. 
  10. ↑ 10.0 10.1 Chi, Peter; Filippo, Joseph San; Sehorn, Michael G.; Petukhova, Galina V.; Sung, Patrick (2007-07-15). "Bipartite stimulatory action of the Hop2–Mnd1 complex on the Rad51 recombinase". Genes & Development 21 (14): 1747–1757. doi:10.1101/gad.1563007. ISSN 0890-9369. PMID 17639080. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 Peng, Min; Yang, Zheqiong; Zhang, Hao; Jaafar, Lahcen; Wang, Guanghu; Liu, Min; Flores-Rozas, Hernan; Xu, Jianming 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. ISSN 1947-6019. PMID 23946869. 
  12. ↑ 12.0 12.1 12.2 Petukhova, Galina V.; Romanienko, Peter J.; Camerini-Otero, R. Daniel (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. ISSN 1534-5807. PMID 14667414. 
  13. ↑ Satoh, Tetsurou; Ishizuka, Takahiro; Tomaru, Takuya; Yoshino, Satoshi; Nakajima, Yasuyo; Hashimoto, Koshi; Shibusawa, Nobuyuki; Monden, Tsuyoshi et al. (2009-07-01). "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. ISSN 0013-7227. PMID 19325002. 
  14. ↑ Cho, Nam Woo; Dilley, Robert L.; Lampson, Michael A.; Greenberg, Roger A. (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. ISSN 0092-8674. PMID 25259924. 
  15. ↑ Enomoto, Rima; Kinebuchi, Takashi; Sato, Makoto; Yagi, Hideshi; Kurumizaka, Hitoshi; Yokoyama, Shigeyuki (2006-03-03). "Stimulation of DNA Strand Exchange by the Human TBPIP/Hop2-Mnd1 Complex". Journal of Biological Chemistry 281 (9): 5575–5581. doi:10.1074/jbc.M506506200. ISSN 0021-9258. PMID 16407260. 
  16. ↑ Rommens, J. M.; Durocher, F.; McArthur, J.; Tonin, P.; LeBlanc, J. F.; Allen, T.; Samson, C.; Ferri, L. et al. (1995-08-10). "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. ISSN 0888-7543. PMID 7490091. 
  17. ↑ Tanaka, Tomoaki; Nakamura, Takahiro; Takagi, Hiroshi; Sato, Makoto (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. doi:10.1006/bbrc.1997.7447. ISSN 0006-291X. PMID 9345291. 
  18. ↑ Zangen, David; Kaufman, Yotam; Zeligson, Sharon; Perlberg, Shira; Fridman, Hila; Kanaan, Moein; Abdulhadi-Atwan, Maha; Abu Libdeh, Abdulsalam et al. (October 2011). "XX Ovarian Dysgenesis Is Caused by a PSMC3IP/HOP2 Mutation that Abolishes Coactivation of Estrogen-Driven Transcription". The American Journal of Human Genetics 89 (4): 572–579. doi:10.1016/j.ajhg.2011.09.006. ISSN 0002-9297. PMID 21963259. 
  19. ↑ Al-Agha, Abdulmoein Eid; Ahmed, Ihab Abdulhamed; Nuebel, Esther; Moriwaki, Mika; Moore, Barry; Peacock, Katherine A; Mosbruger, Tim; Neklason, Deborah W et al. (2017-12-12). "Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation". The Journal of Clinical Endocrinology & Metabolism 103 (2): 555–563. doi:10.1210/jc.2017-01966. ISSN 0021-972X. PMID 29240891. 
  20. ↑ Norling, A.; Hirschberg, A.L.; Karlsson, L.; Rodriguez-Wallberg, K.A.; Iwarsson, E.; Wedell, A.; Barbaro, M. (2014). "No Mutations in the PSMC3IP Gene Identified in a Swedish Cohort of Women with Primary Ovarian Insufficiency" (in en). Sexual Development 8 (4): 146–150. doi:10.1159/000357605. ISSN 1661-5425. PMID 24481226. 
  21. ↑ New Biomarker Identified as Cause of Breast Cancer and Early Indicator. March 2016
  22. ↑ Zhang, Liyong; Wang, Yan; Rashid, Mohammad H.; Liu, Min; Angara, Kartik; Mivechi, Nahid F.; Maihle, Nita J.; Arbab, Ali S. et al. (2017-05-25). "Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis". Oncotarget 8 (31): 51591–51607. doi:10.18632/oncotarget.18196. ISSN 1949-2553. PMID 28881671. 
  23. ↑ Zhang, Liyong; Liu, Yehai; Cheng, Liang; Zhao, Chengquan; Ko, Lan (2019-08-06). "Mutant GT198 in angiogenesis as a common origin of human prostate and bladder cancers" (in en). bioRxiv: 726679. doi:10.1101/726679. https://www.biorxiv.org/content/10.1101/726679v1. 
  24. ↑ Yang, Zheqiong; Gurvich, Vadim J.; Gupta, Mohan L.; Mivechi, Nahid F.; Ko, Lan (2019-06-19). "Oncoprotein GT198 is a direct target of taxol" (in en). bioRxiv: 675579. doi:10.1101/675579. https://www.biorxiv.org/content/10.1101/675579v1. 
  25. ↑ Achyut, Bhagelu R.; Zhang, Hao; Angara, Kartik; Mivechi, Nahid F.; Arbab, Ali S.; Ko, Lan (2020-04-28). "Oncoprotein GT198 vaccination delays tumor growth in MMTV-PyMT mice". Cancer Letters 476: 57–66. doi:10.1016/j.canlet.2020.02.005. ISSN 1872-7980. PMID 32061755. 
  26. ↑ "Cells that make blood vessels can also make tumors and enable their spread". Jagwire. 2017-06-19. https://jagwire.augusta.edu/archives/45419. 
  27. ↑ 27.0 27.1 27.2 Pang, Junfeng; Gao, Jie; Zhang, Liyong; Mivechi, Nahid F.; Ko, Lan (2021-06-11). "GT198 Is a Target of Oncology Drugs and Anticancer Herbs". Frontiers in Oral Health 2: 679460. doi:10.3389/froh.2021.679460. ISSN 2673-4842. PMID 34476412. 



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