DOI QR코드

DOI QR Code

Emerging role of anti-proliferative protein BTG1 and BTG2

  • Kim, Sang Hyeon (Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Severance Biomedical Science Institute and Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • Jung, In Ryeong (Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Severance Biomedical Science Institute and Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • Hwang, Soo Seok (Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Severance Biomedical Science Institute and Brain Korea 21 Project, Yonsei University College of Medicine)
  • Received : 2022.05.01
  • Accepted : 2022.07.20
  • Published : 2022.08.31

Abstract

The B cell translocation gene 1 (BTG1) and BTG2 play a key role in a wide range of cellular activities including proliferation, apoptosis, and cell growth via modulating a variety of central biological steps such as transcription, post-transcriptional, and translation. BTG1 and BTG2 have been identified by genomic profiling of B-cell leukemia and diverse lymphoma types where both genes are commonly mutated, implying that they serve as tumor suppressors. Furthermore, a low expression level of BTG1 or BTG2 in solid tumors is frequently associated with malignant progression and poor treatment outcomes. As physiological aspects, BTG1 and BTG2 have been discovered to play a critical function in regulating quiescence in hematopoietic lineage such as Hematopoietic stem cells (HSCs) and naive and memory T cells, highlighting their novel role in maintaining the quiescent state. Taken together, emerging evidence from the recent studies suggests that BTG1 and BTG2 play a central anti-proliferative role in various tissues and cells, indicating their potential as targets for innovative therapeutics.

Keywords

Acknowledgement

We thank all members of the Department of Biochemistry and Molecular Biology of Yonsei University College of Medicine for administrative support. This work was supported by the Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine. This work of SSH has supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2021R1A2C2093640 and 2018R1A5A2025079) and a faculty research grant (6-2021-0156) and a new faculty research seed money grant (2021-32-0055) of Yonsei University College of Medicine.

References

  1. Coleman WB (2015) Genomic catastrophe and neoplastic transformation. Am J Pathol 185, 1846-1849 https://doi.org/10.1016/j.ajpath.2015.05.001
  2. Chen Y, Wang C, Wu J and Li L (2015) BTG/Tob family members Tob1 and Tob2 inhibit proliferation of mouse embryonic stem cells via Id3 mRNA degradation. Biochem Biophys Res Commun 462, 208-214 https://doi.org/10.1016/j.bbrc.2015.04.117
  3. Yoshida Y, Matsuda S, Ikematsu N et al (1998) ANA, a novel member of Tob/BTG1 family, is expressed in the ventricular zone of the developing central nervous system. Oncogene 16, 2687-2693 https://doi.org/10.1038/sj.onc.1201805
  4. el-Ghissassi F, Valsesia-Wittmann S, Falette N, Duriez C, Walden PD and Puisieux A (2002) BTG2(TIS21/PC3) induces neuronal differentiation and prevents apoptosis of terminally differentiated PC12 cells. Oncogene 21, 6772-6778 https://doi.org/10.1038/sj.onc.1205888
  5. Rouault JP, Rimokh R, Tessa C et al (1992) BTG1, a member of a new family of antiproliferative genes. EMBO J 11, 1663-1670 https://doi.org/10.1002/j.1460-2075.1992.tb05213.x
  6. Sasajima H, Nakagawa K, Kashiwayanagi M and Yokosawa H (2012) Polyubiquitination of the B-cell translocation gene 1 and 2 proteins is promoted by the SCF ubiquitin ligase complex containing betaTrCP. Biol Pharm Bull 35, 1539-1545 https://doi.org/10.1248/bpb.b12-00330
  7. Park TJ, Kim JY, Park SH, Kim HS and Lim IK (2009) Skp2 enhances polyubiquitination and degradation of TIS21/BTG2/PC3, tumor suppressor protein, at the downstream of FoxM1. Exp Cell Res 315, 3152-3162 https://doi.org/10.1016/j.yexcr.2009.07.009
  8. Fei JF, Haffner C and Huttner WB (2014) 3' UTR-dependent, miR-92-mediated restriction of Tis21 expression maintains asymmetric neural stem cell division to ensure proper neocortex size. Cell Rep 7, 398-411 https://doi.org/10.1016/j.celrep.2014.03.033
  9. Kawakubo H, Brachtel E, Hayashida T et al (2006) Loss of B-cell translocation gene-2 in estrogen receptor-positive breast carcinoma is associated with tumor grade and overexpression of cyclin d1 protein. Cancer Res 66, 7075-7082 https://doi.org/10.1158/0008-5472.CAN-06-0379
  10. Rouault JP, Falette N, Guehenneux F et al (1996) Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway. Nat Genet 14, 482-486 https://doi.org/10.1038/ng1296-482
  11. Cortes U, Moyret-Lalle C, Falette N et al (2000) BTG gene expression in the p53-dependent and -independent cellular response to DNA damage. Mol Carcinog 27, 57-64 https://doi.org/10.1002/(SICI)1098-2744(200002)27:2<57::AID-MC1>3.0.CO;2-I
  12. Prevot D, Voeltzel T, Birot AM et al (2000) The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. J Biol Chem 275, 147-153 https://doi.org/10.1074/jbc.275.1.147
  13. Busson M, Carazo A, Seyer P et al (2005) Coactivation of nuclear receptors and myogenic factors induces the major BTG1 influence on muscle differentiation. Oncogene 24, 1698-1710 https://doi.org/10.1038/sj.onc.1208373
  14. Hu XD, Meng QH, Xu JY et al (2011) BTG2 is an LXXLL-dependent co-repressor for androgen receptor transcriptional activity. Biochem Biophys Res Commun 404, 903-909 https://doi.org/10.1016/j.bbrc.2010.12.064
  15. Lin WJ, Gary JD, Yang MC, Clarke S and Herschman HR (1996) The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. J Biol Chem 271, 15034-15044 https://doi.org/10.1074/jbc.271.25.15034
  16. Bedford MT and Clarke SG (2009) Protein arginine methylation in mammals: who, what, and why. Mol Cell 33, 1-13 https://doi.org/10.1016/j.molcel.2008.12.013
  17. Passeri D, Marcucci A, Rizzo G et al (2006) Btg2 enhances retinoic acid-induced differentiation by modulating histone H4 methylation and acetylation. Mol Cell Biol 26, 5023-5032 https://doi.org/10.1128/MCB.01360-05
  18. Hata K, Nishijima K and Mizuguchi J (2007) Role for Btg1 and Btg2 in growth arrest of WEHI-231 cells through arginine methylation following membrane immunoglobulin engagement. Exp Cell Res 313, 2356-2366 https://doi.org/10.1016/j.yexcr.2007.03.021
  19. Cho JW, Kim JJ, Park SG et al (2004) Identification of B-cell translocation gene 1 as a biomarker for monitoring the remission of acute myeloid leukemia. Proteomics 4, 3456-3463 https://doi.org/10.1002/pmic.200400968
  20. Hong JW, Ryu MS and Lim IK (2005) Phosphorylation of serine 147 of tis21/BTG2/pc3 by p-Erk1/2 induces Pin-1 binding in cytoplasm and cell death. J Biol Chem 280, 21256-21263 https://doi.org/10.1074/jbc.M500318200
  21. Lin WJ, Chang YF, Wang WL and Huang CY (2001) Mitogen-stimulated TIS21 protein interacts with a protein-kinase-Calpha-binding protein rPICK1. Biochem J 354, 635-643 https://doi.org/10.1042/bj3540635
  22. Sasajima H, Nakagawa K and Yokosawa H (2002) Antiproliferative proteins of the BTG/Tob family are degraded by the ubiquitin-proteasome system. Eur J Biochem 269, 3596-3604 https://doi.org/10.1046/j.1432-1033.2002.03052.x
  23. Hwang SS, Lim J, Yu Z et al (2020) mRNA destabilization by BTG1 and BTG2 maintains T cell quiescence. Science 367, 1255-1260 https://doi.org/10.1126/science.aax0194
  24. Mauxion F, Faux C and Seraphin B (2008) The BTG2 protein is a general activator of mRNA deadenylation. EMBO J 27, 1039-1048 https://doi.org/10.1038/emboj.2008.43
  25. Stupfler B, Birck C, Seraphin B and Mauxion F (2016) BTG2 bridges PABPC1 RNA-binding domains and CAF1 deadenylase to control cell proliferation. Nat Commun 7, 10811
  26. Aslam A, Mittal S, Koch F, Andrau JC and Winkler GS (2009) The Ccr4-NOT deadenylase subunits CNOT7 and CNOT8 have overlapping roles and modulate cell proliferation. Mol Biol Cell 20, 3840-3850 https://doi.org/10.1091/mbc.e09-02-0146
  27. Venezia TA, Merchant AA, Ramos CA et al (2004) Molecular signatures of proliferation and quiescence in hematopoietic stem cells. PLoS Biol 2, e301
  28. Tijchon E, van Emst L, Yuniati L et al (2016) Tumor suppressors BTG1 and BTG2 regulate early mouse B-cell development. Haematologica 101, e272-276 https://doi.org/10.3324/haematol.2015.139675
  29. Konrad MA and Zuniga-Pflucker JC (2005) The BTG/TOB family protein TIS21 regulates stage-specific proliferation of developing thymocytes. Eur J Immunol 35, 3030-3042 https://doi.org/10.1002/eji.200526345
  30. Farioli-Vecchioli S, Micheli L, Saraulli D et al (2012) Btg1 is required to maintain the pool of stem and progenitor cells of the Dentate Gyrus and Subventricular Zone. Front Neurosci 6, 124
  31. Zhu R, Zou ST, Wan JM, Li W, Li XL and Zhu W (2013) BTG1 inhibits breast cancer cell growth through induction of cell cycle arrest and apoptosis. Oncol Rep 30, 2137-2144 https://doi.org/10.3892/or.2013.2697
  32. Farioli-Vecchioli S, Saraulli D, Costanzi M et al (2009) Impaired terminal differentiation of hippocampal granule neurons and defective contextual memory in PC3/Tis21 knockout mice. PLoS One 4, e8339
  33. Miyata S, Mori Y and Tohyama M (2008) PRMT1 and Btg2 regulates neurite outgrowth of Neuro2a cells. Neurosci Lett 445, 162-165 https://doi.org/10.1016/j.neulet.2008.08.065
  34. Evangelisti C, Astolfi A, Gaboardi GC et al (2009) TIS21/BTG2/PC3 and cyclin D1 are key determinants of nuclear diacylglycerol kinase-zeta-dependent cell cycle arrest. Cell Signal 21, 801-809 https://doi.org/10.1016/j.cellsig.2009.01.027
  35. Kim S, Hong JW and Park KW (2016) B cell translocation gene 2 (Btg2) is regulated by Stat3 signaling and inhibits adipocyte differentiation. Mol Cell Biochem 413, 145-153 https://doi.org/10.1007/s11010-015-2648-z
  36. Cho BO, Jeong YW, Kim SH et al (2008) Up-regulation of the BTG2 gene in TPA- or RA-treated HL-60 cell lines. Oncol Rep 19, 633-637
  37. Wei S, Hao C, Li X, Zhao H, Chen J and Zhou Q (2012) Effects of BTG2 on proliferation inhibition and anti-invasion in human lung cancer cells. Tumour Biol 33, 1223-1230 https://doi.org/10.1007/s13277-012-0370-y
  38. Micheli L, D'Andrea G, Leonardi L and Tirone F (2017) HDAC1, HDAC4, and HDAC9 bind to PC3/Tis21/Btg2 and are required for its inhibition of cell cycle progression and cyclin D1 expression. J Cell Physiol 232, 1696-1707 https://doi.org/10.1002/jcp.25467
  39. Guardavaccaro D, Corrente G, Covone F et al (2000) Arrest of G(1)-S progression by the p53-inducible gene PC3 is Rb dependent and relies on the inhibition of cyclin D1 transcription. Mol Cell Biol 20, 1797-1815 https://doi.org/10.1128/MCB.20.5.1797-1815.2000
  40. Lim IK, Lee MS, Ryu MS et al (1998) Induction of growth inhibition of 293 cells by downregulation of the cyclin E and cyclin-dependent kinase 4 proteins due to overexpression of TIS21. Mol Carcinog 23, 25-35 https://doi.org/10.1002/(SICI)1098-2744(199809)23:1<25::AID-MC4>3.0.CO;2-G
  41. Dolezal E, Infantino S, Drepper F et al (2017) The BTG2-PRMT1 module limits pre-B cell expansion by regulating the CDK4-Cyclin-D3 complex. Nat Immunol 18, 911-920 https://doi.org/10.1038/ni.3774
  42. Chang BD, Swift ME, Shen M, Fang J, Broude EV and Roninson IB (2002) Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc Natl Acad Sci U S A 99, 389-394 https://doi.org/10.1073/pnas.012602599
  43. Wheaton K, Muir J, Ma W and Benchimol S (2010) BTG2 antagonizes Pin1 in response to mitogens and telomere disruption during replicative senescence. Aging Cell 9, 747-760 https://doi.org/10.1111/j.1474-9726.2010.00601.x
  44. Kuo ML, Duncavage EJ, Mathew R et al (2003) Arf induces p53-dependent and -independent antiproliferative genes. Cancer Res 63, 1046-1053
  45. Nahta R, Yuan LX, Fiterman DJ et al (2006) B cell translocation gene 1 contributes to antisense Bcl-2-mediated apoptosis in breast cancer cells. Mol Cancer Ther 5, 1593-1601 https://doi.org/10.1158/1535-7163.MCT-06-0133
  46. Zhang Z, Chen C, Wang G et al (2011) Aberrant expression of the p53-inducible antiproliferative gene BTG2 in hepatocellular carcinoma is associated with overexpression of the cell cycle-related proteins. Cell Biochem Biophys 61, 83-91 https://doi.org/10.1007/s12013-011-9164-x
  47. Boiko AD, Porteous S, Razorenova OV, Krivokrysenko VI, Williams BR and Gudkov AV (2006) A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation. Genes Dev 20, 236-252 https://doi.org/10.1101/gad.1372606
  48. Choi OR, Ryu MS and Lim IK (2016) Shifting p53-induced senescence to cell death by TIS21(/BTG2/Pc3) gene through posttranslational modification of p53 protein. Cell Signal 28, 1172-1185 https://doi.org/10.1016/j.cellsig.2016.05.014
  49. Yuniati L, van der Meer LT, Tijchon E et al (2016) Tumor suppressor BTG1 promotes PRMT1-mediated ATF4 function in response to cellular stress. Oncotarget 7, 3128-3143 https://doi.org/10.18632/oncotarget.6519
  50. Wagener N, Bulkescher J, Macher-Goeppinger S et al (2013) Endogenous BTG2 expression stimulates migration of bladder cancer cells and correlates with poor clinical prognosis for bladder cancer patients. Br J Cancer 108, 973-982 https://doi.org/10.1038/bjc.2012.573
  51. Kanda M, Oya H, Nomoto S et al (2015) Diversity of clinical implication of B-cell translocation gene 1 expression by histopathologic and anatomic subtypes of gastric cancer. Dig Dis Sci 60, 1256-1264 https://doi.org/10.1007/s10620-014-3477-8
  52. Zhang SQ, Yang Z, Cai XL et al (2017) miR-511 promotes the proliferation of human hepatoma cells by targeting the 3'UTR of B cell translocation gene 1 (BTG1) mRNA. Acta Pharmacol Sin 38, 1161-1170 https://doi.org/10.1038/aps.2017.62
  53. He C, Yu T, Shi Y et al (2017) MicroRNA 301A promotes intestinal inflammation and colitis-associated cancer development by inhibiting BTG1. Gastroenterology 152, 1434-1448 e1415
  54. Hu X, Xing L, Jiao Y et al (2013) BTG2 overexpression increases the radiosensitivity of breast cancer cells in vitro and in vivo. Oncol Res 20, 457-465
  55. Quy LN, Choi YW, Kim YH, Chwae YJ, Park TJ and Lim IK (2013) TIS21(/BTG2/PC3) inhibits interleukin-6 expression via downregulation of STAT3 pathway. Cell Signal 25, 2391-2399 https://doi.org/10.1016/j.cellsig.2013.07.024
  56. Hunter ZR, Xu L, Yang G et al (2014) The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood 123, 1637-1646 https://doi.org/10.1182/blood-2013-09-525808
  57. Morin RD, Mendez-Lago M, Mungall AJ et al (2011) Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298-303 https://doi.org/10.1038/nature10351
  58. De Falco G, Leucci E, Lenze D et al (2007) Gene-expression analysis identifies novel RBL2/p130 target genes in endemic Burkitt lymphoma cell lines and primary tumors. Blood 110, 1301-1307 https://doi.org/10.1182/blood-2006-12-064865
  59. Pasqualucci L, Khiabanian H, Fangazio M et al (2014) Genetics of follicular lymphoma transformation. Cell Rep 6, 130-140 https://doi.org/10.1016/j.celrep.2013.12.027
  60. Reddy A, Zhang J, Davis NS et al (2017) Genetic and functional drivers of diffuse large B cell lymphoma. Cell 171, 481-494 e415
  61. Yan W, Li SX, Gao H and Yang W (2019) Identification of B-cell translocation gene 1-controlled gene networks in diffuse large B-cell lymphoma: a study based on bioinformatics analysis. Oncol Lett 17, 2825-2835
  62. Waanders E, Scheijen B, van der Meer LT et al (2012) The origin and nature of tightly clustered BTG1 deletions in precursor B-cell acute lymphoblastic leukemia support a model of multiclonal evolution. PLoS Genet 8, e1002533
  63. Scheijen B, Boer JM, Marke R et al (2017) Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients. Haematologica 102, 541-551 https://doi.org/10.3324/haematol.2016.153023
  64. Irving JA, Enshaei A, Parker CA et al (2016) Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia. Blood 128, 911-922