Abstract
Somatic cells express genes that suppress telomerase activity and these genes may be inactivated in tumour cells. We postulated that cancer cells acquire immortality by activation of telomerase by the loss of such a gene. We have reported recently that a telomerase repressor gene may be located on 10p15.1 by deletion mapping using microcell-mediated chromosome transfer (MMCT), radiated microcell fusion (RMF), fluorescent in situ hybridization (FISH) and STS analysis. To independently confirm this result, we correlated expression of RNA component of telomerase (hTR) as a marker of telomerase expression by in situ hybridization with allelic loss in pulmonary carcinoid tumours. Unlike most malignant tumours, pulmonary carcinoids (which are low-grade malignant tumours) are heterogeneous for telomerase expression. Loss of 5 closely spaced polymorphic markers on 10p15.1, especially D10S1728, were highly correlated with hTR expression. In an additional experiment, 10p15.1 showed higher and more significant correlation than any region of 3p where it has been predicted as another chromosomal location of telomerase repressor with allelic loss of the region. Our findings strongly suggest that 10p15.1 harbours a gene involved in repression of telomerase RNA component in human somatic cells and each putative repressor (on 3p and 10p) may act independently. © 2001 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Bhattacharyya A and Blackburn EH (1994) Architecture of telomerase RNA. EMBO J 13: 5721–5723
Bickenbach JR, Vormwald DV, Bachor C, Bleuel K, Schnapp G and Boukamp P (1998) Telomerase is not an epidermal stem cell marker and is downregulated by calcium. J Invest Dermatol 111: 1045–1052
Bigner SH, Mark J and Bigner DD (1990) Cytogenetics of human brain tumors. Cancer Genet Cytogenet 47: 141–154
Campisi J (1997) The biology of replicative senescence. Eur J Cancer 33: 703–709
Chiu C-P and Harley CB (1997) Replicative senescence and cell immortality: the role of telomeres and telomerase. Proc Soc Exp Biol Med 214: 99–106
Cuthbert AP, Bond J, Trott DA, Gill S, Broni J, Marriott A, Khoudoli G, Parkinson EK, Cooper CS and Newbold RF (1999) Telomerase repressor sequences on chromosome 3 and induction of permanent growth arrest in human breast cancer cells. J Natl Cancer Inst 91: 37–45
Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP, Adams RR, Chang E, Allsopp RC, Yu J, Le S, West MD, Harley CB, Andrews WH, Greider CW and Villeponteau B (1995) The RNA component of human telomerase. Science 269: 1236–1241
Greider CW and Blackburn EH (1989) A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337: 331–337
Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek MA, Shay JW, Ishioka S and Yamakido M (1995) Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol 155: 3711–3715
Holt SE, Wright WE and Shay JW (1997) Multiple pathways for the regulation of telomerase activity. Eur J Cancer 33: 761–766
Horikawa I, Oshimura M and Barrett JC (1998) Repression of the telomerase catalytic subunit by a gene on human chromosome 3 that induces cellular senescence. Mol Carcinog 22: 65–72
Isshiki K, Elder DE, Guerry D and Linnenbach AJ (1993) Chromosome 10 allelic loss in malignant melanoma. Genes Chromosomes Cancer 8: 178–184
Karlbom AE, James CD, Boethius J, Cavenee WK, Collins VP, Nordenskjold M and Larsson C (1993) Loss of heterozygosity in malignant gliomas involves at least three distinct regions on chromosome 10. Hum Genet 92: 169–174
Kim NM, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PLC, Coviello GM, Wright WE, Weinrich SL and Shay JW (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 226: 2011–2015
Kirk KE, Harmon BP, Reichardt IK, Sedat JW and Blackburn EH (1997) Block in anaphase chromosome separation caused by a telomerase template mutation. Science 275: 1478–1481
Koi M, Shimizu M, Morita H, Yamada H, Satoh H, Barrett JC and Oshimura M (1989) Normal human chromosome 11 suppresses tumorigenicity of human cervical tumor cell line SiHa. Mol Carcinogen 2: 12–21
Kon H, Sonoda Y, Kumabe T, Yoshimoto T, Sekiya T and Murakami Y (1998) Structural and functional evidence for the presence of tumour suppressor genes on the short arm of chromosome 10 in human gliomas. Oncogene 16: 257–263
Mehle C, Lindblom A, Ljungberg B, Stenling R and Roos G (1998) Loss of heterozygosity at chromosome 3p correlates with telomerase activity in renal cell carcinoma. Int J Oncol 13: 289–295
Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA and Weinberg RA (1997) hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90: 785–795
Miura N, Horikawa I, Nishimoto A, Ohmura H, Ito H, Hirohashi S, Shay JW and Oshimura M (1997) Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis. Cancer Genet Cytogenet 93: 56–62
Moyzis RK, Buckingham JM, Cram LS, Dani M, Daven LL, Jones MD, Meyne J, Ratliff RL and Wu JR (1988) A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeras of human chromosomes. Proc Natl Acad Sci USA 85: 6622–6626
Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V and Cech TR (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 276: 561–567
Nakayama J-I, Tahara H and Tahara E (1998) Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet 18: 65–68
Nishimoto A, Miura N, Horikawa I, Kugoh H, Murakami Y, Hirohashi S, Kawasaki H, Gazdar AF, Shay JW, Barrett JC and Oshimura M (2001) Functional evidence for a telomerase repressor gene on human chromosome 10p15.1. Oncogene 20: 828–835
Norwood TH, Pendergrass WR, Spraque CA and Martin GM (1974) Dominance of the senescent phenotype in heterokaryons between replicative and post-replicative human fibroblast-like cells. Proc Natl Acad Sci USA 71: 2231–2235
Ohmura H, Tahara H, Suzuki M, Ide T, Shimizu M, Yoshida MA, Tahara E, Shay JW, Barrett JC and Oshimura M (1995) Restoration of the cellular senescence program and repression of telomerase by human chromosome 3. Jpn J Cancer Res 86: 899–904
Onuki N, Wistuba II, Travis WD, Virmani AK, Yashima K, Brambilla E, Hasleton P and Gazdar AF (1999) Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer 85: 600–607
Oshimura M and Barrett JC (1997) Multiple pathways to cellular senescence: role of telomerase repressors. Eur J Cancer 33: 710–715
Pereira-Smith OM and Smith JR (1988) Genetic analysis of indefinite division in human cells: identification of four complementation groups. Proc Natl Acad Sci USA 85: 6042–6046
Pershouse MA, Stubblefield E, Hadi A, Killary AM, Yung WK and Steck PA (1993) Analysis of the functional role of chromosome 10 loss in human glioblastomas. Cancer Res 55: 5043–5050
Rempel SA, Schwechheimer K, Davis RL, Cavenee WK and Rosenblum, (1993) Loss of heterozygosity for loci on chromosome 10 is associated with morphologically malignant meningioma progression. Cancer Res 53: 2386–2392
Rhyu MS (1995) Telomeres, telomerase, and immortality. J Natl Cancer Inst 87: 884–894
Robertson GP, Herbst RA, Nagane M, Huang HS and Cavenee WK (1999) The Chomosome 10 monosomy common in human melanomas results from the loss of two separate tumor suppressor loci. Cancer Res 59: 3596–3601
Sager R (1991) Senescence as a mode of tumor suppression. Environ Health Perspect 93: 59–62
Sanchez Y, Lovell M, Marin MC, Wong PE, Wolf-Ledbetter ME, McDonnell TJ and Killary AM (1996) Tumor suppression and apoptosis of human prostate carcinoma mediated by a genetic locus within human chromosome 10pter-q11. Proc Natl Acad Sci USA 93: 2551–2556
Sasaki M, Honda T, Yamada H, Wake N, Barrett JC and Oshimura M (1994) Evidence for multiple pathways to cellular senescence. Cancer Res 54: 6090–6093
Sedivy JM (1998) Can ends justify the means?: telomeres and the mechanisms of replicative senescence and immortalization in mammalian cells. Proc Natl Acad Sci USA 95: 9078–9081
Shay JW and Bacchetti S (1997) A survey of telomerase activity in human cancer. Eur J Cancer 33: 787–791
Shimizu M, Yokota J, Mori N, Shuin T, Shinoda M, Terada M and Oshimura M (1990) Introduction of normal chromosome 3p modulates the tumorigenicity of a human renal cell carcinoma cell line YCR. Oncogene 5: 185–194
Steck PA, Ligon AH, Cheong P, Alfred-Yung WK and Pershouse MA (1995) Two tumor suppressive loci on chromosome 10 involved in human glioblastomas. Genes Chromosomes Cancer 12: 255–261
Steenbergen RDM, Walboomers JMM, Meijer CJLM, van der Raaij-Helmer EM, Parker JN, chow LT, Broker TR and Snijders PJF (1996) Transition of human papillomavirus type 16 and 18 transfected human foreskin keratinocytes towards immortality: activation of telomerase and allele losses at 3p, 10p, 11q and/or 18q. Oncogene 13: 1249–1257
Tanaka H, Shimizu M, Horikawa I, Kugoh H, Yokota J, Barrett JC and Oshimura M (1998) Evidence for a putative telomerase repressor gene in the 3p14.2-p21.1 region. Genes Chromosomes Cancer 23: 123–133
Travis WD, Rush W, Flieder DB, Falk R, Fleming MV, Gal AA and Koss MN (1998) Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 22: 934–944
Tsuda T, Marinetti MR, Masuelli LI and Cutler ML (1995) The Ras suppressor RSU-1 localizes to 10p13 and its expression in the U251 glioblastoma cell line correlates with a decrease in growth rate and tumorigenic potential. Oncogene 11: 397–403
Ulaner GA, Hu JF, Vu TH, Giudice LC and Hoffman AR (1998) Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res 58: 4168–4172
Vieten L, Belair CD, Savelieva L, Julicher K, Brocker F, Bardenheuer W, Schutte J, Opalka B and Reznikoff CA (1998) Minimal deletion of 3p13 → 14.2 associated with immortalization of human uroepithelial cells. Genes Chromosomes Cancer 21: 39–48
Voesten AM, Bijleveld EH, Westerveld A and Hulsebos TJ (1997) Fine mapping of a region of common deletion on chromosome arm 10p in human glioma. Gene Chromosome Cancer 20: 167–172
Wright WE, Piatyszek MA, Rainey WE, Byrd W and Shay JW (1996) Telomerase activity in human germline and embryonic tissues and cells. Dev Genet 18: 173–179
Yashima K, Piatyszek MA, Saboorian HM, Virmani AK, Brown D, Shay JW and Gazdar AF (1997) Telomerase activity and in situtelomerase RNA expression in malignant and non-malignant lymph nodes. J. Clin Pathol 50: 110–117
Zakian VA (1989) Structure and function of telomeres. Annu Rev Genet 23: 579–604
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Miura, N., Onuki, N., Rathi, A. et al. hTR repressor-related gene on human chromosome 10p15.1. Br J Cancer 85, 1510–1514 (2001). https://doi.org/10.1054/bjoc.2001.2121
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.2121