Long Telomeres Bypass the Requirement for Telomere Maintenance in Human Tumorigenesis

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2012 Jul 27

PMID 22832159

Citations 18

Authors

Michael A S Taboski

David C F Sealey

Jennifer Dorrens

Chandrakant Tayade

Dean H Betts

Lea Harrington

Affiliations

Soon will be listed here.

Abstract

Despite the importance of telomere maintenance in cancer cell survival via the elongation of telomeres by telomerase reverse transcriptase (TERT) or alternative lengthening of telomeres (ALT), it had not been tested directly whether telomere maintenance is dispensable for human tumorigenesis. We engineered human tumor cells containing loxP-flanked hTERT to enable extensive telomere elongation prior to complete hTERT excision. Despite unabated telomere erosion, hTERT-excised cells formed tumors in mice and proliferated in vitro for up to 1 year. Telomerase reactivation or ALT was not observed, and the eventual loss of telomeric signal coincided with loss of tumorigenic potential and cell viability. Crisis was averted via the reintroduction of active but not inactive hTERT. Thus, telomere maintenance is dispensable for human tumorigenesis when telomere reserves are long. Yet, despite telomere instability and the presence of oncogenic RAS, human tumors remain susceptible to crisis induced by critically short telomeres.

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References

Tatsumoto N, Hiyama E, Murakami Y, Imamura Y, Shay J, Matsuura Y . High telomerase activity is an independent prognostic indicator of poor outcome in colorectal cancer. Clin Cancer Res. 2000; 6(7):2696-701. View

Parkinson E, Fitchett C, Cereser B . Dissecting the non-canonical functions of telomerase. Cytogenet Genome Res. 2009; 122(3-4):273-80. DOI: 10.1159/000167813. View

Fattah K, Ruis B, Hendrickson E . Mutations to Ku reveal differences in human somatic cell lines. DNA Repair (Amst). 2008; 7(5):762-74. PMC: 2427147. DOI: 10.1016/j.dnarep.2008.02.008. View

Hahn W, Stewart S, Brooks M, York S, Eaton E, Kurachi A . Inhibition of telomerase limits the growth of human cancer cells. Nat Med. 1999; 5(10):1164-70. DOI: 10.1038/13495. View

Weinstein I, Joe A . Oncogene addiction. Cancer Res. 2008; 68(9):3077-80. DOI: 10.1158/0008-5472.CAN-07-3293. View

Gritz L, Davies J . Plasmid-encoded hygromycin B resistance: the sequence of hygromycin B phosphotransferase gene and its expression in Escherichia coli and Saccharomyces cerevisiae. Gene. 1983; 25(2-3):179-88. DOI: 10.1016/0378-1119(83)90223-8. View

Matsuo T, Shay J, Wright W, Hiyama E, Shimose S, Kubo T . Telomere-maintenance mechanisms in soft-tissue malignant fibrous histiocytomas. J Bone Joint Surg Am. 2009; 91(4):928-37. DOI: 10.2106/JBJS.G.01390. View

Ouellette M, Liao M, Herbert B, Johnson M, Holt S, Liss H . Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase. J Biol Chem. 2000; 275(14):10072-6. DOI: 10.1074/jbc.275.14.10072. View

Cifone M, Fidler I . Correlation of patterns of anchorage-independent growth with in vivo behavior of cells from a murine fibrosarcoma. Proc Natl Acad Sci U S A. 1980; 77(2):1039-43. PMC: 348419. DOI: 10.1073/pnas.77.2.1039. View

10.

Greider C . Telomerase activation. One step on the road to cancer?. Trends Genet. 1999; 15(3):109-12. DOI: 10.1016/s0168-9525(98)01681-3. View

11.

Liang S, Kahlenberg M, Rousseau Jr D, Hornsby P . Neoplastic conversion of human colon smooth muscle cells: No requirement for telomerase. Mol Carcinog. 2007; 47(6):478-84. DOI: 10.1002/mc.20405. View

12.

Elenbaas B, Spirio L, Koerner F, Fleming M, Zimonjic D, Donaher J . Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev. 2001; 15(1):50-65. PMC: 312602. DOI: 10.1101/gad.828901. View

13.

Faul F, Erdfelder E, Buchner A, Lang A . Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009; 41(4):1149-60. DOI: 10.3758/BRM.41.4.1149. View

14.

Gupta J, Han L, Wang P, Gallie B, Bacchetti S . Development of retinoblastoma in the absence of telomerase activity. J Natl Cancer Inst. 1996; 88(16):1152-7. DOI: 10.1093/jnci/88.16.1152. View

15.

Hahn W, Dessain S, Brooks M, King J, Elenbaas B, Sabatini D . Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol Cell Biol. 2002; 22(7):2111-23. PMC: 133688. DOI: 10.1128/MCB.22.7.2111-2123.2002. View

16.

Mazurier F, Fontanellas A, Salesse S, Taine L, Landriau S, Moreau-Gaudry F . A novel immunodeficient mouse model--RAG2 x common cytokine receptor gamma chain double mutants--requiring exogenous cytokine administration for human hematopoietic stem cell engraftment. J Interferon Cytokine Res. 1999; 19(5):533-41. DOI: 10.1089/107999099313983. View

17.

Vidal-Cardenas S, Greider C . Comparing effects of mTR and mTERT deletion on gene expression and DNA damage response: a critical examination of telomere length maintenance-independent roles of telomerase. Nucleic Acids Res. 2009; 38(1):60-71. PMC: 2800220. DOI: 10.1093/nar/gkp855. View

18.

Stewart S, Hahn W, OConnor B, Banner E, Lundberg A, Modha P . Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc Natl Acad Sci U S A. 2002; 99(20):12606-11. PMC: 130507. DOI: 10.1073/pnas.182407599. View

19.

Vaziri H, Benchimol S . Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol. 1998; 8(5):279-82. DOI: 10.1016/s0960-9822(98)70109-5. View

20.

Bodnar A, Ouellette M, Frolkis M, Holt S, Chiu C, Morin G . Extension of life-span by introduction of telomerase into normal human cells. Science. 1998; 279(5349):349-52. DOI: 10.1126/science.279.5349.349. View