The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis

Cancer Research

Volumn 73, Issue 9, 2013, Pages 2817-2828

  Listerman, Imke ^a   Sun, Jie ^a   Gazzaniga, Francesca S ^a   Lukas, Jason L ^a   Blackburn, Elizabeth H ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PROTEIN HNRNPH2; PROTEIN HNRNPL; PROTEIN SRSF11; REGULATOR PROTEIN; TELOMERASE; TELOMERASE REVERSE TRANSCRIPTASE; UNCLASSIFIED DRUG;

ALTERNATIVE RNA SPLICING; APOPTOSIS; ARTICLE; BREAST CANCER; CANCER CELL; CELL PROTECTION; CELLULAR DISTRIBUTION; CONTROLLED STUDY; ENZYME ACTIVITY; ENZYME INHIBITION; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; POLYSOME; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN RNA BINDING;

ALTERNATIVE SPLICING; APOPTOSIS; BREAST NEOPLASMS; CELL NUCLEUS; CELL PROLIFERATION; CISPLATIN; GENE DELETION; GENES, REPORTER; HEK293 CELLS; HELA CELLS; HUMANS; ISOENZYMES; JURKAT CELLS; MITOCHONDRIA; PROTEIN BINDING; RIBOSOMES; RNA; TELOMERASE;

EID: 84877748662     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-12-3082     Document Type: Article

References (50)

1. Blackburn EH. Telomere states and cell fates. Nature 2000;408:53-6.
2. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 1990;345:458-60.
3. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994;266:2011-5.
4. Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 1997; 90:785-95.
5. Sykorova E, Fajkus J. Structure-function relationships in telomerase genes. Biol Cell 2009;101:375-92.
6. Saeboe-Larssen S, Fossberg E, Gaudernack G. Characterization of novel alternative splicing sites in human telomerase reverse transcriptase (hTERT): analysis of expression and mutual correlation in mRNA isoforms from normal and tumour tissues. BMC Mol Biol 2006;7:26.
7. Ulaner GA, Hu JF, Vu TH, Oruganti H, Giudice LC, Hoffman AR. Regulation of telomerase by alternate splicing of human telomerase reverse transcriptase (hTERT) in normal and neoplastic ovary, endometrium and myometrium. Int J Cancer 2000;85: 330-5.
8. Ulaner GA, Hu JF, Vu TH, Giudice LC, Hoffman AR. Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res 1998;58:4168-72.
9. Kilian A, Bowtell D, Abud H, Hime G, Venter D, Keese P, et al. Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. Hum Mol Genet 1997;6:2011-9.
10. Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE, et al. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet 1997;17:498-502.
11. Yi X, White DM, Aisner DL, Baur JA, Wright WE, Shay JW. An alternate splicing variant of the human telomerase catalytic subunit inhibits telomerase activity. Neoplasia 2000;2:433-40.
12. Yi X, Shay JW, Wright WE. Quantitation of telomerasecomponents and hTERT mRNA splicing patterns in immortal human cells. Nucl Acids Res 2001;29:4818-25.
13. Liu WJ, Zhang YW, Zhang ZX, Ding J. Alternative splicing of human telomerase reverse transcriptase may not be involved in telomerase regulation during all-trans-retinoic acid-induced HL-60 cell differentiation. J Pharmacol Sci 2004;96:106-14.
14. Lincz LF, Mudge LM, Scorgie FE, Sakoff JA, Hamilton CS, Seldon M. Quantification of hTERT splice variants in melanoma by SYBR green real-time polymerase chain reaction indicates a negative regulatory role for the beta deletion variant. Neoplasia 2008;10: 1131-7.
15. Liu Y, Wu BQ, Zhong HH, Tian XX, Fang WG. Quantification of alternative splicing variants of human telomerase reverse transcriptase and correlations with telomerase activity in lung cancer. PLoS ONE 2012;7:e38868.
16. Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, et al. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 2009;460:66-72.
17. Rahman R, Latonen L, Wiman KG. hTERT antagonizes p53-induced apoptosis independently of telomerase activity. Oncogene 2005;24: 1320-7.
18. Cao Y, Li H, Deb S, Liu JP. TERT regulates cell survival independent of telomerase enzymatic activity. Oncogene 2002;21:3130-8.
19. Stohr BA, Blackburn EH. ATM mediates cytotoxicity of a mutant telomerase RNA in human cancer cells. Cancer Res 2008;68: 5309-17.
20. Buhler M, Muhlemann O. Alternative splicing induced by nonsense mutations in the immunoglobulin mu VDJ exon is independent of truncation of the open reading frame. RNA 2005;11:139-46.
21. Cheeseman IM, Desai A. A combined approach for the localization and tandem affinity purification of protein complexes from metazoans. Sci STKE 2005;2005:pl1.
22. Jin L, Guzik BW, Bor YC, Rekosh D, Hammarskjold ML. Tap and NXT promote translation of unspliced mRNA. Genes Dev 2003;17: 3075-86.
23. Lareau LF, Inada M, Green RE, Wengrod JC, Brenner SE. Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 2007;446:926-9.
24. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 2012;9:676-82.
25. Kishore S, Khanna A, Stamm S. Rapid generation of splicing reporters with pSpliceExpress. Gene 2008;427:104-10.
26. Mavrogiannou E, Strati A, Stathopoulou A, Tsaroucha EG, Kaklamanis L, Lianidou ES. Real-time RT-PCR quantification of human telomerase reverse transcriptase splice variants in tumor cell lines and non-small cell lung cancer. Clin Chem 2007;53:53-61.
27. Wege H, Chui MS, Le HT, Tran JM, Zern MA. SYBR Green real-time telomeric repeat amplification protocol for the rapid quantification of telomerase activity. Nucl Acids Res 2002;31:e3
28. Holt SE, Aisner DL, Baur J, Tesmer VM, Dy M, Ouellette M, et al. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev 1999;13:817-26.
29. Holbrook JA, Neu-Yilik G, Hentze MW, Kulozik AE. Nonsense-mediated decay approaches the clinic. Nat Genet 2004;36:801-8.
30. Linde L, Boelz S, Neu-Yilik G, Kulozik AE, Kerem B. The efficiency of nonsense-mediated mRNA decay is an inherent character and varies among different cells. Eur J Hum Genet 2007;15:1156-62.
31. Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, Wiltshire T, et al. Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci U S A 2002;99:4465-70.
32. Strahl C, Blackburn EH. Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in twoimmortalized human cell lines. Mol Cell Biol 1996;16:53-65.
33. Santos JH, Meyer JN, Skorvaga M, Annab LA, Van Houten B. Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage. Aging Cell 2004;3:399-411.
34. Chen M, Manley JL. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 2009;10:741-54.
35. Wu JY, Kar A, Kuo D, Yu B, Havlioglu N. SRp54 (SFRS11), a regulator for tau exon 10 alternative splicing identified by an expression cloning strategy. Mol Cell Biol 2006;26:6739-47.
36. Lai CK, Mitchell JR, Collins K. RNA binding domain of telomerase reverse transcriptase. Mol Cell Biol 2001;21:990-1000.
37. Harrington L, Zhou W, McPhail T, Oulton R, Yeung DS, Mar V, et al. Human telomerase contains evolutionarily conserved catalytic and structural subunits. Genes Dev 1997;11:3109-15.
38. Bryan TM, Marusic L, Bacchetti S, Namba M, Reddel RR. The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit. Hum Mol Genet 1997;6:921-6.
39. Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ, Reddel RR. Protein composition of catalytically active human telomerase from immortal cells. Science 2007;315:1850-3.
40. Xu L, Blackburn EH. Human cancer cells harbor T-stumps, a distinct class of extremely short telomeres. Mol Cell 2007;28:315-27.
41. Cairney CJ, Keith WN. Telomerase redefined: integrated regulation of hTR and hTERT for telomere maintenance and telomerase activity. Biochimie 2008;90:13-23.
42. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 2006;10:515-27.
43. Heiser LM, Sadanandam A, Kuo WL, Benz SC, Goldstein TC, Ng S, et al. Subtype and pathway specific responses to anticancer compounds in breast cancer. Proc Natl Acad Sci U S A 2012; 109:2724-9.
44. Lee MK, Hande MP, Sabapathy K. Ectopic mTERT expression in mouse embryonic stem cells does not affect differentiation but confers resistance to differentiation- and stress-induced p53-dependent apoptosis. J Cell Sci 2005;118:819-29.
45. Massard C, Zermati Y, Pauleau AL, Larochette N, Metivier D, Sabatier L, et al. hTERT: a novel endogenous inhibitor of the mitochondrial cell death pathway. Oncogene 2006;25:4505-14.
46. Del Bufalo D, Rizzo A, Trisciuoglio D, Cardinali G, Torrisi MR, Zangemeister- Wittke U, et al. Involvement of hTERT in apoptosis induced by interference with Bcl-2 expression and function. Cell Death Differ 2005;12:1429-38.
47. Colgin LM, Wilkinson C, Englezou A, Kilian A, Robinson MO, Reddel RR. The hTERTalpha splice variant is a dominant negative inhibitor of telomerase activity. Neoplasia 2000;2:426-32.
48. Bieche I, Nogues C, Paradis V, Olivi M, Bedossa P, Lidereau R, et al. Quantitation of hTERT gene expression in sporadic breast tumors with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res 2000;6:452-9.
49. Ito T, Watanabe H, Yamamichi N, Kondo S, Tando T, Haraguchi T, et al. Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54(nrb). Biochem J 2008;411:201-9.
50. Sharma GG, Gupta A, Wang H, Scherthan H, Dhar S, Gandhi V, et al. hTERT associates with human telomeres and enhances genomic stability and DNA repair. Oncogene 2003;22:131-46.