To examine the role of telomerase in normal and neo-plastic growth, the telomerase RNA component (mTR) was deleted from the mouse germline. mTR (-/- ) mice lacked detectable telomerase activity yet were viable for the six generations analyzed. Telomerase-deficient cells could be immortalized in culture, transformed by vital oncogenes, and generated tumors in nude mice following transformation. Telomeres were shown to shorten at a rate of 4.8 ± 2.4 kb per mTR(-/-) generation. Cells from the fourth mTR(-/-) generation onward possessed chromosome ends lacking detectable telomere repeats, aneuploidy, and chromosomal abnormalities, including end-to-end fusions. These results indicate that telomerase is essential for telomere length maintenance but is not required for establishment of cell lines, oncogenic transformation, or tumor formation in mice.
Bibliographical noteFunding Information:
We thank Scott Lowe for providing the pLPC-EIR retrovirus expressing E1A and ras v12 and Lisa Bianco for excellent technical assistance in the nude mouse experiments. We thank Dr. Titia de Lange for the (TTAGGG) probe and Dr. David Kipling for the mouse major satellite probe. We also thank Manuel Serrano for helpful discussions and Steve Buck, Alyson Kass-Eisler, Roger Greenberg, Siyuan Le, Nicole Schreiber-Agus, and Stephanie Smith for reading the manuscript before publication. Work in the lab of C. W. G. was supported by National Institutes of Health grant RO1AG09383, Cancer Center grant 5P30-CA45508, and by the Geron Corporation. R. A. D. is a recipient of the Irma T. Hirschl award, and work in his lab was supported by NIH grant RO1HD348880, a grant from the AHA, 96015040, and a NIH Cancer Center Core grant, 2P30CA13330. Work in the lab of P. M. L. was supported by NIH grant R01AI29524 and a grant from the National Institute of Cancer with funds from the Terry Fox Run. M. A. B. was supported by the Leukemia Society of America, and M. A. B. and E. S. were supported by grant PM95-0014 from the Ministry of Education, Spain, and by the Department of Immunology and Oncology, National Center of Biotechnology, Madrid, and H. W. L. was supported by an Immunology-Oncology training grant from the NIH, RT32-CA09173.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)