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Telomerase modulates expression of growth-controlling genes and enhances cell proliferation

Nature Cell Biology volume 5, pages 474–479 (2003)Cite this article

Abstract

Most somatic cells do not express sufficient amounts of telomerase to maintain a constant telomere length during cycles of chromosome replication. Consequently, there is a limit to the number of doublings somatic cells can undergo before telomere shortening triggers an irreversible state of cellular senescence1,2. Ectopic expression of telomerase overcomes this limitation, and in conjunction with specific oncogenes can transform cells to a tumorigenic phenotype3. However, recent studies have questioned whether the stabilization of chromosome ends entirely explains the ability of telomerase to promote tumorigenesis and have resulted in the hypothesis that telomerase has a second function that also supports cell division4,5,6,7,8,9,10,11. Here we show that ectopic expression of telomerase in human mammary epithelial cells (HMECs) results in a diminished requirement for exogenous mitogens and that this correlates with telomerase-dependent induction of genes that promote cell growth. Furthermore, we show that inhibiting expression of one of these genes, the epidermal growth factor receptor (EGFR), reverses the enhanced proliferation caused by telomerase. We conclude that telomerase may affect proliferation of epithelial cells not only by stabilizing telomeres, but also by affecting the expression of growth-promoting genes.

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Figure 1: Catalytically active hTERT provides a growth advantage in MM.
Figure 2: Gene expression in hTERT-HMECs and controls.
Figure 3: Inhibition of EGFR decreases proliferation of hTERT-HMECs in MM.

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Acknowledgements

We thank R. Brem, L. Kruglyak, A. Klingelhutz and R. DePinho for advice, assistance and helpful discussions; members of the Fred Hutchinson Cancer Research Center array facility (J. Delrow, C. Neal, R. Bassom and D. O'Hare); E. Bryant of the Seattle Cancer Care Alliance cytogenetics laboratory; Z. Fan for monoclonal antibody 225 against EGFR; and R. Weinberg for plasmids encoding hTERT and DNhTERT. We also thank J. Grim and B. Clurman for helpful suggestions and the pBABE vector used for shRNA experiments. H.A.C. acknowledges postdoctoral fellowships from the Jane Coffin Childs Memorial Fund and the Leukemia Lymphoma Society. L.L.S. acknowledges a postdoctoral fellowship from the National Institutes of Health (#1 F32 CA83311-01). J.M.R. is an investigator of the Howard Hughes Medical Institute.

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  1. Laura L. Smith and Hilary A. Coller: These two authors contributed equally to this work.

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  1. Howard Hughes Medical Institute and Dept. of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, 98109, WA, USA

    Laura L. Smith, Hilary A. Coller & James M. Roberts

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Correspondence to James M. Roberts.

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Smith, L., Coller, H. & Roberts, J. Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat Cell Biol 5, 474–479 (2003). https://doi.org/10.1038/ncb985

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