Telomerase: regulation, function and transformation

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Abstract

Work from several laboratories over the past decade indicates that the acquisition of constitutive telomerase expression is a critical step during the malignant transformation of human cells. Normal human cells transiently express low levels of telomerase, the ribonucleoprotein responsible for extending and maintaining telomeres, and exhibit telomere shortening after extended passage, whereas most cancers exhibit constitutive telomerase expression and maintain telomeres at stable lengths. These observations establish a direct connection between immortalization and stabilization of telomere structure. However, recent work suggests that telomerase also contributes to cancer development beyond its role in maintaining stable telomere lengths. In this review, we summarize recent observations that support the concept that telomerase plays multiple roles in facilitating human cell transformation.

Section snippets

Telomere structure

Telomeres, the G-rich DNA arrays and associated proteins that cap most eukaryotic chromosomes, protect chromosome ends from damage and degradation [1]. Since unprotected ends trigger checkpoint responses and recombination events, telomeres prevent DNA from being recognized as double-stranded breaks [2] and may utilize the cellular machinery involved in the DNA damage response in their maintenance [3]. The protective function of telomeres plays critical roles in regulating genomic integrity and

Biochemistry

The enzyme responsible for maintaining telomeres, telomerase (telomere terminal transferase), is detectable at low levels in some human somatic cell lines, such as BJ and WI-38 fibroblasts, as well as bone marrow and peripheral blood leukocytes, as compared with most cancer cells and immortalized tumor cell lines in which telomerase is often upregulated [18], [19], [20], [21], [22]. First characterized in Tetrahymena thermophila, telomerase extends the lagging strand of each chromosome after

Telomerase and replicative senescence

Normal human cells display a limited replicative capacity when explanted and maintained in culture [73]. After passage in culture, these cells enter a growth arrest state called replicative senescence or mortality stage 1 (Ml) [74]. Replicative senescence is characterized by stereotypical morphological changes and the activation of P-galactosidase active at acidic pH [75], and recent work suggests that senescent cells display activation of the cellular machinery that responds to DNA damage [76]

Is telomerase activation required for tumor formation?

The experiments described in the previous section suggest that telomerase activation plays a critical role in tumor formation. However, as described in the previous section, some tumors lack detectable telomerase activity, are immortal, and maintain long telomeres [120]. These tumors appear to maintain telomeres by ALT. Recent work indicates that ALT cells and tumors contain a specific intranuclear structure termed an ALT-associated PML body [121]. This ALT-associated PML body harbors telomeric

Alternative role(s) of telomerase in transformation

Several lines of evidence indicate that telomerase activation facilitates immortalization and that this unlimited replicative capacity contributes to the transformed state. However, a growing number of studies suggest that telomerase contributes to cancer development beyond its effects on immortalization and telomere length. For example, the expression of an oncogenic RAS allele in an ALT cell line that expresses the SV40 ER but lacks telomerase activity failed to permit tumor formation when

Concluding remarks

Telomere stabilization is associated with cellular immortalization, and constitutive expression of telomerase is linked to oncogenic transformation. However, several lines of evidence also indicate that telomere shortening may limit cell proliferation and suppress tumor formation. These observations highlight the complex roles of telomeres and telomerase in malignant transformation. Although further work will clarify the roles of telomeres and telomerase in cancer development in specific types

Reviewers

Dr. Irmgard Irminger, Chief, Monitoring Laboratory and Biology of Aging Laboratory, Hopitaux Universitaires de Geneva (HUG) 2, ch. du Petit-Bel-Air, CH-1225 Chene-Bourg, Switzerland.
Sandy Chang, M.D., Ph.D., Assistant Professor, M.D. Anderson Cancer center, MSA Y7.6028 (Unit 11), 1515 Holcombe Blvd, Houston, TX 77030, USA.

Acknowledgments

This work was supported in part by grants from the National Cancer Institute KOI CA94223 (WCH), the National Institute of Aging R01 AG23145 (WCH), a Doris Duke Clinical Scientist Development Award (WCH), a Kimmel Scholar Award (WCH), a Claudia Adams Barr Research Award (WCH), a Medical Foundation Fellowship (KM), and a Uehara Memorial Foundation Research Fellowship (KM).

Dr. William C. Hahn is a medical oncologist and cancer researcher in the Department of Medical Oncology at the Dana-Farber Cancer Institute. Dr. Hahn received his A.B. (1987) from Harvard University in the field of biochemical sciences summa cum laude. He then went on to Harvard Medical School where he simultaneously completed his medical (M.D.) training and his graduate (Ph.D.) training in molecular and cellular immunology with Drs. Steven J. Burakoff and Barbara Bierer (1994). After his

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    Dr. William C. Hahn is a medical oncologist and cancer researcher in the Department of Medical Oncology at the Dana-Farber Cancer Institute. Dr. Hahn received his A.B. (1987) from Harvard University in the field of biochemical sciences summa cum laude. He then went on to Harvard Medical School where he simultaneously completed his medical (M.D.) training and his graduate (Ph.D.) training in molecular and cellular immunology with Drs. Steven J. Burakoff and Barbara Bierer (1994). After his residency in internal medicine at the Massachusetts General Hospital, Dr. Hahn completed a clinical fellowship in medical oncology at the Dana-Farber Cancer Institute and a postdoctoral fellowship with Dr. Robert A. Weinberg at the Whitehead Institute for Biomedical Research. He is currently on the faculty of Harvard Medical School and the Dana-Farber Cancer Institute.

    Dr. Hahn and his colleagues demonstrated that that activation of the reverse transcriptase telomerase plays an essential role in malignant transformation. His current work focuses on the understanding the cooperative genetic interactions that lead to malignant transformation and the creation of novel experimental model systems for the study of normal and malignant epithelial biology. Clinically, he is a member of the Lank Center for Genitourinary Oncology and is devoted to the development of new therapeutic strategies for the treatment of prostate cancers.

    Dr. Hahn has been the recipient of many honors and awards including a Harvard National Scholarship, a Damon Runyon-Walter Winchell Cancer Research Fund Fellowship, a Culpeper Biomedical Pilot Award, Howard Hughes Medical Institute Predoctoral and Postdoctoral Fellowships, a Herman and Margaret Sokol Fellowship, a Doris Duke Charitable Foundation Clinical Scientist Development Award, a CaPCURE research Award, the 2000 Wilson S. Stone Award from M.D. Anderson Cancer Center for outstanding research in cancer, a Kimmel Scholar Award, and the Howard Temin Award from the National Cancer Institute.

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