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Molecular and Cellular Biology, February 2000, p. 1436-1447, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Human Keratinocytes That Express hTERT and Also Bypass a p16INK4a-Enforced Mechanism That Limits Life Span Become Immortal yet Retain Normal Growth and Differentiation Characteristics

Mark A. Dickson,1 William C. Hahn,2,3 Yasushi Ino,4 Vincent Ronfard,5 Jenny Y. Wu,1 Robert A. Weinberg,2 David N. Louis,4 Frederick P. Li,6 and James G. Rheinwald1,*

Division of Dermatology, Department of Medicine and Harvard Skin Disease Research Center, Brigham and Women's Hospital,1 Department of Adult Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital,3 Department of Pathology and Neurosurgical Service, Massachusetts General Hospital,4 and Department of Adult Oncology, Dana-Farber Cancer Institute,6 Harvard Medical School, Boston, Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge,2 and Laboratory of Cell and Tissue Development, Organogenesis, Inc., Canton,5 Massachusetts

Received 11 August 1999/Returned for modification 11 October 1999/Accepted 18 November 1999

Normal human cells exhibit a limited replicative life span in culture, eventually arresting growth by a process termed senescence. Progressive telomere shortening appears to trigger senescence in normal human fibroblasts and retinal pigment epithelial cells, as ectopic expression of the telomerase catalytic subunit, hTERT, immortalizes these cell types directly. Telomerase expression alone is insufficient to enable certain other cell types to evade senescence, however. Such cells, including keratinocytes and mammary epithelial cells, appear to require loss of the pRB/p16INK4a cell cycle control mechanism in addition to hTERT expression to achieve immortality. To investigate the relationships among telomerase activity, cell cycle control, senescence, and differentiation, we expressed hTERT in two epithelial cell types, keratinocytes and mesothelial cells, and determined the effect on proliferation potential and on the function of cell-type-specific growth control and differentiation systems. Ectopic hTERT expression immortalized normal mesothelial cells and a premalignant, p16INK4a-negative keratinocyte line. In contrast, when four keratinocyte strains cultured from normal tissue were transduced to express hTERT, they were incompletely rescued from senescence. After reaching the population doubling limit of their parent cell strains, hTERT+ keratinocytes entered a slow growth phase of indefinite length, from which rare, rapidly dividing immortal cells emerged. These immortal cell lines frequently had sustained deletions of the CDK2NA/INK4A locus or otherwise were deficient in p16INK4a expression. They nevertheless typically retained other keratinocyte growth controls and differentiated normally in culture and in xenografts. Thus, keratinocyte replicative potential is limited by a p16INK4a-dependent mechanism, the activation of which can occur independent of telomere length. Abrogation of this mechanism together with telomerase expression immortalizes keratinocytes without affecting other major growth control or differentiation systems.

* Corresponding author. Mailing address: Harvard Institutes of Medicine, Room 664, 77 Ave. Louis Pasteur, Boston, MA 02115. Phone: (617) 525-5553. Fax: (617) 525-5571. E-mail: JRheinwald{at}rics.bwh.harvard.edu.

Molecular and Cellular Biology, February 2000, p. 1436-1447, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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