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§§
From the Department of Otolaryngology, Head-Neck
Surgery,*
University of Washington, Seattle, Washington;
the Program in Cancer
Biology,
Fred Hutchinson Cancer Research
Center, Seattle, Washington; the Children’s Hospital and
Regional Medical Center,
Seattle, Washington;
the Department of Pathology,§
University of Washington, Seattle, Washington; and the Lineberger
Cancer Center,¶
Chapel Hill, North Carolina
Exogenous expression of hTERT, the catalytic component of telomerase, is sufficient for the immortalization of human fibroblasts but insufficient for the immortalization of human foreskin keratinocytes (HFKs) and human mammary epithelial cells (HMECs). These latter cell types can overcome senescence by coexpression of hTERT and human papillomavirus (HPV) E7 or by expression of hTERT and loss of p16INK4a expression, indicating that the retinoblastoma (Rb) pathway, along with a telomere maintenance pathway, plays a role in determining the life span of epithelial cells. In this study, we further characterize hTERT-immortalized HFKs and human adenoid epithelial cells (HAKs) for genotypic and phenotypic alterations that are associated with immortalization. Of five hTERT-immortalized HFK and HAK cell lines examined, four exhibited repression of p16INK4a expression by promoter methylation or specific large-scale deletion of chromosome 9p, the location of p16INK4a. Interestingly, one cell line exhibited complete down-regulation of expression of p14ARF, with only slight down-regulation of expression of p16INK4a. Yet, all of the immortal cells lines exhibited hyperphosphorylated Rb. Cytogenetic analysis revealed clonal chromosome aberrations in three of the five cell lines. All of the cell lines retained a growth block response with the expression of mutant ras. When grown on organotypic raft cultures, however, the hTERT-immortalized cells exhibited a maturation delay on terminal differentiation. Our results indicate that immortalization of epithelial cells may require both activation of telomerase and other genetic and/or epigenetic alterations that abrogate normal differentiation.
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