Journal article
Genetic and Epigenetic Changes in Human Epithelial Cells Immortalized by Telomerase
The American journal of pathology, Vol.156(5), pp.1537-1547
05/2000
DOI: 10.1016/S0002-9440(10)65025-0
PMCID: PMC1876907
PMID: 10793065
Abstract
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 p16
INK4a
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 p16
INK4a
expression by promoter methylation or specific large-scale deletion of chromosome 9p, the location of p16
INK4a
. Interestingly, one cell line exhibited complete down-regulation of expression of p14
ARF
, with only slight down-regulation of expression of p16
INK4a
. 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.
Details
- Title: Subtitle
- Genetic and Epigenetic Changes in Human Epithelial Cells Immortalized by Telomerase
- Creators
- D. Gregory Farwell - Chapel Hill, North CarolinaKatherine A Shera - Chapel Hill, North CarolinaJennifer I Koop - Chapel Hill, North CarolinaGeorge A Bonnet - Chapel Hill, North CarolinaConnie P Matthews - Chapel Hill, North CarolinaGary W Reuther - Chapel Hill, North CarolinaMarc D Coltrera - Chapel Hill, North CarolinaJames K McDougall - Chapel Hill, North CarolinaAloysius J Klingelhutz - Chapel Hill, North Carolina
- Resource Type
- Journal article
- Publication Details
- The American journal of pathology, Vol.156(5), pp.1537-1547
- Publisher
- American Society for Investigative Pathology
- DOI
- 10.1016/S0002-9440(10)65025-0
- PMID
- 10793065
- PMCID
- PMC1876907
- ISSN
- 0002-9440
- eISSN
- 1525-2191
- Language
- English
- Date published
- 05/2000
- Academic Unit
- Microbiology and Immunology; Radiation Oncology
- Record Identifier
- 9984002398502771
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