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- Title
Telomerase suppression by chromosome 6 in a human papillomavirus type 16-immortalized keratinocyte cell line and in a cervical cancer cell line.
- Authors
Steenbergen, Renske D.M.; Kramer, Debbie; Meijer, Chris J.L.; Walboomers, Jan M.M.; Trott, Deborah A.; Cuthbert, Andrew P.; Newbold, Robert F.; Overkamp, Wilhelmina J.I.; Zdzienicka, Malgorzata Z.; Snijders, Peter J.F.; Steenbergen, R D; Kramer, D; Meijer, C J; Walboomers, J M; Trott, D A; Cuthbert, A P; Newbold, R F; Overkamp, W J; Zdzienicka, M Z; Snijders, P J
- Abstract
<bold>Background: </bold>High-risk human papillomavirus (HPV) types play a major role in the development of cervical cancer in vivo and can induce immortalization of primary human keratinocytes in vitro. Activation of the telomere-lengthening enzyme telomerase constitutes a key event in both processes. Because losses of alleles from chromosome 6 and increased telomerase activity have been observed in high-grade premalignant cervical lesions, we analyzed whether human chromosome 6 harbors a putative telomerase repressor locus that may be involved in HPV-mediated immortalization.<bold>Methods: </bold>Microcell-mediated chromosome transfer was used to introduce chromosomes 6 and 11 to the in vitro generated HPV type 16 (HPV16)-immortalized keratinocyte cell line FK16A and to the in vivo derived HPV16-containing cervical cancer cell line SIHA: Hybrid clones were analyzed for growth characteristics, telomerase activity, human telomerase reverse transcriptase (hTERT) and HPV16 E6 expression, and telomere length. FK16A hybrid clones were also transduced with an hTERT-containing retrovirus to examine the effect of ectopic hTERT expression on growth. Statistical tests were two-sided.<bold>Results: </bold>Introduction of human chromosome 6 but not of chromosome 11 to both cell lines yielded hybrid cells that demonstrated crisis-like features (i.e., enlarged and flattened morphology, vacuolation, and multinucleation) and underwent growth arrest after a marked lag period. In the chromosome 6 hybrid clones analyzed, telomerase activity and hTERT messenger RNA (mRNA) expression were statistically significantly reduced compared with those in the chromosome 11 hybrid clones (for telomerase activity, P =.004 for the FK16A hybrids and P =.039 for the SiHa hybrids; for hTERT mRNA expression, P =.003 for the FK16A hybrids). The observed growth arrest was associated with telomeric shortening. Ectopic expression of hTERT in FK16A cells could prevent the telomeric shortening-based growth arrest induced by chromosome 6.<bold>Conclusions: </bold>Chromosome 6 may harbor a repressor of hTERT transcription, the loss of which may be involved in HPV-mediated immortalization.
- Subjects
HUMAN chromosomes; TELOMERASE; PAPILLOMAVIRUS diseases; CELL division; CELLS; CHROMOSOMES; COMPARATIVE studies; DNA; GENES; GENETIC techniques; GLYCOSIDASES; KERATINOCYTES; RESEARCH methodology; MEDICAL cooperation; PAPILLOMAVIRUSES; POLYMERASE chain reaction; RESEARCH; RNA; TELOMERES; TRANSFERASES; CERVIX uteri tumors; DNA-binding proteins; EVALUATION research; REVERSE transcriptase polymerase chain reaction; CANCER cell culture
- Publication
JNCI: Journal of the National Cancer Institute, 2001, Vol 93, Issue 11, p865
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/93.11.865