Telomere-driven karyotypic complexity concurs with p16INK4a inactivation in TP53-competent immortal endothelial cells Journal Article
| Authors: | Wen, V. W.; Wu, K.; Baksh, S.; Hinshelwood, R. A.; Lock, R. B.; Clark, S. J.; Moore, M. A. S.; Mackenzie, K. L. |
| Article Title: | Telomere-driven karyotypic complexity concurs with p16INK4a inactivation in TP53-competent immortal endothelial cells |
| Abstract: | Critically short telomeres promote chromosomal fusions, which in TP53-defective cells initiate the formation of cytogenetic aberrations that are typical of human cancer cells. Expression of the enzyme telomerase stabilizes normal and aberrant chromosomes by maintaining telomere length. However, previous investigations, including our own, have shown that overexpression of telomerase reverse transcriptase (hTERT) does not prevent net telomere shortening in human endothelial cells. In the present study, two mass cultures of hTERT transduced bone marrow endothelial cells (BMhTERT) and 26 clones were employed to further investigate the immortalization process and consequences of telomere shortening. Eighty-five percent (22 of 26) of the clones and both mass cultures were immortalized. However, cytogenetic analyses revealed recurring cytogenetic aberrations in the mass cultures and 12 representative clones. Several of the recurring aberrations, including +5p, +11, -13, +19, and +20, and nonreciprocal translocations involving 17p and 2p were previously implicated in human carcinogenesis. One mass culture and a subset of clones (5 of 12) had complex karyotypes, characterized by cytogenetic heterogeneity and at least five chromosomal abnormalities. p16INK4a was silenced exclusively in the five clones and mass culture with complex karyotypes, whereas the p53/p21 cip1 pathway was defective in only one clone. Telomere dysfunction was implicated in the evolution of complex karyotypes by the presence of anaphase bridges, telomere associations, and dicentric chromosomes. These results show that complex karyotypes can evolve in TP53 -competent cells and provide evidence that p16INK4a functions as a gatekeeper to prevent telomere-driven cytogenetic evolution. These investigations provide new insight to the role of p16INK4a as a tumor suppressor. ©2006 American Association for Cancer Research. |
| Keywords: | controlled study; human cell; telomere; bone marrow cells; cytogenetics; phosphorylation; protein p53; telomerase; dna methylation; carcinogenesis; transduction, genetic; endothelium cell; endothelial cells; chromosome aberration; cell culture; bone marrow cell; gene silencing; cyclin-dependent kinase inhibitor p16; cell clone; tumor suppressor protein; chromosome deletion; retinoblastoma protein; chromosome analysis; karyotyping; genes, p53; chromosomes, human, pair 17; cell immortalization; cyclin dependent kinase inhibitor 1; protein p16ink4a; dicentric chromosome |
| Journal Title: | Cancer Research |
| Volume: | 66 |
| Issue: | 22 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2006-11-15 |
| Start Page: | 10691 |
| End Page: | 10700 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-06-0979 |
| PUBMED: | 17108106 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus" |
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