Evidence for a Telomere-Independent “Clock” Limiting RAS Oncogene-Driven Proliferation of Human Thyroid Epithelial Cells
AUTOR(ES)
Jones, C. J.
FONTE
American Society for Microbiology
RESUMO
An initiating role for RAS oncogene mutation in several epithelial cancers is supported by its high incidence in early-stage tumors and its ability to induce proliferation in the corresponding normal cells in vitro. Using retroviral transduction of thyroid epithelial cells as a model we ask here: (i) how mutant RAS can induce long-term proliferation in an epithelial cell in contrast to the premature senescence observed in fibroblasts; and (ii) what is the “clock” which eventually triggers spontaneous growth arrest even in epithelial clones generated by mutant RAS. The early response to RAS activation in thyroid epithelial cells showed two features not seen in fibroblasts: (i) a marked decrease in expression of the cyclin-dependent kinase inhibitor (CDKI) p27kip1 and (ii) the absence of any induction of p21waf1. When proliferation eventually ceased (after up to 20 population doublings) this occurred despite undiminished expression of mutant RAS and was tightly correlated with a return to the initial high level of p27kip1 expression, together with the de novo appearance of p16ink4a. Importantly, neither the CDKI changes nor the proliferative life span of RAS-induced epithelial clones was altered by induction of telomerase activity through forced expression of the catalytic subunit, hTERT, at levels sufficient to immortalize human fibroblasts. These data provide a basis for cell-type differences in sensitivity to RAS-induced proliferation which may explain the corresponding tumor-type specificity of RAS mutation. They also show for the first time in a primary human cell model that a telomere-independent mechanism can limit not only physiological but also oncogene-driven proliferation, pointing therefore to a tumour suppressor mechanism additional, or alternative, to the telomere clock.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=86042Documentos Relacionados
- Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions
- Conditional immortalization of human thyroid epithelial cells: a tool for analysis of oncogene action.
- Introduction of v-Ha-ras oncogene induces differentiation of cultured human medullary thyroid carcinoma cells.
- Dynamics of active lamellae in cultured epithelial cells: effects of expression of exogenous N-ras oncogene.
- Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age.