It is widely accepted that activation of telomerase and maintenance of telomeres play central roles in cellular immortalization for most cancer cells. However, they seem to be insufficient for normal human cells. To elucidate critically responsible genes for telomerase mediated cellular immortalization in non-cancerous cells, we explored the genes that are differentially expressed throughout the immortalization process of normal human cells using cDNA microarrays with novel normalization procedures. We found that the number of genes, differentially expressed during cellular immortalization after ectopic expression of telomerase, dramatically increased in a later phase, especially in fibroblasts. We identified 18 and 20 genes/ESTs dysregulated throughout the cellular immortalization processes in fibroblasts and endothelial cells, respectively, but none of them overlapped. Only BGN and COL5A2 were commonly downregulated, except for at early phase in fibroblasts, and a few genes showed controversial expression changes, with regard to previous reports in cancer cells. These findings indicate that normal somatic cells would require cell-type specific events in addition to telomerase activation, and a rare population that eventually experience such events would acquire immortality. The key molecules that distinguish the immortalization mechanisms in cancerous and non-cancerous cells may become crucial targets for anticancer therapy and regenerative therapy.

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