HTERT gene

If the telomerase activity alone were to determine the life span of a cell, one would expect that cells such as muscle cells and neurons, that do not divide, never age. But, this is obviously not the case. This paradox shows that the relationship between control of senescence and cell death is much more complicated. Recent work of T. Kiyono et reviewed by Robert Weinberg,23 with two human epithelial cell types (keratinocytes and mammary epithelial cells), showed that making cells immortal requires not only expression of the hTERT gene and of the telomerase, but also inactivation of the retinoblastoma (RB) tumour-suppressor pathway (the RB pathway halts cells in the Gi phase of the cell cycle in response to a wide range of inhibitory signals, see Fig. 12.12). 

Trott, D.A., Newbold, R.F., and Nabholz, M. (2003). A chromosome 3-encoded repressor of the human telomerase reverse transcriptase (hTERT) gene controls the state ofhTERT chromatin. Gancer Res. 63, 689-695. 

All finally differentiated eukaryotic cells lack telomerase activity. Thus, when cells divide, the ends of the chromosomes can not be duplicated and the telomeres get shorter and shorter with every cell division, until the cell finally dies. Thus, the lack of telomerase activity may determine the number of divisions a cell can go through. And indeed, disruption of the telomerase gene in yeast leads to senescence and death (see Fig. 12.12). The ageing process in the yeast cells was reversed when human telomerase was expressed. Expression of the catalytic subunit of the human telomerase holoenzyme (hTERT) also enabled human cells to avoid senesce and to multiply indefinitely. This raised hopes to immortalize human cells, without interfering with their differentiation. (For more information, see ref. 21 and Chapter 17). 

Kyo S, Takakura M, Taira T, Kanaya T, Itoh H, et al. 2000. Spl cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT). Nucleic Acids Res. 28 669-77... 

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