Telomerase the Primary Target in Human Cells

It has long been known that human cells are far more difficult to transform in vitro than rodent cells. Immortalization (the acquisition of an infinite lifespan) is the first step in transformation, and molecular events required for immortalization are more tightly regulated in some species compared to others.

In human cells the available life span is controlled by the progressive shortening of telomeres; these are repetitive DNA elements that protect the chromosome ends from degradation and fusion with other chromosomes. When telomeres are eroded below a certain threshold, they fail to protect chromosome ends, and this causes senescence and crisis. In contrast, rodent somatic cells possess stable and substantially longer telomeres. The control of telomere length offers an additional level of protection against tumor formation in animals with a higher life expectancy (for a review, see [17]). Dogs are valuable animal models in drug testing, as they are less expensive than nonhuman primates and the results can be better extrapolated to human physiology. Cellular systems derived from dog primary cells are desirable to improve interpretation and study design. However, similar to human - and in contrast to rodent primary cells - dog telomerase activity also is tightly regulated [18].

Human ESC have an infinite lifespan because the telomeres are continuously maintained: in contrast to somatic cells, stem cells stably express functional telomerase, a ribonucleoprotein with template-specific reverse trancriptase activity. Human telomerase regulation is based on expression of the protein component (the TERT catalytic subunit) by control ofpromoter activity and alternative splicing [19]. The RNA component of the enzyme and other proteins involved in telomere maintenance (POT1, TRF1, and TRF2) are ubiquitously expressed. The discovery that human telomerase activity is regulated via a single protein subunit suggested that an unlimited supply of differentiated cells lines from any tissue could be obtained by ectoptic expression of the tert gene. Indeed, several groups have shown that this approach allows some human cell types, including fibroblasts, retinal pigment epithelial cells and mesothelia (mesoderm-derived epithelial cells) to bypass senescence and become immortalized in a single step [20, 21]. However, for other cell types such as endothelial cells, immortalization by tert alone remains controversial [22, 23]; for example, mammary epithelial cells and keratinocytes require additional genetic changes for immortalization [21].

Although adult tissue stem cells have a high reproductive capacity, telomerase levels are mostly insufficient to maintain telomere length [24]. Neuronal stem cells and mesenchymal stem cells have a silent tert gene and require exogenous gene transfer or endogenous gene activation [25, 26]. Only hematopoietic stem cells (CD34-positive) retain full telomerase activity [27].

The function of telomerase in immortalization seems to extend beyond the maintenance of telomere length. It has been shown that telomerase can cooperate with other oncogenes for transformation in cells that maintain telomeres by an alternative mechanism [28]. The pleiotropic effects of TERT are tissue-specific: it has been found that telomerase activates cell cycle-promoting genes and down-regulates apoptosis-promoting genes in fibroblasts, whereas it fails to do so in endothelial cells [29]. Furthermore, very high-level ectopic expression oftelomerase alone may induce, rather than prevent, senescence in fibroblasts [30].

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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