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In some figures, sample sizes were omitted or incorrectly stated. Data shown in Figure 2, A-C, and Supplemental Figure 5, A-C, were from the same experiment, which, as indicated, included [...]

Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been test-ed in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocar-cinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumori-genesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice., Introduction Telomere shortening limits the proliferative life span of cells by induction of senescence or crisis (1). Both checkpoints represent potent tumor-suppressor mechanisms, and tumor cells need to activate telomere [...]

Research was conducted to test whether the tumor suppressor gene product , p19(super Arf) hinders oncogenic transformation in primary cells and whether its role is abrogated when p53 is neutralized by viral oncoproteins and dominant-negative mutants. Cell cultures were monitored and maintained by calcium phosphate using the same amounts of DNA as in p53 degradation. Results showed high levels of genetic instability in p53 and that potent tumor suppressor activity resulted from the encoding of unrelated antioncogenic proteins with cooperating modes of action.

Mice deficient for the mouse telomerase RNA (mTR­/­) and lacking telomerase activity can only be bred for approximately six generations due to decreased male and female fertility and to an increased embryonic lethality associated with a neural tube closure defect. Although late generation mTR­/­ mice show defects in the hematopoietic system, they are viable to adulthood, only showing a decrease in viability in old age. To assess the contribution of genetic background to the effect of telomerase deficiency on viability, we generated mTR­/­ mutants on a C57BL6 background, which showed shorter telomeres than the original mixed genetic background C57BL6/129Sv. Interestingly, these mice could be bred for only four generations and the survival of late generation mTR­/­ mice decreased dramatically with age as compared with their wild-type counter parts. Fifty percent of the generation 4 mice die at only 5 months of age. This decreased viability with age in the late generation mice is coincident with telomere shortening, sterility, splenic atrophy, reduced proliferative capacity of B and T cells, abnormal hematology and atrophy of the small intestine. These results indicate that telomere shortening in mTR­/­ mice leads to progressive loss of organismal viability. [ABSTRACT FROM AUTHOR]