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Lessons from mice without telomerase.

Lansdorp PM - J. Cell Biol. (1997)

View Article: PubMed Central - PubMed

Affiliation: Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada, V5Z 1L3. peter@terryfox.ubc.ca

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Surprisingly, cells from mice without a functional telomerase RNA gene and no telomerase activity are indistinguishable from normal cells in different transformation and immortalization assays... Such data have now been obtained by Blasco et al., who developed mice in which the telomerase RNA template gene has been removed from the germ line using standard gene knock-out (KO) techniques... The results obtained with (the cells from) the telomerase KO mice contain valuable lessons for anyone interested in telomere biology... It has been suggested that cellular defects may be demonstrated upon challenges to such tissues or with aging of the mice, but details of such defects are currently not known... If the cells of self-renewing tissues are affected, it will be important to distinguish between the absence of telomerase and a decreased proliferative potential (resulting from overall shorter telomeres; see below) as primary defects... Furthermore, cells from telomerase-deficient mice were as efficiently transformed into immortal and in vivo tumor-forming cells as cells from telomerase-positive animals, demonstrating conclusively that, in the mouse, telomerase is not an essential requirement for the establishment of cell lines, oncogenic transformation, or tumor formation... The surprises did not end there... A similar adaptation of signal transduction systems may apply to cells of telomerase KO mice... In any event, it seems that murine cells with one or more uncapped chromosomes can divide for many times with or without an initial arrest... Indeed, normal development and even fertility does not seem to be immediately affected by the presence of such uncapped chromosomes... Indeed, the overall long telomeres in the mouse could favor the use of such a nonreciprocal recombination: a critically short telomere in a murine cell could perhaps easily recombine with remaining long telomeres on other chromosomes... As the overall telomere length decreases in subsequent generations of the telomerase KO animals, the efficiency of this pathways could decrease, possibly with the increased frequencies of chromosomal abnormalities seen at later generations as a result... Approximately a quarter of immortalized human cell lines lack detectable telomerase activity (for review see reference ), indicating that alternatives to telomerase for the maintenance of telomeres also exist in human cells... The observation that cells from M. spretus (with telomeres of comparable length to human cells) will spontaneously, be it less efficiently, immortalize in culture indicates that overall telomere length cannot be a major factor predisposing cells towards spontaneous immortalization... In general, many questions about the role of telomerase and recombination pathways in the proliferation, senescence, and immortalization of normal and malignant cells from different murine and human tissues remain.

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Chromosomal abnormalities in embryonic fibroblasts derived from the  sixth generation of telomerase   mice. Results were obtained by Q-FISH using peptide nucleic acid (PNA) probes  as described (25, 36). Yellow  and orange represent telomere signals obtained with  Cy3-labeled (CCCTAA)3  PNA, and blue represents  DAPI-stained chromosomal  DNA. Pseudocolors were assigned using Adobe Photoshop software (San Jose, CA).  Asterisks indicate metacentric  Robertsonian fusion products between acrocentric chromosomes. Number signs indicate chromosome arms without  detectable TTAGGG repeats.
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Figure 2: Chromosomal abnormalities in embryonic fibroblasts derived from the sixth generation of telomerase mice. Results were obtained by Q-FISH using peptide nucleic acid (PNA) probes as described (25, 36). Yellow and orange represent telomere signals obtained with Cy3-labeled (CCCTAA)3 PNA, and blue represents DAPI-stained chromosomal DNA. Pseudocolors were assigned using Adobe Photoshop software (San Jose, CA). Asterisks indicate metacentric Robertsonian fusion products between acrocentric chromosomes. Number signs indicate chromosome arms without detectable TTAGGG repeats.

Mentions: The presence of the Robertsonian fusions observed in later generations of the telomerase KO mice deserves special mention (Fig. 2). Given that telomeres on the short P arm of acrocentric murine chromosomes are, in general, significantly shorter than q arm telomeres (36), a gradual loss of telomere repeats would be expected to predispose to this type of chromosomal abnormality. Are the Robertsonian chromosomes in the telomerase KO mouse stable? If the primary fusion event was indeed between two different uncapped chromosomes, the prediction would be that they are not, as such chromosomes are expected to have two functional centromeres (23). Further studies of these Robertsonian chromosomes should reveal whether they represent unique cytogenetic abnormalities in telomerase KO mice.


Lessons from mice without telomerase.

Lansdorp PM - J. Cell Biol. (1997)

Chromosomal abnormalities in embryonic fibroblasts derived from the  sixth generation of telomerase   mice. Results were obtained by Q-FISH using peptide nucleic acid (PNA) probes  as described (25, 36). Yellow  and orange represent telomere signals obtained with  Cy3-labeled (CCCTAA)3  PNA, and blue represents  DAPI-stained chromosomal  DNA. Pseudocolors were assigned using Adobe Photoshop software (San Jose, CA).  Asterisks indicate metacentric  Robertsonian fusion products between acrocentric chromosomes. Number signs indicate chromosome arms without  detectable TTAGGG repeats.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2139790&req=5

Figure 2: Chromosomal abnormalities in embryonic fibroblasts derived from the sixth generation of telomerase mice. Results were obtained by Q-FISH using peptide nucleic acid (PNA) probes as described (25, 36). Yellow and orange represent telomere signals obtained with Cy3-labeled (CCCTAA)3 PNA, and blue represents DAPI-stained chromosomal DNA. Pseudocolors were assigned using Adobe Photoshop software (San Jose, CA). Asterisks indicate metacentric Robertsonian fusion products between acrocentric chromosomes. Number signs indicate chromosome arms without detectable TTAGGG repeats.
Mentions: The presence of the Robertsonian fusions observed in later generations of the telomerase KO mice deserves special mention (Fig. 2). Given that telomeres on the short P arm of acrocentric murine chromosomes are, in general, significantly shorter than q arm telomeres (36), a gradual loss of telomere repeats would be expected to predispose to this type of chromosomal abnormality. Are the Robertsonian chromosomes in the telomerase KO mouse stable? If the primary fusion event was indeed between two different uncapped chromosomes, the prediction would be that they are not, as such chromosomes are expected to have two functional centromeres (23). Further studies of these Robertsonian chromosomes should reveal whether they represent unique cytogenetic abnormalities in telomerase KO mice.

View Article: PubMed Central - PubMed

Affiliation: Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada, V5Z 1L3. peter@terryfox.ubc.ca

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Surprisingly, cells from mice without a functional telomerase RNA gene and no telomerase activity are indistinguishable from normal cells in different transformation and immortalization assays... Such data have now been obtained by Blasco et al., who developed mice in which the telomerase RNA template gene has been removed from the germ line using standard gene knock-out (KO) techniques... The results obtained with (the cells from) the telomerase KO mice contain valuable lessons for anyone interested in telomere biology... It has been suggested that cellular defects may be demonstrated upon challenges to such tissues or with aging of the mice, but details of such defects are currently not known... If the cells of self-renewing tissues are affected, it will be important to distinguish between the absence of telomerase and a decreased proliferative potential (resulting from overall shorter telomeres; see below) as primary defects... Furthermore, cells from telomerase-deficient mice were as efficiently transformed into immortal and in vivo tumor-forming cells as cells from telomerase-positive animals, demonstrating conclusively that, in the mouse, telomerase is not an essential requirement for the establishment of cell lines, oncogenic transformation, or tumor formation... The surprises did not end there... A similar adaptation of signal transduction systems may apply to cells of telomerase KO mice... In any event, it seems that murine cells with one or more uncapped chromosomes can divide for many times with or without an initial arrest... Indeed, normal development and even fertility does not seem to be immediately affected by the presence of such uncapped chromosomes... Indeed, the overall long telomeres in the mouse could favor the use of such a nonreciprocal recombination: a critically short telomere in a murine cell could perhaps easily recombine with remaining long telomeres on other chromosomes... As the overall telomere length decreases in subsequent generations of the telomerase KO animals, the efficiency of this pathways could decrease, possibly with the increased frequencies of chromosomal abnormalities seen at later generations as a result... Approximately a quarter of immortalized human cell lines lack detectable telomerase activity (for review see reference ), indicating that alternatives to telomerase for the maintenance of telomeres also exist in human cells... The observation that cells from M. spretus (with telomeres of comparable length to human cells) will spontaneously, be it less efficiently, immortalize in culture indicates that overall telomere length cannot be a major factor predisposing cells towards spontaneous immortalization... In general, many questions about the role of telomerase and recombination pathways in the proliferation, senescence, and immortalization of normal and malignant cells from different murine and human tissues remain.

Show MeSH
Related in: MedlinePlus