In article <370563F3.449D at itsa.ucsf.edu>, csoka at ITSA.UCSF.EDU says...
>>>P.N.A.S. Vol. 96, Issue 7, 3723-3728, March 30, 1999
>>>> Cell Biology
>> Telomerase extends the lifespan of virus-transformed human
>> cells without net telomere lengthening
>>>> Jiyue Zhu*,, He Wang*,, J. Michael Bishop,, and Elizabeth H. Blackburn,§
>>>> The G. W. Hooper Foundation, Department of Microbiology and Immunology,
University of California,
>> San Francisco, CA 94143
>>>> Contributed by Elizabeth H. Blackburn, January 14, 1999
>>
Human fibroblasts whose lifespan in culture has been extended by expression
of a viral oncogene eventually undergo a growth crisis marked by failure to
proliferate. It has been proposed that telomere shortening in these cells
is the property that limits their proliferation. Here we report that
ectopic expression of the wild-type reverse transcriptase protein (hTERT)
of human telomerase averts crisis, at the same time reducing the frequency
of dicentric and abnormal chromosomes. Surprisingly, as the resulting
immortalized cells containing active telomerase continue to proliferate,
their telomeres continue to shorten to mean lengths below those in control
cells that enter crisis. These results provide evidence for a protective
function of human telomerase that allows cell proliferation without
requiring net lengthening of telomeres.
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These results would explain the very short telomeres seen in cancers with
active telomerase.
Complimentary results were recently published in;
(Mol Cell Biol 1999 Mar;19(3):1864-70 "Telomerase activity is sufficient To
allow transformed cells To escape from crisis." Halvorsen TL, Leibowitz G,
Levine F).
Here they showed that "Telomere lengths initially increased, but telomeres
were then maintained at their new lengths for at least 20 population
doublings."
Both of these findings seem to suggest that telomerase allows cells to avoid
and/or escape senescence and crisis by a process unrelated to telomeric
lengthening.
A possible mechanism by which this might occur would be the silencing of the
p-53 gene and its downstream products. This is suggested by the lack of p-53
proteins observed in immortalized cells.
As a reverse transcriptase protein it may actually silence this gene itself
or it may possibly have some effects on the chromatin structure of the
chromosomes that then acts to silence this gene.
Thus having avoided the p-53 induced senescence the telomerase may avoid any
additional telomeric shortening by attaching to the telomeres during
replication rather than adding additional telomeric repeats.
These are just some thoughts on the subject and additional research will
delineate the exact processes at work.
Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.
http://home.earthlink.net/~excelife/index.html
