I have received a number of e-mails regarding a paper by Kiyono et al, in;
Nature 396, 84-88 (1998) and a related commentary by R. Weinberg, Nature 396,
23-24.
The gist of these articles is that in addition to telomerase activity,
deactivation of the p16/retinoblastoma pathway may also be required for the
immortalization of epithelial cells.
The kiyono, et al findings seem to confirm the paper by Xu HJ et al,
(Oncogene 1997 Nov 20;15(21):2589-96, Reexpression of the retinoblastoma
protein in tumor cells induces senescence and telomerase inhibition.) Here it
was found that "overexpression of pRB alone in RB/p53-defective tumor cells
is sufficient to reverse their immortality".
These results have been suggested to contradict the findings of Bodnar, et al
in Science 1998 Jan 16;279(5349):349-352 wherein h-TRT activation of
telomerase alone was sufficient to immortalize epithelial cells and foreskin
fibroblasts.
Fortunately, these findings are readily reconciled. Both the nature and the
Oncogene studies dealt with cells that had encountered senescence. Whereas
the Science study related to the activation of telomerase prior to the
initiation of senescence.
In senescence, it appears,the mdm2 block on the expression of the p-53 gene
is released and the downstream products, including both p-16 and p-21,
initiate CDK inhibition and the retinoblastoma pathway stopping further
cellular division.
The major cause of this sequence of events leading to senescence has been
suggested to be the recognition of shortened telomeres as being genetic
"damage", (Vaziri H, Biochemistry (Mosc) 1997 Nov;62(11):1306-1310).
However, as noted in this Nature study, there are several other events that
can initiate this senescence program including physiological stress,
activities of oncogenes as well as "other" genetic damage.
Since most cells in vivo don't encounter senescence, as opposed to those in
culture that often do, the introduction of h-TRT and subsequent activation of
telomerase should avoid the major cause of senescence and avoid the
retinoblastoma pathway altogether.
Thus, while this nature study does support the two step process of cancer
progression, (ie; the overcoming of senescence and the re-activation of
telomerase), it should have no significant detrimental effects on the
immortalization of cells that don't encounter senescence.
Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.
http://home.earthlink.net/~excelife/index.html
