| As eukaryotic cells divide, the ends of their chromosomes, the telomeres, shorten. It has been proposed that telomere length might determine how many times a cell can divide. In cells which are highly proliferative, such as cancer and germline cells, telomere length is maintained by the enzyme telomerase. It has been proposed that telomerase could be a therapeutic target for cancer treatment, or could enable damaged tissue to regenerate. Because telomerase is associated with proliferative populations, and because B lymphocytes proliferate during development and activation, I proposed that telomerase would be expressed in murine B cells. In peritoneal B cells, telomerase is expressed constitutively in the self-renewing populations, but not in the conventional cells. In splenic B cells telomerase activity is induced by LPS, anti-CD40, anti-IgM, and interleukin-4. Any of these stimuli alone could induce telomerase activity, in contrast to human B cells which require two signals for telomerase induction. In contrast to LPS, anti-CD40, and anti-IgM, IL-4 stimulation induced telomerase without apparent proliferation. Extensive analysis of IL-4 stimulated B cells indicated that the cells do proliferate at a low rate. Whether the proliferating cells were the ones expressing telomerase activity could not be determined. Interleukin-4 activates two signaling pathways. One involves the JAK/STAT signaling family, and results in activation of Stat6. The other utilizes the insulin receptor substrate-2 molecule (IRS-2). When Stat6 knockout mice were used as a source of B cells, telomerase was activated in response to all Stimuli, indicating that Stat6 is not required for telomerase induction in murine B cells. To determine if the IRS-2 was required for telomerase activation, B cells were treated with drugs which inhibit signaling. Cells treated with wortmannin to inhibit phosphatidylinositol-3-kinase (PI3-K), a target of IRS-2, Showed lower telomerase induction in response to stimulation by IL-4 or anti-Igm, but not LPS or anti-CD40. Rapamycin, a drug which inhibits p70S6K, a downstream target of PI3-K, had no effect on telomerase induction by any Stimuli. This suggests that multiple signaling pathways are responsible for telomerase activation in B lymphocytes, and that the IRS-2 pathway is utilized to activate telomerase. |
