FIG. 10.

NS regulates the protein stability of TRF1 and controls cell proliferation and senescence. (A) Our findings support a model in which NS promotes the degradation of TRF1 protein without affecting its ubiquitination level. This activity of NS will favor the removal of TRF1 from the telomeres and allow telomerase to access and elongate the telomere. (B) NS exerts a threshold effect on dividing cells. Cells undergo continuous proliferation when their NS expression levels (y axis) are within a certain threshold (between H and M). When the expression of NS drops below the M point, cells begin to enter into senescence. Most cells will become mitotically inactive when NS falls below the low level (L). Paradoxically, excessive amounts of NS will inhibit cell proliferation, as seen in the P1 and P2 cultures of TG#17 MEFs. Over passages, NS expression in the NS^+/− MEFs begins to fall below the M level first, followed by the WT, TG#1, and TG#17 cells, which explains why the effect of NS perturbation in these models is most obvious between P5 and P8.