Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1

K Itahana, Y Zou, Y Itahana, JL Martinez… - … and cellular biology, 2003 - Taylor & Francis
K Itahana, Y Zou, Y Itahana, JL Martinez, C Beausejour, JJL Jacobs, M Van Lohuizen…
Molecular and cellular biology, 2003Taylor & Francis
The polycomb protein Bmi-1 represses the INK4a locus, which encodes the tumor
suppressors p16 and p14ARF. Here we report that Bmi-1 is downregulated when WI-38
human fibroblasts undergo replicative senescence, but not quiescence, and extends
replicative life span when overexpressed. Life span extension by Bmi-1 required the pRb,
but not p53, tumor suppressor protein. Deletion analysis showed that the RING finger and
helix-turn-helix domains of Bmi-1 were required for life span extension and suppression of …
The polycomb protein Bmi-1 represses the INK4a locus, which encodes the tumor suppressors p16 and p14ARF. Here we report that Bmi-1 is downregulated when WI-38 human fibroblasts undergo replicative senescence, but not quiescence, and extends replicative life span when overexpressed. Life span extension by Bmi-1 required the pRb, but not p53, tumor suppressor protein. Deletion analysis showed that the RING finger and helix-turn-helix domains of Bmi-1 were required for life span extension and suppression of p16. Furthermore, a RING finger deletion mutant exhibited dominant negative activity, inducing p16 and premature senescence. Interestingly, presenescent cultures of some, but not all, human fibroblasts contained growth-arrested cells expressing high levels of p16 and apparently arrested by a p53- and telomere-independent mechanism. Bmi-1 selectively extended the life span of these cultures. Low O2 concentrations had no effect on p16 levels or life span extension by Bmi-1 but reduced expression of the p53 target, p21. We propose that some human fibroblast strains are more sensitive to stress-induced senescence and have both p16-dependent and p53/telomere-dependent pathways of senescence. Our data suggest that Bmi-1 extends the replicative life span of human fibroblasts by suppressing the p16-dependent senescence pathway.
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