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

Koji Itahana, Ying Zou, Yoko Itahana, Jose Luis Martinez, Christian Beausejour, Jacqueline J.L. Jacobs, Maarten Van Lohuizen, Vimla Band, Judith Campisi, Goberdhan P. Dimri

Research output: Contribution to journalArticlepeer-review

331 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)389-401
Number of pages13
JournalMolecular and cellular biology
Volume23
Issue number1
DOIs
StatePublished - Jan 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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