Bmi-1 reduction plays a key role in physiological and premature aging of primary human keratinocytes

Sonia Cordisco, Riccardo Maurelli, Sergio Bondanza, Miria Stefanini, Giovanna Zambruno, Liliana Guerra, Elena Dellambra

Research output: Contribution to journalArticlepeer-review


Accumulation of senescent cells contributes to the reduced regenerative capacity in aged tissues. By evaluating the molecular pathways of senescence in relation to proliferative potential of primary keratinocyte cultures from young and old healthy donors, and from young patients with inherited defects leading to premature aging, we demonstrated that p16 INK4a is a reliable marker of both physiological and premature epidermal aging. Analysis of the expression and activity of p16 INK4a regulators showed that stem cell depletion, reduced proliferation, and p16 INK4a upregulation in keratinocytes derived from the chronologically and prematurely aged epidermis strongly correlate with Bmi-1 downregulation. In highly proliferative tissues, replicative and premature senescence participate in determining senescent cell accumulation. Our findings demonstrated that Bmi-1 is downregulated in human keratinocytes during both in vitro processes, in parallel with p16 INK4a upregulation and accomplishment of clonal conversion. When premature senescence was induced by specific exogenous stimuli, concomitant Ets-1 upregulation was also observed. Moreover, Bmi-1 inhibited Ets-1-mediated p16 INK4a upregulation. Finally, Bmi-1 overexpression reduced p16 INK4a promoter activity and decreased protein expression in aged and diseased keratinocytes, inducing a delay of clonal conversion and an increase of cell clonogenic ability. Altogether these findings underline a key role of Bmi-1 downregulation in enforcing aging in primary human keratinocytes.

Original languageEnglish
Pages (from-to)1048-1062
Number of pages15
JournalJournal of Investigative Dermatology
Issue number4
Publication statusPublished - Apr 2010

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology


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