Bmi-1 reduction plays a key role in physiological and premature aging of primary human keratinocytes.
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.
Cordisco
Sonia
S
Laboratory of Tissue Engineering and Cutaneous Physiopathology, IDI, Istituto Dermopatico dell'Immacolata, Rome, Italy.
Maurelli
Riccardo
R
Bondanza
Sergio
S
Stefanini
Miria
M
Zambruno
Giovanna
G
Guerra
Liliana
L
Dellambra
Elena
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019588:Aging, Premature / Q000473:pathology* / Q000503:physiopathology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology*; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D063150:Polycomb Repressive Complex 1; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D055815:Young Adult
C069077:BMI1 protein, human; D016895:Culture Media, Serum-Free; D019941:Cyclin-Dependent Kinase Inhibitor p16; C494041:ETS1 protein, human; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D009687:Nuclear Proteins; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1