Id-1 delays senescence but does not immortalize keratinocytes.
Defining the molecular basis responsible for regulating the proliferative potential of keratinocytes has important implications for normal homeostasis and neoplasia of the skin. Under current culture conditions, neonatal foreskin-derived human keratinocytes possess a relatively short replicative lifespan. Recently it was reported that forced overexpression of the helix-loop-helix protein Id-1 was capable of immortalizing keratinocytes, secondary to activation of telomerase activity and suppression of p16/Rb-mediated growth arrest pathways. To investigate the relationship between Id-1, telomerase activity, telomere length, p16, Rb cell cycle regulators, and senescence, whole populations of keratinocytes were infected with a retrovirus to induce overexpression of Id-1. In these unselected cultures, enhanced Id-1 levels clearly extended the lifespan of keratinocytes, but Id-1 did not prevent the onset of replicative senescence. Under these experimental conditions, Id-1 expression did not trigger induction of telomerase activity, and there was progressive shortening of the telomeres that was accompanied by elevated p16 levels and prevalence of active Rb. The ability of Id-1 to postpone, but not prevent, senescence may be related to partial inhibition of p16 expression, as the Id-1-overexpressing cultures displayed a decreased capacity for 12-O-tetradecanoylphorbol-13-acetate-mediated p16 induction. Thus, while no immortalization was observed, Id-1 could delay the onset of replicative senescence in unselected human keratinocyte populations.
Nickoloff
B J
BJ
Department of Pathology and the Department of Medicine, Loyola University Medical Center, Maywood, Illinois 60153, USA. bnickol@lumc.edu
Chaturvedi
V
V
Bacon
P
P
Qin
J Z
JZ
Denning
M F
MF
Diaz
M O
MO
D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016161:Genes, Retinoblastoma; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D007231:Infant, Newborn; D051798:Inhibitor of Differentiation Protein 1; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology*; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins; D012867:Skin / Q000166:cytology; D019098:Telomerase / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D051020:bcl-X Protein; D019098:Telomerase