title: The secreted protein S100A7 (psoriasin) is induced by telomere dysfunction in human keratinocytes independently of a DNA damage response and cell cycle regulators.
abstract: BACKGROUND
  Replicative senescence is preceded by loss of repeat sequences of DNA from the telomeres that eventually leads to telomere dysfunction, the accumulation of irreparable DNA double strand breaks and a DNA damage response (DDR). However, we have previously reported that whilst telomere dysfunction in human keratinocytes is associated with a permanent cell cycle arrest, the DDR was very weak and transcriptional profiling also revealed several molecules normally associated with keratinocytes terminal differentiation, including S100A7 (psoriasin).
  
  
  RESULTS
  We show here that S100A7 and the closely related S100A15 (koebnerisin) are not induced by repairable or irreparable DSBs, ruling out the hypotheses that these genes are induced either by the low DDR observed or by non-specific cell cycle arrest. We next tested whether S100A7 was induced by the cell cycle effectors ARF (p14(ARF)), CDKN2A (p16(INK4A)) and TP53 (p53) and found that, although all induced a similar level of acute and permanent cell cycle arrest to telomere dysfunction, none induced S100A7 (except p53 over-expression at high levels), showing that cell cycle arrest is not sufficient for its induction. The closely related transcript S100A15 was also upregulated by telomere dysfunction, to a similar extent by p16(INK4A) and p53 and to a lesser extent by p14(ARF).
  
  
  CONCLUSIONS
  Our results show that mere cell cycle arrest, the upregulation of senescence-associated cell cycle effectors and DNA damage are not sufficient for the induction of the S100 transcripts; they further suggest that whilst the induction of S100A15 expression is linked to both telomere-dependent and -independent senescence, S100A7 expression is specifically associated with telomere-dependent senescence in normal keratinocytes. As both S100A7 and S100A15 are secreted proteins, they may find utility in the early detection of human keratinocyte telomere dysfunction and senescence.
authors.affiliation: Centre for Clinical & Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Turner Street, London E1 2AD, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: de Castro
authors.affiliation: Centre for Clinical & Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Turner Street, London E1 2AD, UK.
authors.forename: Fay
authors.initials: F
authors.lastname: Minty
authors.affiliation: Department of Dermatology, Ludwig-Maximilian University Munich, Frauenlobstrasse 9-11, 80337 Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hattinger
authors.affiliation: Department of Dermatology, Ludwig-Maximilian University Munich, Frauenlobstrasse 9-11, 80337 Munich, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Wolf
authors.affiliation: Centre for Clinical & Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Turner Street, London E1 2AD, UK ; Blizard Building, 4, Newark Street, London E1 2AT, UK.
authors.forename: Eric Kenneth
authors.initials: EK
authors.lastname: Parkinson
keywords: Differentiation; Keratinocyte; S100; SASP; Senescence; Telomere