title: Deciphering c-MYC-regulated genes in two distinct tissues.
abstract: BACKGROUND
  The transcription factor MYC is a critical regulator of diverse cellular processes, including both replication and apoptosis. Differences in MYC-regulated gene expression responsible for such opposing outcomes in vivo remain obscure. To address this we have examined time-dependent changes in global gene expression in two transgenic mouse models in which MYC activation, in either skin suprabasal keratinocytes or pancreatic islet β-cells, promotes tissue expansion or involution, respectively.
  
  
  RESULTS
  Consistent with observed phenotypes, expression of cell cycle genes is increased in both models (albeit enriched in β-cells), as are those involved in cell growth and metabolism, while expression of genes involved in cell differentiation is down-regulated. However, in β-cells, which unlike suprabasal keratinocytes undergo prominent apoptosis from 24 hours, there is up-regulation of genes associated with DNA-damage response and intrinsic apoptotic pathways, including Atr, Arf, Bax and Cycs. In striking contrast, this is not the case for suprabasal keratinocytes, where pro-apoptotic genes such as Noxa are down-regulated and key anti-apoptotic pathways (such as Igf1-Akt) and those promoting angiogenesis are up-regulated. Moreover, dramatic up-regulation of steroid hormone-regulated Kallikrein serine protease family members in suprabasal keratinocytes alone could further enhance local Igf1 actions, such as through proteolysis of Igf1 binding proteins.
  
  
  CONCLUSIONS
  Activation of MYC causes cell growth, loss of differentiation and cell cycle entry in both β-cells and suprabasal keratinocytes in vivo. Apoptosis, which is confined to β-cells, may involve a combination of a DNA-damage response and downstream activation of pro-apoptotic signalling pathways, including Cdc2a and p19(Arf)/p53, and downstream targets. Conversely, avoidance of apoptosis in suprabasal keratinocytes may result primarily from the activation of key anti-apoptotic signalling pathways, particularly Igf1-Akt, and induction of an angiogenic response, though intrinsic resistance to induction of p19(Arf) by MYC in suprabasal keratinocytes may contribute.
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, Cambridge, CB2 1QN, UK.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Robson
authors.forename: Lesley
authors.initials: L
authors.lastname: Ward
authors.forename: Helen
authors.initials: H
authors.lastname: Brown
authors.forename: Heather
authors.initials: H
authors.lastname: Turner
authors.forename: Ewan
authors.initials: E
authors.lastname: Hunter
authors.forename: Stella
authors.initials: S
authors.lastname: Pelengaris
authors.forename: Michael
authors.initials: M
authors.lastname: Khan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D005786:Gene Expression Regulation; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018797:Cell Cycle Proteins; D016271:Proto-Oncogene Proteins c-myc