Deciphering c-MYC-regulated genes in two distinct tissues

• Main Authors: Hunter Ewan, Turner Heather, Brown Helen, Ward Lesley, Robson Samuel C, Pelengaris Stella, Khan Michael
• Format: Article
• Language: English
• Published: BMC 2011-09-01
• Series: BMC Genomics
• Online Access: http://www.biomedcentral.com/1471-2164/12/476

<p>Abstract</p> <p>Background</p> <p>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 <it>in vivo </it>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.</p> <p>Results</p> <p>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 <it>Atr</it>, <it>Arf</it>, <it>Bax </it>and <it>Cycs</it>. In striking contrast, this is not the case for suprabasal keratinocytes, where pro-apoptotic genes such as <it>Noxa </it>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.</p> <p>Conclusions</p> <p>Activation of MYC causes cell growth, loss of differentiation and cell cycle entry in both β-cells and suprabasal keratinocytes <it>in vivo</it>. 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^Arfby MYC in suprabasal keratinocytes may contribute.</p>