期刊
BMC GENOMICS
卷 12, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1471-2164-12-476
关键词
-
资金
- EPSRC
- BBSRC
- AICR
- Wellcome Trust
- Eli Lilly Co. Ltd.
- Amylin Pharmaceuticals, Inc.
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 beta-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 beta-cells), as are those involved in cell growth and metabolism, while expression of genes involved in cell differentiation is down-regulated. However, in beta-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 beta-cells and suprabasal keratinocytes in vivo. Apoptosis, which is confined to beta-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.
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