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Deciphering c-MYC-regulated genes in two distinct tissues
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Robson, Samuel C, Ward, Lesley, Brown, Helen, Turner, Heather, Hunter, Ewan, Pelengaris, Stella and Khan, Michael (2011) Deciphering c-MYC-regulated genes in two distinct tissues. BMC Genomics, 12 (1). 476. doi:10.1186/1471-2164-12-476 ISSN 1471-2164.
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Official URL: http://dx.doi.org/10.1186/1471-2164-12-476
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 p19Arf/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 p19Arf by MYC in suprabasal keratinocytes may contribute.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Statistics | ||||||
| Journal or Publication Title: | BMC Genomics | ||||||
| Publisher: | BioMed Central Ltd. | ||||||
| ISSN: | 1471-2164 | ||||||
| Official Date: | 30 September 2011 | ||||||
| Dates: |
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| Volume: | 12 | ||||||
| Number: | 1 | ||||||
| Article Number: | 476 | ||||||
| DOI: | 10.1186/1471-2164-12-476 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Open Access (Creative Commons) |
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