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Deciphering c-MYC-regulated genes in two distinct tissues
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Robson, Samuel Charles, Ward, Lesley (Lesley A.), Brown, Helen (Helen E.), Turner, Heather, Hunter, Ewan, Pelengaris, Stella and Khan, Michael (2011) Deciphering c-MYC-regulated genes in two distinct tissues. BMC Genomics, Vol.12 (No.9(Sept)). Article No.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 bcells,
promotes tissue expansion or involution, respectively.
Results: Consistent with observed phenotypes, expression of cell cycle genes is increased in both models (albeit
enriched in b-cells), as are those involved in cell growth and metabolism, while expression of genes involved in
cell differentiation is down-regulated. However, in b-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 b-cells and
suprabasal keratinocytes in vivo. Apoptosis, which is confined to b-cells, may involve a combination of a DNAdamage
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 | ||||
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Subjects: | Q Science > QL Zoology Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) > Biological Sciences ( -2010) Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Myc proteins, Gene expression, Mice -- Physiology | ||||
Journal or Publication Title: | BMC Genomics | ||||
Publisher: | BioMed Central Ltd. | ||||
ISSN: | 1471-2164 | ||||
Official Date: | 30 September 2011 | ||||
Dates: |
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Volume: | Vol.12 | ||||
Number: | No.9(Sept) | ||||
Page Range: | Article No.476 | ||||
DOI: | 10.1186/1471-2164-12-476 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Open Access (Creative Commons) | ||||
Date of first compliant deposit: | 18 December 2015 | ||||
Date of first compliant Open Access: | 18 December 2015 | ||||
Funder: | Engineering and Physical Sciences Research Council (EPSRC), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Association for International Cancer Research (AICR), Wellcome Trust (London, England), Eli Lilly and Company, Amylin Pharmaceuticals |
Data sourced from Thomson Reuters' Web of Knowledge
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