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. ISSN 1471-2164

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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
Subjects:	Q Science > QL Zoology Q Science > QP Physiology
Divisions:	Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010) Faculty of Science > Life Sciences (2010- ) Faculty of Medicine > Warwick Medical School
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
Date:	30 September 2011
Volume:	Vol.12
Number:	No.9(Sept)
Page Range:	Article No.476
Identification Number:	10.1186/1471-2164-12-476
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
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
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URI:	http://wrap.warwick.ac.uk/id/eprint/39129

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