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V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a.

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journal contribution
posted on 24.10.2012, 08:58 by Linda A. S. Carragher, Kimberley R. Snell, Susan M. Giblett, Victoria S. S. Aldridge, Bipin Patel, S. J. Cook, D. J. Winton, R. Marais, Catrin A. Pritchard
The majority of human colorectal cancers (CRCs) are initiated by mutations arising in the adenomatous polyposis coli (APC) tumour suppressor gene. However, a new class of non-APC mutated CRCs has been defined that have a serrated histopathology and carry the (V600E)BRAF oncogene. Here we have investigated the pathogenesis of serrated CRCs by expressing (V600E)Braf in the proliferative cells of the mouse gastrointestinal tract. We show that the oncogene drives an initial burst of Mek-dependent proliferation, leading to the formation of hyperplastic crypts. This is associated with β-catenin nuclear localization by a mechanism involving Mapk/Erk kinase (Mek)-dependent, Akt-independent phosphorylation of Gsk3β. However, hyperplastic crypts remain dormant for prolonged periods due to the induction of crypt senescence accompanied by upregulation of senescence-associated β-galactosidase and p16(Ink4a). We show that tumour progression is associated with down-regulation of p16(Ink4a) through enhanced CpG methylation of exon 1 and knockout of Cdkn2a confirms this gene is a barrier to tumour progression. Our studies identify (V600E)BRAF as an early genetic driver mutation in serrated CRCs and indicate that, unlike APC-mutated cancers, this subtype arises by the bypassing of a (V600E)Braf driven oncogene-induced senescence programme.

History

Citation

EMBO Molecular Medicine, 2010, 2 (11), pp. 458-471

Published in

EMBO Molecular Medicine

Publisher

Wiley Open Access with European Molecular Biology Organization (EMBO) with Wiley-VCH Verlag, EMBO Press

issn

1757-4676

eissn

1757-4684

Copyright date

2010

Available date

24/10/2012

Publisher version

http://embomolmed.embopress.org/content/2/11/458

Language

eng