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p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium

Cole, A. M. and Ridgway, R.A. and Derkits, S. E. and Parry, L. and Barker, N. and Clevers, H. and Clarke, A.R. and Sansom, O.J. (2010) p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium. EMBO Molecular Medicine, 2, 472-86. ISSN 1757-4676.

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Official URL: http://dx.doi.org/10.1002/emmm.201000101

Abstract

Senescence has been implicated as an important mechanism of tumour suppression in a number of human malignancies, including colorectal cancer (CRC). However, we still have a relatively poor understanding of how the underlying mutations that occur in cancer cause senescence and its relevance in vivo. The Apc gene is mutated in approximately 80% of CRC as the initiating event, but rarely elsewhere. In this study we have examined the capacity of Apc loss to induce senescence in the intestinal epithelium compared to the renal epithelium. Within the renal epithelium, loss of Apc function led to an induction of senescence, however, bypassing senescence through combined Apc and p21 or Ink4A gene deletion rapidly initiated renal carcinoma. Within the intestinal epithelium, loss of Apc did not induce senescence. Moreover, combined Apc and p21 or Ink4A loss had no impact upon tumourigenesis. Taken together, these results show that Apc loss in vivo invokes a senescence program in a context-dependent fashion, and implies senescence may play a key barrier to tumourigenesis in the kidney. However, in CRC, escape from senescence is likely to only be a barrier in cancers initiated by other mutations.

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:9459
Deposited On:04 Jan 2011 01:00
Last Modified:07 Sep 2011 17:01

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