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

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....

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Autores principales: Cole, Alicia M, Ridgway, Rachel A, Derkits, Sahra E, Parry, Lee, Barker, Nick, Clevers, Hans, Clarke, Alan R, Sansom, Owen J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394507/
https://www.ncbi.nlm.nih.gov/pubmed/20976827
http://dx.doi.org/10.1002/emmm.201000101
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author Cole, Alicia M
Ridgway, Rachel A
Derkits, Sahra E
Parry, Lee
Barker, Nick
Clevers, Hans
Clarke, Alan R
Sansom, Owen J
author_facet Cole, Alicia M
Ridgway, Rachel A
Derkits, Sahra E
Parry, Lee
Barker, Nick
Clevers, Hans
Clarke, Alan R
Sansom, Owen J
author_sort Cole, Alicia M
collection PubMed
description 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.
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spelling pubmed-33945072012-09-17 p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium Cole, Alicia M Ridgway, Rachel A Derkits, Sahra E Parry, Lee Barker, Nick Clevers, Hans Clarke, Alan R Sansom, Owen J EMBO Mol Med Research Articles 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. WILEY-VCH Verlag 2010-11 /pmc/articles/PMC3394507/ /pubmed/20976827 http://dx.doi.org/10.1002/emmm.201000101 Text en Copyright © 2010 EMBO Molecular Medicine
spellingShingle Research Articles
Cole, Alicia M
Ridgway, Rachel A
Derkits, Sahra E
Parry, Lee
Barker, Nick
Clevers, Hans
Clarke, Alan R
Sansom, Owen J
p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium
title p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium
title_full p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium
title_fullStr p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium
title_full_unstemmed p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium
title_short p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium
title_sort p21 loss blocks senescence following apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394507/
https://www.ncbi.nlm.nih.gov/pubmed/20976827
http://dx.doi.org/10.1002/emmm.201000101
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