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Enhanced sensitivit...
Enhanced sensitivity to IGF-II signalling links loss of imprinting of IGF2 to increased cell proliferation and tumour risk
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Kaneda, Atsushi (författare)
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Wang, Chiaochun J. (författare)
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Cheong, Raymond (författare)
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visa fler...
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Timp, Winston (författare)
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Onyango, Patrick (författare)
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Wen, Bo (författare)
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Lacobuzio-Donahuel, Christine A. (författare)
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- Ohlsson, Rolf (författare)
- Karolinska Institutet,Uppsala universitet,Institutionen för fysiologi och utvecklingsbiologi
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Andraos, Rita (författare)
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Pearson, Mark A. (författare)
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Sharov, Alexei A. (författare)
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Longol, Dan L. (författare)
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Ko, Minoru S. H. (författare)
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Levchenko, Andre (författare)
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Feinberg, Andrew P. (författare)
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(creator_code:org_t)
- 2007-12-26
- 2007
- Engelska.
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:52, s. 20926-20931
- Relaterad länk:
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http://www.pnas.org/...
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http://www.pnas.org/...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Loss of imprinting (LOI) of the insulin-like growth factor-II gene (IGF2), leading to abnormal activation of the normally silent maternal allele, is a common human epigenetic population variant associated with a 5-fold increased frequency of colorectal neoplasia. Here, we show first that LOI leads specifically to increased expression of proliferation-related genes in mouse intestinal crypts. Surprisingly, LOI(+) mice also have enhanced sensitivity to IGF-II signaling, not simply increased IGF-II levels, because in vivo blockade with NVP-AEW541, a specific inhibitor of the IGF-II signaling receptor, showed reduction of proliferation-related gene expression to levels half that seen in LOI(-) mice. Signal transduction assays in microfluidic chips confirmed this enhanced sensitivity with marked augmentation of Akt/PKB signaling in LOI(+) cells at low doses of IGF-II, which was reduced in the presence of the inhibitor to levels below those found in LOI(-) cells, and was associated with increased expression of the IGF1 and insulin receptor genes. We exploited this increased IGF-II sensitivity to develop an in vivo chemopreventive strategy using the azoxymethane (AOM) mutagenesis model. LOI(+) mice treated with AOM showed a 60% increase in premalignant aberrant crypt foci (ACF) formation over LOI(-) mice. In vivo IGF-II blockade with NVP-AEW541 abrogated this effect, reducing ACF to a level 30% lower even than found in exposed LOI(-) mice. Thus, LOI increases cancer risk in a counterintuitive way, by increasing the sensitivity of the IGF-II signaling pathway itself, providing a previously undescribed epigenetic chemoprevention strategy in which cells with LOI are "IGF-II addicted" and undergo reduced tumorigenesis in the colon upon IGF-II pathway blockade.
Ämnesord
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Nyckelord
- Akt
- cancer
- chemoprevention
- epigenetics
- signal transduction
- Biology
- Biologi
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Kaneda, Atsushi
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Wang, Chiaochun ...
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Cheong, Raymond
-
Timp, Winston
-
Onyango, Patrick
-
Wen, Bo
-
visa fler...
-
Lacobuzio-Donahu ...
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Ohlsson, Rolf
-
Andraos, Rita
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Pearson, Mark A.
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Sharov, Alexei A ...
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Longol, Dan L.
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Ko, Minoru S. H.
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Levchenko, Andre
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Feinberg, Andrew ...
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visa färre...
- Om ämnet
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- NATURVETENSKAP
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NATURVETENSKAP
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och Biologi
- Artiklar i publikationen
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Proceedings of t ...
- Av lärosätet
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Uppsala universitet
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Karolinska Institutet