Adenomatous polyposis coli mutants dominantly activate Hsf1-dependent cell stress pathways through inhibition of microtubule dynamics

Oncotarget
Alexander E DaviesKenneth B Kaplan

Abstract

Cancer cells up-regulate cell stress pathways, including the protein chaperone Hsp90. Increases in Hsp90 are believed "buffer" mutant protein activities necessary for cancer phenotypes. Activation of the cell stress pathway also alters the transcriptional landscape of cells in ways that are critical for cancer progression. However, it is unclear when and how the cell stress pathway is de-regulated during cancer progression. Here we report that mutations in adenomatous polyposis coli (APC) found in colorectal cancer activate cell stress pathways in mouse intestinal crypt cells, prior to loss of heterozygosity at APC or to the appearance of canonical intestinal cancer markers. Hsp90 levels are elevated in normal APC heterozygote crypt cells and further elevated in non-cancer cells adjacent to dysplasias, suggesting that the Hsp90 stress pathway marks the "cancer-field" effect. Expression of mutant APC in normal human epithelial cells is sufficient to activate a cell stress pathway via perturbations in microtubule dynamics. Inhibition of microtubule dynamics is sufficient to activate an Hsf1-dependent increase in gene transcription and protein levels. We suggest that the early activation of this Hsf1 dependent cell stress pathway ...Continue Reading

References

Sep 1, 1988·The New England Journal of Medicine·B VogelsteinJ L Bos
Aug 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·Y Xu, S Lindquist
Oct 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·A R MoserM N Gould
Oct 18, 1996·Cell·K W Kinzler, B Vogelstein
Jan 1, 1997·British Journal of Cancer·S PathakL W Chung
Dec 9, 1998·Nature·S L Rutherford, S Lindquist
Aug 16, 2001·American Journal of Physiology. Lung Cellular and Molecular Physiology·A D VerinJ G Garcia
Nov 19, 2003·Current Opinion in Oncology·Len Neckers, S Percy Ivy
Apr 2, 2004·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Todd A SangsterChristine Queitsch
Jul 21, 2005·Molecular Biology of the Cell·Rebecca A GreenKenneth B Kaplan
Jul 26, 2005·Cell Stress & Chaperones·Daniel R Ciocca, Stuart K Calderwood
Sep 22, 2005·Nature Reviews. Cancer·Luke Whitesell, Susan L Lindquist
Feb 2, 2006·International Journal of Cancer. Journal International Du Cancer·Christopher M HeaphyJeffrey K Griffith
Sep 26, 2007·The Journal of Cell Biology·Christine M CaldwellKenneth B Kaplan
Jan 15, 2008·Oncogene·S Courtois-CoxK Cichowski
May 7, 2008·The Journal of Cell Biology·Francesca BartoliniGregg G Gundersen
May 14, 2008·American Journal of Respiratory Cell and Molecular Biology·Alexander AntonovJohn D Catravas
Nov 26, 2009·Advances in Experimental Medicine and Biology·Christine M Caldwell, Kenneth B Kaplan
Jun 23, 2010·The Journal of Cell Biology·Kyoko OkadaBruce L Goode
Oct 12, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michael C RiskDaniel W Lin
Feb 4, 2011·Cold Spring Harbor Symposia on Quantitative Biology·E M TorresA Amon
Jul 18, 2012·Proceedings of the National Academy of Sciences of the United States of America·Jason M SheltzerAngelika Amon
Aug 14, 2012·Archives of Toxicology·Daniel R CioccaStuart K Calderwood
Sep 12, 2012·Oncotarget·Emmanuel de BillyPaul Workman

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BETA
transfection
transfections
PCR
fluorescence microscopy
Protein Assay

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Adenomatous polyposis coli is a protein encoded by the APC gene and acts as a tumor suppressor. Discover the latest research on adenomatous polyposis coli here.