Tissue-specific p19[superscript Arf] regulation dictates the response to oncogenic K-ras
Name
Jacks_Tissue-specific.pdf
Size
2.13 MB
Format
Adobe PDF
Checksum (MD5)
ada22ec2c022bd38078519e19b7ad4be
Author(s)
Young, Nathan P.
Jacks, Tyler E
Date Issued
May 2010
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Young, N. P., and T. Jacks. “Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras.” Proceedings of the National Academy of Sciences 107, no. 22 (June 1, 2010): 10184-10189.
Version
Final published version
Abstract
The ability of oncogenes to engage tumor suppressor pathways represents a key regulatory mechanism that can limit the outgrowth of incipient tumor cells. For example, in a number of settings oncogenic Ras strongly activates the Ink4a/Arf locus, resulting in cell cycle arrest or senescence. The capacity of different cell types to execute tumor suppressor programs following expression of endogenous K-ras[superscript G12D] in vivo has not been examined. Using compound mutant mice containing the Arf[superscript GFP] reporter and the spontaneously activating K-ras[superscript LA2] allele, we have uncovered dramatic tissue specificity of K-ras[superscript G12D]-dependent p19[superscript Arf] up-regulation. Lung tumors, which can arise in the presence of functional p19[superscript Arf], rarely display p19[superscript Arf] induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19[superscript Arf]-p53 pathway is a requisite event for sarcomagenesis. Using constitutive and inducible RNAi systems in vivo, we highlight cell type-specific chromatin regulation of Ink4a/Arf as a critical determinant of cellular responses to oncogenic K-ras. Polycomb-group complexes repress the locus in lung tumors, whereas the SWI/SNF family member Snf5 acts as an important mediator of p19[superscript Arf] induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1073/pnas.1004796107
