RAS Mutations Affect Tumor Necrosis Factor–Induced Apoptosis in Colon Carcinoma Cells via ERK-Modulatory Negative and Positive Feedback Circuits Along with Non-ERK Pathway Effects
Name
Lauffenburger-2009-Ras Mutations Affect Tumor Necrosis Factor.pdf
Size
1.67 MB
Format
Adobe PDF
Checksum (MD5)
48d02013225a3178cce83dd7dc45bfe9
Author(s)
Kreeger, Pamela K.
Mandhana, Roli
Haigis, Kevin M.
Hughes-Alford, Shannon Kay
Lauffenburger, Douglas A
Date Issued
October 2009
Journal
Cancer Research
Publisher
American Association for Cancer Research
Citation
Kreeger, P. K. et al. “RAS Mutations Affect Tumor Necrosis Factor-Induced Apoptosis in Colon Carcinoma Cells via ERK-Modulatory Negative and Positive Feedback Circuits Along with Non-ERK Pathway Effects.” Cancer Research 69 (2009): 8191-8199.
Version
Author's final manuscript
Abstract
More than 40% of colon cancers have a mutation in K-RAS or N-RAS, GTPases that operate as central hubs for multiple key signaling pathways within the cell. Utilizing an isogenic panel of colon carcinoma cells with K-RAS or N-RAS variations, we observed differences in tumor necrosis factor-α (TNFα)–induced apoptosis. When the dynamics of phosphorylated ERK response to TNFα were examined, K-RAS mutant cells showed lower activation whereas N-RAS mutant cells exhibited prolonged duration. These divergent trends were partially explained by differential induction of two ERK-modulatory circuits: negative feedback mediated by dual-specificity phosphatase 5 and positive feedback by autocrine transforming growth factor-α. Moreover, in the various RAS mutant colon carcinoma lines, the transforming growth factor-α autocrine loop differentially elicited a further downstream chemokine (CXCL1/CXCL8) autocrine loop, with the two loops having opposite effects on apoptosis. Although the apoptotic responses of the RAS mutant panel to TNFα treatment showed significant dependence on the respective phosphorylated ERK dynamics, successful prediction across the various cell lines required contextual information concerning additional pathways including IKK and p38. A quantitative computational model based on weighted linear combinations of these pathway activities successfully predicted not only the spectrum of cell death responses but also the corresponding chemokine production responses. Our findings indicate that diverse RAS mutations yield differential cell behavioral responses to inflammatory cytokine exposure by means of (a) differential effects on ERK activity via multiple feedback circuit mechanisms, and (b) differential effects on other key signaling pathways contextually modulating ERK-related dependence.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike 3.0
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1158/0008-5472.can-09-1921
