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
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)–i...
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| Format: | Article |
| Language: | en_US |
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American Association for Cancer Research
2011
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| Online Access: | http://hdl.handle.net/1721.1/67255 |
| _version_ | 1811085485355827200 |
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| author | Kreeger, Pamela K. Mandhana, Roli Haigis, Kevin M. Hughes-Alford, Shannon Kay Lauffenburger, Douglas A |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Kreeger, Pamela K. Mandhana, Roli Haigis, Kevin M. Hughes-Alford, Shannon Kay Lauffenburger, Douglas A |
| author_sort | Kreeger, Pamela K. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:10:21Z |
| format | Article |
| id | mit-1721.1/67255 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:10:21Z |
| publishDate | 2011 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/672552022-09-28T12:23:51Z 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 Kreeger, Pamela K. Mandhana, Roli Haigis, Kevin M. Hughes-Alford, Shannon Kay Lauffenburger, Douglas A Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT Lauffenburger, Douglas A. Kreeger, Pamela K. Mandhana, Roli Alford, Shannon K. Lauffenburger, Douglas A. 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. National Institutes of Health (U.S.) (NIH grants U54-CA112967) National Institutes of Health (U.S.) (NIH grant P50-GM68762) American Cancer Society (grant PF-08-026-01-CCG) 2011-11-21T17:23:20Z 2011-11-21T17:23:20Z 2009-10 2009-08 Article http://purl.org/eprint/type/JournalArticle 0008-5472 1538-7445 http://hdl.handle.net/1721.1/67255 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. en_US http://dx.doi.org/10.1158/0008-5472.can-09-1921 Cancer Research Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf American Association for Cancer Research PubMed Central |
| spellingShingle | Kreeger, Pamela K. Mandhana, Roli Haigis, Kevin M. Hughes-Alford, Shannon Kay Lauffenburger, Douglas A 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://hdl.handle.net/1721.1/67255 |
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