{'fraction_non_alphanumeric': 0.021948608137044967, 'fraction_numerical': 0.003747323340471092, 'mean_word_length': 5.747292418772563, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
RAS Mutations Impact TNF-Induced Apoptosis in Colon Carcinoma Cells via ERK-Modulatory Negative and Positive Feedback Circuits along with non-ERK Pathway Effects

Over 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 TNFα-induced apoptosis. When the dynamics of phosphorylated ERK (pERK) response to TNFα were examined, K-RAS mutant cells showed lower activation while N-RAS mutant cells exhibited prolonged duration. These divergent trends were partially explained by differential induction of two ERKmodulatory circuits: negative feedback mediated by DUSP5 and positive feedback by autocrine TGFα. Moreover, in the various RAS-mutant colon carcinoma lines, the TGFα autocrine loop differentially elicited a further downstream chemokine (CXCL1/CXCL8) autocrine loop, with the two loops having opposite impacts on apoptosis. While the apoptotic responses of the RAS-mutant panel to TNFα treatment showed significant dependence on the respective pERK 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.