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Title: p21Ras downstream effectors are increased in activity or expression in mouse liver tumors but do not differ between ras-mutated and ras-wild-type lesions.
Authors: Kalkuhl A; Troppmair J; Buchmann A; Stinchcombe S; Buenemann CL ; Rapp UR ; Kaestner K ; Schwarz M
Journal: Hepatology
Volume: 27
Issue: 4
Year: 1998
Pages: 1081-8
Abstract: Mouse liver tumors frequently harbor activating ras gene mutations, Downstream effector molecules of p21(Ras) include Raf-l kinase which mediates external signals via kinase signaling pathways to nuclear transcription factors including c-Fos and c-Jun, Mouse liver tumors with differing uas-mutational status were analyzed for alterations in Ras/Raf-1 signal transduction. Tumors were characterized with respect to the presence of base substitutions in the 3 known hot-spot positions at codons 12, 13, and 61 of Ha-ras, Ki-vas, and N-ras. Ha-uas codon 61 or Ki-ms codon 13 mutations, but no N-ras mutations, were detected in 23 out of 33 tumors analyzed, while no ras-mutations were found in 10 of the tumors, There was no significant difference in the expression of p21(Ras) proteins between ras-mutated tumors and tumors without detectable ras mutations, To allow for determination of Raf-l kinase activity in tumors, a sensitive and specific assay was developed for measurements with tissue homogenates, Raf-l kinase activity was increased about four-fold in liver tumors as compared with normal liver tissue, No significant differences in kinase activity however, were evident between uas-mutated and ras-wild- type tumors. The same was true with respect to the levels of c-fos and c-jun mRNAs, Moreover, there were no significant differences in cell division (5-bromo-2'- deoxyuridine-labeling indices) of hepatocytes from ras- mutated and ras-wild-type tumors, The similar degree of constitutive activation of the Ras/Raf-1 signaling pathway in liver tumors, with and without detectable vas mutations, suggests that other molecules within the signaling pathway may substitute for vas-mutations during oncogenic conversion of ras-wild-type hepatocytes.
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J:47091  Mouse Genome Informatics
9537449  National Library of Medicine/PubMed