Journal Article

Carcinogen and dietary lipid regulate ras expression and localization in rat colon without affecting farnesylation kinetics

Laurie A. Davidson, Joanne R. Lupton, Yi-Hai Jiang and Robert S. Chapkin

in Carcinogenesis

Volume 20, issue 5, pages 785-791
Published in print May 1999 | ISSN: 0143-3334
Published online May 1999 | e-ISSN: 1460-2180 | DOI:
Carcinogen and dietary lipid regulate ras expression and localization in rat colon without affecting farnesylation kinetics

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics


Show Summary Details


Epidemiological and experimental data suggest that dietary fiber and fat are major determinants of colorectal cancer. However, the mechanisms by which these dietary constituents alter the incidence of colon cancer have not been elucidated. Evidence indicates that dominant gain-of-function mutations short-circuit protooncogenes and contribute to the pathogenesis of cancer. Therefore, we began to dissect the mechanisms whereby dietary fat and fiber, fed during the initiation, promotion and progression stages of colon tumorigenesis, regulate ras p21 localization, expression and mutation frequency. Male Sprague–Dawley rats (140) were provided with corn oil or fish oil and pectin or cellulose plus or minus the carcinogen azoxymethane (AOM) in a 2×2×2 factorial design and killed after 34 weeks. We have previously shown adenocarcinoma incidence in these animals to be 70.3% (52/74) for corn oil + AOM and 56.1% (37/66) for fish oil + AOM (P < 0.05). Total ras expression as well as ras membrane:cytosol ratio was 4- to 6-fold higher in colon tumors than in mucosa from AOM- or saline-injected rats. Expression of ras in the mucosal membrane fraction was 13% higher for animals fed corn oil compared with fish oil feeding (P < 0.05), which is noteworthy since ras must be localized at the plasma membrane to function. The elevated ras membrane:cytosol ratio in tumors was not due to increased farnesyl protein transferase activity or prenylation state, as nearly all detectable ras was in the prenylated form. Phosphorylated p42 and p44 mitogen activated protein kinase (ERK) expression was two-fold higher in tumor extracts compared with uninvolved mucosa from AOM- and saline-injected rats (P < 0.05). The frequency of K-ras mutations was not significantly different between the various groups, but there was a trend toward a greater incidence of mutations in tumors from corn oil fed rats (85%) compared with fish oil fed rats (58%). Our results indicate that the carcinogen-induced changes in ras expression and membrane localization are associated with the in vivo activation of the ERK pathway. In addition, suppression of tumor development by dietary n-3 polyunsaturated fatty acids may be partly due to a combined effect on colonic ras expression, membrane localization, and mutation frequency.

Keywords: AOM, azoxymethane; DAG, 1,2-diacyl-sn-glycerol; EDTA, ethylenediaminetetraacetic acid; EGTA, ethylenebis(oxyethylene-nitro)tetraacetic acid; ERK(s), mitogen activated protein kinase(s)/extracellular signal-regulated kinase(s); FPTase, farnesyl protein transferase; PBS, phosphate-buffered saline; PKC, protein kinase C; PUFA(s), polyunsaturated fatty acid(s); YAMC, young adult mouse colon.

Journal Article.  6361 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.