Science Inventory

Propiconazole Enhances Cell Proliferation by Dysregulation of Ras Farnesylation and theMAPK pathway

Citation:

MURPHY, L. A., T. MOORE, AND S. NESNOW. Propiconazole Enhances Cell Proliferation by Dysregulation of Ras Farnesylation and theMAPK pathway. Presented at Society of Toxicology (SOT) Annual Meeting, Washington, DC, March 06 - 10, 2011.

Impact/Purpose:

The goal of this study was to determine if mevalonate and propiconazole would increase AML12 hepatocyte proliferation by modulation of Ras membrane localization and further downstream effects.

Description:

Previous studies of mice exposed to the hepatotumorigenic fungicide, propiconazole, revealed an increase in hepatic cell proliferation and over-expression of hepatic genes within the cholesterol biosynthesis pathway. Mevalonate, an intermediate in this pathway, has long been a target for anti-cancer therapies as mevalonate promotes proliferation in numerous cancer cell lines and serves as the precursor for isoprenoids (e.g. famesyl pyrophosphate) which are crucial in the farnesylation of the Ras protein. Farnesylation targets Ras to the cell membrane where it is involved in signal transduction of numerous pathways, including the mitogen-activated protein kinase (MAPK) pathway. The goal of this study was to determine if mevalonate and propiconazole would increase AML12 hepatocyte proliferation by modulation of Ras membrane localization and further downstream effects. Mevalonolactone (MVAL) treatment increased cell numbers, while treatment with L-744,832, a famesyl transferase inhibitor, reversed the MVAL mediated increase in proliferation. AML12 cells treated with propiconazole led to a significant (p

Record Details:

Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Product Published Date: 03/10/2011
Record Last Revised: 09/26/2016
OMB Category: Other
Record ID: 230851

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY

INTEGRATED SYSTEMS TOXICOLOGY DIVISION

CARCINOGENESIS BRANCH