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Research Paper
Genetic Response to Farnesyltransferase Inhibitors: Proapoptotic Targets of RhoB
Uma Kamasani, Ai-xue Liu and George C. Prendergast
volume 2 | issue 3
may/june 2003Pages: 273-280
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Knockout mouse studies have established that the transformation-selective death program triggered by farnesyltransferase inhibitor (FTI) requires a gain-of-function in the stress-regulated small GTPase RhoB. To gain insight into this death program, we compared the genetic response of cells with different RhoB genotypes to FTI treatment. The microarray hybridization strategy we employed focused specifically on events preceding the execution of RhoB-dependent apoptosis, which is crucial for effective antineoplastic responses in mouse, rather than on other aspects of the FTI response mediated by RhoB gain-of-function (e.g. growth inhibition). Genes that control cell adhesion and cell shape were represented prominently among upregulated targets, as were genes that control signal transduction, vesicle dynamics, transcription, and immunity. Genes that control cell cycle checkpoints and progression through S phase and mitosis were among the major downregulated targets. In support of the concept of RhoB as a negative regulator of Ras signaling pathways, the most strongly downregulated gene scored was farnesyl pyrophosphate synthetase, the enzyme that produces the substrate used by FT to farnesylate Ras proteins. Gene clustering revealed modules for MAPK signaling, cell cycle progression, and immune response as proapoptotic targets of RhoB. This report identifies genes that pertain to the transformation-selective apoptotic program triggered by FTI. Further study of this program may yield insights into the dramatic differences in efficacy and apoptotic prowess of most FTIs in human cancers, versus transgenic mouse models.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.