rHVDM: an R package to predict the activity and targets of a transcription factor.

SUMMARY: Highly parallel genomic platforms like microarrays often present researchers with long lists of differentially expressed genes but contain little or no information on how these genes are regulated. rHVDM is a novel R package which uses gene expression time course data to predict the activity and targets of a transcription factor. In the first step, rHVDM uses a small number of known targets to derive the activity profile of a given transcription factor. Then, in a subsequent step, this activity profile is used to predict other putative targets of that transcription factor. A dynamic and mechanistic model of gene expression is at the heart of the technique. Measurement error is taken into account during the process, which allows an objective assessment of the robustness of fit and, therefore, the quality of the predictions. The package relies on efficient algorithms and vectorization to accomplish potentially time consuming tasks including optimization and differential equation integration. We demonstrate the efficiency and accuracy of rHVDM by examining the activity of the tumour-suppressing transcription factor, p53. AVAILABILITY: The version of the package presented here (1.8.1) is freely available from the Bioconductor Web site (http://bioconductor.org/packages/2.3/bioc/html/rHVDM.html).

Involvement of apoptosis in mitomycin C hypersensitivity of Chinese hamster cell mutants.

To elucidate the mechanisms of the mammalian cell defense against cross-linking agents, we studied previously cellular responses to mitomycin C (MMC) treatment in two MMC-hypersensitive hamster cell mutants' V-H4 and V-C8, as well as their parental cell line V79. In the present report, we investigated whether alterations in cell cycle checkpoints and induction of apoptosis could be responsible for the MMC hypersensitivity of the V-H4 and V-C8 mutant cell lines. First, we found that parental and mutant cells exhibited similar cell cycle responses to MMC concentrations of equivalent cytotoxicity, arguing against a defective cell cycle checkpoint in hypersensitive cell lines. In contrast, we showed that mutant cells underwent greater levels of apoptosis following MMC treatment than parental cells. These findings indicate that increased induction of apoptosis contributes to the hypersensitivity of V-H4 and V-C8 cells to the growth inhibitory effect of MMC. This differential apoptotic response was observed with both equimolar and equitoxic MMC doses and was specific to the cross-linking agent MMC, suggesting that control of the apoptotic process is altered in both MMC-hypersensitive mutants. The defective genes in V-H4 and V-C8 cells would then function in the regulation of an apoptotic pathway triggered by MMC-induced damage and independent of p53-mediated transcription.