-
[show abstract]
[hide abstract]
ABSTRACT: Feedback control is an important regulatory process in biological systems, which confers robustness against external and internal disturbances. Genes involved in feedback structures are therefore likely to have a major role in regulating cellular processes. Here we rely on a dynamic Bayesian network approach to identify feedback loops in cell cycle regulation. We analyzed the transcriptional profile of the cell cycle in HeLa cancer cells and identified a feedback loop structure composed of 10 genes. In silico analyses showed that these genes hold important roles in system's dynamics. The results of published experimental assays confirmed the central role of 8 of the identified feedback loop genes in cell cycle regulation. In conclusion, we provide a novel approach to identify critical genes for the dynamics of biological processes. This may lead to the identification of therapeutic targets in diseases that involve perturbations of these dynamics.
Journal of Biomedical Informatics 02/2011; 44(4):565-75. · 1.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Despite the growing understanding of pdgf signaling, studies of pdgf function have encountered two major obstacles: the functional redundancy of PDGFRalpha and PDGFRbeta in vitro and their distinct roles in vivo. Here we used wild-type mouse embryonic fibroblasts (MEF), MEF null for either PDGFRalpha, beta, or both to dissect PDGF-PDGFR signaling pathways. These four PDGFR genetically defined cells provided us a platform to study the relative contributions of the pathways triggered by the two PDGF receptors. They were treated with PDGF-BB and analyzed for differential gene expression, in vitro proliferation and differential response to pharmacological effects. No genes were differentially expressed in the double null cells, suggesting minimal receptor-independent signaling. Protean differentiation and proliferation pathways are commonly regulated by PDGFRalpha, PDGFRbeta and PDGFRalpha/beta while each receptor is also responsible for regulating unique signaling pathways. Furthermore, some signaling is solely modulated through heterodimeric PDGFRalpha/beta.
PLoS ONE 02/2008; 3(11):e3794. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Natural products derived from plants provide a rich source for development of new anticancer drugs. Dulxanthone A was found to be an active cytotoxic component in Garcinia cowa by bioactivity-directed isolation. Studies to elucidate the cytotoxic mechanisms of dulxanthone A showed that dulxanthone A consistently induced S phase arrest and apoptosis in the most sensitive cell line HepG2. Furthermore, p53 was dramatically up-regulated, leading to altered expression of downstream proteins upon dulxanthone A treatment. Cell cycle related proteins, such as cyclin A, cyclin B, cyclin E, cdc-2, p21 and p27 were down-regulated. Some apoptosis correlated proteins were also altered following the drug treatment. Bcl-2 family members PUMA was up-regulated while Bcl-2 and Bax were down-regulated. However, the expression ratio of Bax/Bcl-2 was increased. This resulted in the release of cytochrome C from the mitochondria to the cytosol. Concurrently, Apaf-1 was stimulated with p53 by dulxanthone A. In result, cytochrome C, Apaf-1 and procaspase-9 form an apoptosome, which in turn triggered the activation of caspase-9, caspase-3 and downstream caspase substrates. Lamin A/C and PARP were down-regulated or cleaved, respectively. Moreover, cell cycle arrest and apoptosis in HepG2 cells induced by dulxanthone A were markedly inhibited by siRNA knockdown of p53. In summary, dulxanthone A is an active cytotoxic component of G. cowa. It induces cell cycle arrest at lower concentrations and triggers apoptosis at higher concentrations via up-regulation of p53 through the intrinsic mitochondrial pathway in HepG2 cells. Dulxanthone A is therefore likely a promising preventive and/or therapeutic agent against Hepatoma.
International Journal of Cancer 02/2008; 122(1):31-8. · 5.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The receptor tyrosine kinase/PI3K/Akt/mammalian target of rapamycin (RTK/PI3K/Akt/mTOR) pathway is frequently altered in tumors. Inactivating mutations of either the TSC1 or the TSC2 tumor-suppressor genes cause tuberous sclerosis complex (TSC), a benign tumor syndrome in which there is both hyperactivation of mTOR and inhibition of RTK/PI3K/Akt signaling, partially due to reduced PDGFR expression. We report here that activation of PI3K or Akt, or deletion of phosphatase and tensin homolog (PTEN) in mouse embryonic fibroblasts (MEFs) also suppresses PDGFR expression. This was a direct effect of mTOR activation, since rapamycin restored PDGFR expression and PDGF-sensitive Akt activation in Tsc1-/- and Tsc2-/- cells. Akt activation in response to EGF in Tsc2-/- cells was also reduced. Furthermore, Akt activation in response to each of EGF, IGF, and PMA was reduced in cells lacking both PDGFRalpha and PDGFRbeta, implying a role for PDGFR in transmission of growth signals downstream of these stimuli. Consistent with the reduction in PI3K/Akt signaling, in a nude mouse model both Tsc1-/- and Tsc2-/- cells had reduced tumorigenic potential in comparison to control cells, which was enhanced by expression of either active Akt or PDGFRbeta. In conclusion, PDGFR is a major target of negative feedback regulation in cells with activated mTOR, which limits the growth potential of TSC tumors.
Journal of Clinical Investigation 04/2007; 117(3):730-8. · 15.39 Impact Factor
