4 research outputs found

    Inferring cell cycle feedback regulation from gene expression data

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    AbstractFeedback 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

    Comprehensive Dissection of PDGF-PDGFR Signaling Pathways in PDGFR Genetically Defined Cells

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    Despite the growing understanding of PDGF signaling, studies of PDGF function have encountered two major obstacles: the functional redundancy of PDGFRα and PDGFRβ in vitro and their distinct roles in vivo. Here we used wild-type mouse embryonic fibroblasts (MEF), MEF null for either PDGFRα, β, 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 PDGFRα, PDGFRβ and PDGFRα/β while each receptor is also responsible for regulating unique signaling pathways. Furthermore, some signaling is solely modulated through heterodimeric PDGFRα/β

    PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR

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    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 PDGFRα and PDGFRβ, 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 PDGFRβ. In conclusion, PDGFR is a major target of negative feedback regulation in cells with activated mTOR, which limits the growth potential of TSC tumors
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