Dataset Information

MicroRNA-mediated positive feedback loop and optimized bistable switch in a cancer network Involving miR-17-92.

ABSTRACT: MicroRNAs (miRNAs) are small, noncoding RNAs that play an important role in many key biological processes, including development, cell differentiation, the cell cycle and apoptosis, as central post-transcriptional regulators of gene expression. Recent studies have shown that miRNAs can act as oncogenes and tumor suppressors depending on the context. The present work focuses on the physiological significance of miRNAs and their role in regulating the switching behavior. We illustrate an abstract model of the Myc/E2F/miR-17-92 network presented by Aguda et al. (2008), which is composed of coupling between the E2F/Myc positive feedback loops and the E2F/Myc/miR-17-92 negative feedback loop. By systematically analyzing the network in close association with plausible experimental parameters, we show that, in the presence of miRNAs, the system bistability emerges from the system, with a bistable switch and a one-way switch presented by Aguda et al. instead of a single one-way switch. Moreover, the miRNAs can optimize the switching process. The model produces a diverse array of response-signal behaviors in response to various potential regulating scenarios. The model predicts that this transition exists, one from cell death or the cancerous phenotype directly to cell quiescence, due to the existence of miRNAs. It was also found that the network involving miR-17-92 exhibits high noise sensitivity due to a positive feedback loop and also maintains resistance to noise from a negative feedback loop.

SUBMITTER: Li Y

PROVIDER: S-EPMC3194799 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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MicroRNA-mediated positive feedback loop and optimized bistable switch in a cancer network Involving miR-17-92.

Li Yichen Y Li Yumin Y Zhang Hui H Chen Yong Y

PloS one 20111014 10

MicroRNAs (miRNAs) are small, noncoding RNAs that play an important role in many key biological processes, including development, cell differentiation, the cell cycle and apoptosis, as central post-transcriptional regulators of gene expression. Recent studies have shown that miRNAs can act as oncogenes and tumor suppressors depending on the context. The present work focuses on the physiological significance of miRNAs and their role in regulating the switching behavior. We illustrate an abstract ...[more]

PMID: 22022595

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Project description:Cytokines and lineage-specific transcription factors are critical molecular effectors for terminal differentiation during hematopoiesis. Intrinsic transcription factor activity is often believed to drive commitment and differentiation, whereas cytokine receptor signals have been implicated in the regulation of cell proliferation, survival, and differentiation. In erythropoiesis, recent experimental findings provide direct evidence that erythropoietin (Epo) can generate commitment cues via the erythropoietin receptor (EpoR); specifically, EpoR signaling leads to activation of the transcription factor GATA-1, which then triggers transcription of erythrocyte-specific genes. In particular, activated GATA-1 induces two positive feedback loops in the system through the enhanced expression of both inactive GATA-1 and EpoR, the latter of which is externally regulatable by Epo. Based upon this network architecture, we present a mathematical model of GATA-1 activation by EpoR, which bidirectionally links a lineage-specific receptor and transcription factor. Our deterministic model offers insight into stimulus-response relationships between Epo and several downstream effectors. In addition to the survival signals that EpoR provides, steady-state analysis of our model suggests that receptor upregulation during lineage commitment can also generate ultrasensitivity to Epo and bistability in GATA-1 activity. These system-level properties can induce a switch-like characteristic during differentiation and provide robustness to the mature state. The topology also suggests a novel mechanism for achieving robust bistability in a purely deterministic manner without molecular cooperativity. The analytical solution of a generalized, minimal model is provided and the significance of each of the two positive feedback loops is elucidated through bifurcation analysis. This network topology, or variations thereof, may link other receptor-transcription factor pairs and may therefore be of general relevance in cellular decision-making.

Dataset Information

MicroRNA-mediated positive feedback loop and optimized bistable switch in a cancer network Involving miR-17-92.

Publications

MicroRNA-mediated positive feedback loop and optimized bistable switch in a cancer network Involving miR-17-92.

Similar Datasets

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