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Dissecting microregulation of a master regulatory network.

Sinha AU, Kaimal V, Chen J, Jegga AG - BMC Genomics (2008)

Bottom Line: Here, we use bioinformatics-based integrative approach to identify and prioritize putative p53-regulated miRNAs, and unravel the miRNA-based microregulation of the p53 master regulatory network.Specifically, we identify putative microRNA regulators of a) transcription factors that are upstream or downstream to p53 and b) p53 interactants.Our predicted p53-miRNA-gene networks strongly suggest that coordinated transcriptional and p53-miR mediated networks could be integral to tumorigenesis and the underlying processes and pathways.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Ohio, USA. sinhaam@ececs.uc.edu

ABSTRACT

Background: The master regulator p53 tumor-suppressor protein through coordination of several downstream target genes and upstream transcription factors controls many pathways important for tumor suppression. While it has been reported that some of the p53's functions are microRNA-mediated, it is not known as to how many other microRNAs might contribute to the p53-mediated tumorigenesis.

Results: Here, we use bioinformatics-based integrative approach to identify and prioritize putative p53-regulated miRNAs, and unravel the miRNA-based microregulation of the p53 master regulatory network. Specifically, we identify putative microRNA regulators of a) transcription factors that are upstream or downstream to p53 and b) p53 interactants. The putative p53-miRs and their targets are prioritized using current knowledge of cancer biology and literature-reported cancer-miRNAs.

Conclusion: Our predicted p53-miRNA-gene networks strongly suggest that coordinated transcriptional and p53-miR mediated networks could be integral to tumorigenesis and the underlying processes and pathways.

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Related in: MedlinePlus

Four possible scenarios for the upstream regulators (A-D) and downstream targets (E-H) of p53. For the downstream coherent models, the p53 action on downstream target gene and miRNA is opposite (F and H). In case of downstream incoherent models (E and G), the p53 action on downstream target gene and miRNA is same. There may be a sequential gap in the activation time of the target gene and miRNA facilitating maintenance of steady states.
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Figure 1: Four possible scenarios for the upstream regulators (A-D) and downstream targets (E-H) of p53. For the downstream coherent models, the p53 action on downstream target gene and miRNA is opposite (F and H). In case of downstream incoherent models (E and G), the p53 action on downstream target gene and miRNA is same. There may be a sequential gap in the activation time of the target gene and miRNA facilitating maintenance of steady states.

Mentions: Transcriptional networks commonly contain positive- and negative-feedback loops, which provide robustness and fine-tuning to gene programs [30,31]. Recent studies have suggested a possible coordinated transcriptional and miRNA-mediated regulation as a recurrent motif to enhance the robustness of gene regulation in mammalian genomes [32-35]. It was also reported that miRNAs predominantly target positive regulatory motifs, highly connected scaffolds and most downstream network components such as signaling transcription factors, but less frequently target negative regulatory motifs, common components of basic cellular machines and most upstream network components such as ligands [32]. Using the p53 master regulatory network as a case study, we investigated the potential crosstalk between the miRNAs and the p53 transcriptional network itself involving transcription factors upstream and downstream to p53. At least four possible scenarios can be envisaged for the upstream regulators (Figures 1A–D) and downstream targets (Figures 1E–H) of p53.


Dissecting microregulation of a master regulatory network.

Sinha AU, Kaimal V, Chen J, Jegga AG - BMC Genomics (2008)

Four possible scenarios for the upstream regulators (A-D) and downstream targets (E-H) of p53. For the downstream coherent models, the p53 action on downstream target gene and miRNA is opposite (F and H). In case of downstream incoherent models (E and G), the p53 action on downstream target gene and miRNA is same. There may be a sequential gap in the activation time of the target gene and miRNA facilitating maintenance of steady states.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2289817&req=5

Figure 1: Four possible scenarios for the upstream regulators (A-D) and downstream targets (E-H) of p53. For the downstream coherent models, the p53 action on downstream target gene and miRNA is opposite (F and H). In case of downstream incoherent models (E and G), the p53 action on downstream target gene and miRNA is same. There may be a sequential gap in the activation time of the target gene and miRNA facilitating maintenance of steady states.
Mentions: Transcriptional networks commonly contain positive- and negative-feedback loops, which provide robustness and fine-tuning to gene programs [30,31]. Recent studies have suggested a possible coordinated transcriptional and miRNA-mediated regulation as a recurrent motif to enhance the robustness of gene regulation in mammalian genomes [32-35]. It was also reported that miRNAs predominantly target positive regulatory motifs, highly connected scaffolds and most downstream network components such as signaling transcription factors, but less frequently target negative regulatory motifs, common components of basic cellular machines and most upstream network components such as ligands [32]. Using the p53 master regulatory network as a case study, we investigated the potential crosstalk between the miRNAs and the p53 transcriptional network itself involving transcription factors upstream and downstream to p53. At least four possible scenarios can be envisaged for the upstream regulators (Figures 1A–D) and downstream targets (Figures 1E–H) of p53.

Bottom Line: Here, we use bioinformatics-based integrative approach to identify and prioritize putative p53-regulated miRNAs, and unravel the miRNA-based microregulation of the p53 master regulatory network.Specifically, we identify putative microRNA regulators of a) transcription factors that are upstream or downstream to p53 and b) p53 interactants.Our predicted p53-miRNA-gene networks strongly suggest that coordinated transcriptional and p53-miR mediated networks could be integral to tumorigenesis and the underlying processes and pathways.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Ohio, USA. sinhaam@ececs.uc.edu

ABSTRACT

Background: The master regulator p53 tumor-suppressor protein through coordination of several downstream target genes and upstream transcription factors controls many pathways important for tumor suppression. While it has been reported that some of the p53's functions are microRNA-mediated, it is not known as to how many other microRNAs might contribute to the p53-mediated tumorigenesis.

Results: Here, we use bioinformatics-based integrative approach to identify and prioritize putative p53-regulated miRNAs, and unravel the miRNA-based microregulation of the p53 master regulatory network. Specifically, we identify putative microRNA regulators of a) transcription factors that are upstream or downstream to p53 and b) p53 interactants. The putative p53-miRs and their targets are prioritized using current knowledge of cancer biology and literature-reported cancer-miRNAs.

Conclusion: Our predicted p53-miRNA-gene networks strongly suggest that coordinated transcriptional and p53-miR mediated networks could be integral to tumorigenesis and the underlying processes and pathways.

Show MeSH
Related in: MedlinePlus