The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Interleukin-6 Modulates the Expression of the Bone Morphogenic Protein Receptor Type II Through a Novel STAT3–microRNA Cluster 17/92 Pathway
Open accessAbstract
Dysregulated expression of bone morphogenetic protein receptor type II (BMPR2) is a pathogenetic hallmark of pulmonary hypertension. Downregulation of BMPR2 protein but not mRNA has been observed in multiple animal models mimicking the disease, indicating a posttranscriptional mechanism of regulation. Because microRNAs (miRNAs) regulate gene expression mainly through inhibition of target gene translation, we hypothesized that miRNAs may play a role in the modulation of BMPR2. Performing a computational algorithm on the BMPR2 gene, several miRNAs encoded by the miRNA cluster 17/92 (miR-17/92) were retrieved as potential regulators. Ectopic overexpression of miR-17/92 resulted in a strong reduction of the BMPR2 protein, and a reporter gene system showed that BMPR2 is directly targeted by miR-17-5p and miR-20a. By stimulation experiments, we found that the miR-17/92 cluster is modulated by interleukin (IL)-6, a cytokine involved in the pathogenesis of pulmonary hypertension. Because IL-6 signaling is mainly mediated by STAT3 (signal transducer and activator of transcription 3), the expression of STAT3 was knocked down by small interfering RNA, which abolished the IL-6–mediated expression of miR-17/92. Consistent with these data, we found a highly conserved STAT3-binding site in the promoter region of the miR-17/92 gene (C13orf25). Promoter studies confirmed that IL-6 enhances transcription of C13orf25 through this distinct region. Finally, we showed that persistent activation of STAT3 leads to repressed protein expression of BMPR2. Taken together, we describe here a novel STAT3–miR-17/92—BMPR2 pathway, thus providing a mechanistic explanation for the loss of BMPR2 in the development of pulmonary hypertension.
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Cites
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“To improve prediction rates the focus was put only on highly conserved seed regions.(17) TargetScan retrieved several miRNAs for BMPR2, including miR-17-5p, miR-19a, miR-19b, miR-20a and miR-92.”
BackgroundSTATs: transcriptional control and biological impact
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Cited by
Soon, E., Holmes, A. M., Treacy, C. M., Doughty, N. J., Southgate, L., Machado, R. D., Trembath, R. C., Jennings, S., Barker, L., Nicklin, P., et al. (2010) · Circulation · doi:10.1161/circulationaha.109.933762 · Cited by 802
Mechanisms of disease: pulmonary arterial hypertension
Schermuly, R. T., Ghofrani, H. A., Wilkins, M. R., & Grimminger, F. (2011) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2011.87 · Cited by 800
Stenmark, K. R., Meyrick, B., Galie, N., Mooi, W. J., & McMurtry, I. F. (2009) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00217.2009 · Cited by 774
Signaling Receptors for TGF-β Family Members
Heldin, C.-H., & Moustakas, A. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022053 · Cited by 711
The role of STAT3 in autophagy
You, L., Wang, Z., Li, H., Shou, J., Jing, Z., Xie, J., Sui, X., Pan, H., & Han, W. (2015) · Autophagy · doi:10.1080/15548627.2015.1017192 · Cited by 515
Metadata
- Authors
- Brock, M., Trenkmann, M., Gay, R. E., Michel, B. A., Gay, S., Fischler, M., Ulrich, S., Speich, R., & Huber, L. C.
- Venue
- Circulation Research
- Published
- 2009-05-22
- Volume
- 104
- Issue
- 10
- Pages
- 1184-1191
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2145988292
- Cited by
- 465
- References
- 38
- FWCI
- 39.39
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Brock, M., Trenkmann, M., Gay, R. E., Michel, B. A., Gay, S., Fischler, M., Ulrich, S., Speich, R., & Huber, L. C. (2009). Interleukin-6 Modulates the Expression of the Bone Morphogenic Protein Receptor Type II Through a Novel STAT3–microRNA Cluster 17/92 Pathway. Circulation Research. https://doi.org/10.1161/circresaha.109.197491
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