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A non-canonical role and regulations of polo-like kinase-4 in fibroblast cell-type transition

Jing Li, Go Urabe, Mengxue Zhang, Yitao Huang, Bowen Wang, Lynn Marcho, Hongtao Shen, K. Craig Kent, Lian-Wang Guo
doi: https://doi.org/10.1101/570267
Jing Li
1Department of Surgery and Department of Physiology & Cell Biology, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center. The Ohio State University, Columbus, OH 43210, USA
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Go Urabe
1Department of Surgery and Department of Physiology & Cell Biology, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center. The Ohio State University, Columbus, OH 43210, USA
3Department of Surgery, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center. The Ohio State University, Columbus, OH 43210, USA
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Mengxue Zhang
1Department of Surgery and Department of Physiology & Cell Biology, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center. The Ohio State University, Columbus, OH 43210, USA
2Cellular and Molecular Pathology graduate program, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
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Yitao Huang
1Department of Surgery and Department of Physiology & Cell Biology, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center. The Ohio State University, Columbus, OH 43210, USA
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Bowen Wang
3Department of Surgery, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center. The Ohio State University, Columbus, OH 43210, USA
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Lynn Marcho
1Department of Surgery and Department of Physiology & Cell Biology, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center. The Ohio State University, Columbus, OH 43210, USA
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Hongtao Shen
1Department of Surgery and Department of Physiology & Cell Biology, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center. The Ohio State University, Columbus, OH 43210, USA
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K. Craig Kent
3Department of Surgery, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center. The Ohio State University, Columbus, OH 43210, USA
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Lian-Wang Guo
1Department of Surgery and Department of Physiology & Cell Biology, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center. The Ohio State University, Columbus, OH 43210, USA
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  • For correspondence: lianwang.guo@osumc.edu
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Abstract

A divergent member of the polo-like kinase family, PLK4 is known for its canonical role in centriole duplication. Its non-canonical function and regulators are poorly defined. Here we investigated PLK4’s activation and expression and regulations thereof in rat adventitial fibroblast cell-type transition induced by platelet-derived growth factor (PDGF-AA).

Experiments using siRNA and selective inhibitor (centrinone-B) revealed a role for PLK4 not only in AA-induced proliferation/migration, but also in serum response factor (SRF) activation and smooth muscle α-actin expression. PDGFR (receptor) inhibition abrogated AA-stimulated PLK4 activation (phosphorylation) and expression; P38 inhibition (siRNA, inhibitor) downstream of PDGFR also mitigated PLK4 activation. Furthermore, transcription of PLK4 (and PDGFRα) was repressed by pan-inhibition of the bromodomain/extraterminal family of chromatin-bookmark readers (BRD2, BRD3, BRD4), an effect determined herein as mainly mediated by BRD4. In vivo, periadventitial administration of centrinone-B reduced collagen content and thickness of the adventitia in a rat model of carotid artery injury.

In summary, we have identified a non-canonical role for PLK4 in SRF activation and its regulations by BRD4/PDGFRα-dominated pathways. Results in this study suggest PLK4 inhibition as a potential anti-fibrotic intervention.

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  • The authors declare no conflict of interest

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Posted March 31, 2019.
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A non-canonical role and regulations of polo-like kinase-4 in fibroblast cell-type transition
Jing Li, Go Urabe, Mengxue Zhang, Yitao Huang, Bowen Wang, Lynn Marcho, Hongtao Shen, K. Craig Kent, Lian-Wang Guo
bioRxiv 570267; doi: https://doi.org/10.1101/570267
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A non-canonical role and regulations of polo-like kinase-4 in fibroblast cell-type transition
Jing Li, Go Urabe, Mengxue Zhang, Yitao Huang, Bowen Wang, Lynn Marcho, Hongtao Shen, K. Craig Kent, Lian-Wang Guo
bioRxiv 570267; doi: https://doi.org/10.1101/570267

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