Poster abstracts

Poster number 22 submitted by Jing Li

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

Jing Li (DHLRI), Go Urabe (DHLRI), Mengxue Zhang (DHLRI), Yitao Huang (DHLRI), Hongtao Shen (DHLRI), Bowen Wang (DHLRI)

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 selective inhibitor (centrinone-B) and siRNA indicated a role for PLK4 not only in AA-induced proliferation/migration, but also in smooth muscle beta-actin expression and its transcription factor serum response factor’s activation. While PDGFR inhibition abrogated AA-stimulated PLK4 activation (phosphorylation) and expression, p38 inhibition (inhibitor or siRNA) downstream of PDGFR also mitigated PLK4 activation. Furthermore, transcription of PLK4 (and PDGFR-alpha) 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.

Thus, we have identified a non-canonical role for PLK4 in fibroblast cell-type transition and its regulation by a BRD4/PDGFR-alpha-dominated pathway. Results in this study suggest PLK4 inhibition as a potential anti-fibrotic intervention.

References:
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Keywords: PLK4, PDGF receptor-alpha, fibroblast-to-myofibroblast transition