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The MAP3K2-ERK5 pathway upregulates cyclin D1 expression through histone H2A (Thr120) phosphorylation by VRK1


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Title: The MAP3K2-ERK5 pathway upregulates cyclin D1 expression through histone H2A (Thr120) phosphorylation by VRK1
Authors: Kato, Masanori / Yoneda, Mitsuhiro / Takeshima, Yukio / Amatya, Vishwa Jeet / Higashi, Miki / Nakagawa, Takeya / Ito, Takashi
Issue Date: Oct-2018
Publisher: Nagasaki University School of Medicine / 長崎大学医学部
Citation: Acta medica Nagasakiensia, 62(1), pp.15-26; 2018
Abstract: VRK1 plays a pivotal role in the upregulation of cyclin D1 (also known as CCND1) by phosphorylating histone H2A (Thr120) around its promoter region. However, the pathways or proteins that regulate this activity upstream of VRK1 remain unknown. It has been confirmed that after serum stimulation VRK1 is recruited to the cyclin D1 promoter region, and phosphorylation of the neighboring histone H2A (Thr120) is elevated. To clarify the upstream signals that regulate VRK1, we knocked down mitogen-activated protein kinases (MAPKs), including ERK5, MAP3K2, ERK1/2, JNK1/2, JNK3, and p38 in HeLa cells. We found that ERK5 knockdown decreases cyclin D1 expression, and this dependence on ERK5 was confirmed with the ERK5 inhibitors, BIX02188 and XMD8-92. Knockdown of MAP3K2, which is a well-known kinase acting upstream of the MEK5-ERK5 pathway, also reduced cyclin D1 expression, signifying the importance of the MAP3K2–ERK5 axis in regulating the expression of this gene. Next, evidence from chromatin immunoprecipitation qPCR (ChIP-qPCR) assays indicated that ERK5 or MAP3K2 knockdown reduces the recruitment of VRK1 and phosphorylation of H2A (Thr120) around the cyclin D1 promoter. Moreover, public microarray analysis of HeLa cells treated with either EGF or a DNA-damaging agent showed that ERK5 and cyclin D1 expression levels were significantly correlated in both treatments. Pathway analysis using the Ingenuity database supported our experimental observation that the MAP3K2– ERK5 pathway promotes cyclin D1 expression upstream of the VRK1 phosphorylation of H2A (Thr120). Finally, we showed that H2A (Thr120) phosphorylation is correlated with cyclin D1 expression in clinical tissue analysis. These results suggest that the MAP3K2–ERK5 pathway elevates cyclin D1 expression by recruiting VRK1 and elevating H2A (Thr120) phosphorylation in the cyclin D1 promoter region, which may be involved in dysregulated cell proliferation and cancer progression.
Keywords: MAP3K2–ERK5 / histone modification / phosphorylation / VRK1 / cyclin D1 / H2A
URI: http://hdl.handle.net/10069/38669
ISSN: 00016055
Type: Departmental Bulletin Paper
Text Version: publisher
Appears in Collections:Volume 62, No. 1

Citable URI : http://hdl.handle.net/10069/38669

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