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

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タイトル: The MAP3K2–ERK5 pathway upregulates cyclin D1 expression through histone H2A (Thr120) phosphorylation by VRK1
その他のタイトル: MAP3K2-ERK5パスウェイはVRK1によるヒストンH2Aスレオニン120リン酸化を介してcyclin D1の発現を上昇させる
著者: 加藤, 正徳
著者(別表記) : Kato, Masanori
発行日: 2018年 9月 5日
出版者: 長崎大学医学部
引用: Nagasaki University (長崎大学), 博士(医学) (2018-09-05)
抄録: 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.
記述: 長崎大学学位論文 学位記番号:博(医歯薬)甲第1085号 学位授与年月日:平成30年9月5日 / Author: Masanori Kato, Mitsuhiro Yoneda, Yukio Takeshima, Vishwa Jeet Amatya, Miki Higashi, Takeya Nakagawa, Takashi Ito / Citation: Acta Medica Nagasakiensia, 62(1), pp.15-26; 2018
キーワード: MAP3K2–ERK5 / histone modification / phosphorylation / VRK1 / cyclin D1 / H2A
URI: http://hdl.handle.net/10069/38723
ISSN: 00016055
関連リンク : http://hdl.handle.net/10069/38634
権利: (C) 2018 Nagasaki University School of Medicine
資料タイプ: Thesis or Dissertation
原稿種類: ETD
出現コレクション:110 学位論文

引用URI : http://hdl.handle.net/10069/38723



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