Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway.
Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway.
复制标题
DOI：
10.1038/s41467-017-02207-7
复制
发表时间：
2017-12-21
影响因子：
16.6
通讯作者：
Okamura H
中科院分区：
文献类型：
--
作者：
Chao HW;Doi M;Fustin JM;Chen H;Murase K;Maeda Y;Hayashi H;Tanaka R;Sugawa M;Mizukuchi N;Yamaguchi Y;Yasunaga JI;Matsuoka M;Sakai M;Matsumoto M;Hamada S;Okamura H
肝脏代谢在基因表达和肝脏稳态所必需的酶活性方面经历强有力的昼夜节律振荡，但昼夜节律钟是否控制肝细胞的稳态自我更新尚不清楚。在这里，我们表明，肝细胞多倍化显着加速周围的中央静脉，永久性细胞自我更新的网站，在缺乏昼夜节律周期基因的小鼠。在这些小鼠中，由于有丝分裂原活化蛋白激酶磷酸酶1（Mkp 1）介导的细胞外信号调节激酶（Erk 1/2）活性的昼夜节律调节受损，超多倍体单核和双核肝细胞大量蓄积。肝细胞的延时成像表明，在胞质分裂过程中，中间体中Erk 1/2的活性降低，导致分裂失败，导致多倍化。操纵Mkp 1磷酸酶活性足以改变肝细胞的倍性水平。这些数据提供了明确的证据，周期基因不仅协调代谢活动的动态变化，而且还通过Mkp 1-Erk 1/2信号通路调节肝细胞的自我更新。生物钟调节肝脏基因表达和功能。Chao等人在本文中表明，由于丝裂原活化蛋白激酶磷酸酶1对Erk信号传导的调节受损，周期缺失导致的生物钟基因改变诱导肝细胞多倍体。
Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell self-renewal, in mice deficient in circadian Period genes. In these mice, a massive accumulation of hyperpolyploid mononuclear and binuclear hepatocytes occurs due to impaired mitogen-activated protein kinase phosphatase 1 (Mkp1)-mediated circadian modulation of the extracellular signal-regulated kinase (Erk1/2) activity. Time-lapse imaging of hepatocytes suggests that the reduced activity of Erk1/2 in the midbody during cytokinesis results in abscission failure, leading to polyploidization. Manipulation of Mkp1 phosphatase activity is sufficient to change the ploidy level of hepatocytes. These data provide clear evidence that the Period genes not only orchestrate dynamic changes in metabolic activity, but also regulate homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway. Circadian clock regulates hepatic gene expression and functions. Here Chao et al. show that alteration of circadian clock genes by Period deletion induces polyploidy in hepatocytes due to impaired regulation of Erk signaling by mitogen-activated protein kinase phosphatase 1.
登录
查看更多内容
DOI：
10.1073/pnas.1118726109
发表时间：
2012-04-03
影响因子：
11.1
作者：
Eckel-Mahan, Kristin L.;Patel, Vishal R.;Sassone-Corsi, Paolo
通讯作者：
Sassone-Corsi, Paolo
影响因子：
4.8
作者：
Annayev, Yunus;Adar, Sheera;Ye, Rui
通讯作者：
Ye, Rui
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
影响因子：
16.6
作者：
Doi, Masao;Ishida, Atsushi;Miyake, Akiko;Sato, Miho;Komatsu, Rie;Yamazaki, Fumiyoshi;Kimura, Ikuo;Tsuchiya, Soken;Kori, Hiroshi;Seo, Kazuyuki;Yamaguchi, Yoshiaki;Matsuo, Masahiro;Fustin, Jean-Michel;Tanaka, Rina;Santo, Yasuko;Yamada, Hiroyuki;Takahashi, Yukari;Araki, Michihiro;Nakao, Kazuki;Aizawa, Shinichi;Kobayashi, Masaki;Obrietan, Karl;Tsujimoto, Gozoh;Okamura, Hitoshi
通讯作者：
Okamura, Hitoshi
影响因子：
15.9
作者：
Gentric, Geraldine;Maillet, Vanessa;Desdouets, Chantal
通讯作者：
Desdouets, Chantal