The zinc transporter Zip14 influences c-Met phosphorylation and hepatocyte proliferation during liver regeneration in mice.
The zinc transporter Zip14 influences c-Met phosphorylation and hepatocyte proliferation during liver regeneration in mice.
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锌转运蛋白Zip14在小鼠肝脏再生过程中影响c - Met磷酸化和肝细胞增殖。
DOI：
10.1053/j.gastro.2012.02.046
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发表时间：
2012-06
期刊：
影响因子：
29.4
通讯作者：
Cousins RJ
中科院分区：
文献类型：
--
作者：
Aydemir TB;Sitren HS;Cousins RJ
锌在细胞内的稳态是通过锌转运体对锌内流、外排和分布的严格调控来维持的。zrt - irt样蛋白（ZIP）转运体促进锌流入细胞质。ZIP家族成员Zip14的表达可以被炎症细胞因子诱导，也可以启动肝脏再生。肝细胞增殖是肝脏再生所必需的。锌调节细胞增殖、组织生长和许多有丝分裂信号通路；我们研究了它在肝细胞中的作用。采用部分肝切除（70%肝脏切除）的野生型和Zip14−/−小鼠作为肝再生模型。我们还分析了过表达Zip14的AML12肝细胞。通过增殖细胞核抗原、CD1和Ki67标记物以及锌含量与蛋白酪氨酸磷酸酶1B （PTP1B）和细胞外信号调节激酶1/2信号相关的测定来评估增殖。在肝再生过程中，Zip14表达上调，肝脏锌含量增加。肝脏锌的增加抑制了磷酸酶PTP1B的活性，增加了c-Met的磷酸化，从而促进了肝细胞的增殖。过表达Zip14的AML12细胞锌含量增加，增殖能力增强；PTP1B被抑制，c-Met磷酸化升高。在Zip14−/−小鼠中，未观察到部分肝切除术后肝脏锌水平和肝细胞增殖的增加。在肝脏再生和肝细胞增殖过程中，转运蛋白Zip14介导肝脏对锌的摄取。这些发现表明，锌转运蛋白活性通过隔离锌来调节肝组织的生长。调节ZIP14活性的试剂可能被开发为促进慢性肝病患者肝脏再生的治疗药物。
Zinc homeostasis in cells is maintained through tight regulation of zinc influx, efflux, and distribution to intracellular organelles by zinc transporters. The Zrt-Irt-like protein (ZIP) transporters facilitate zinc influx to the cytosol. Expression of the ZIP family member Zip14 can be induced by inflammatory cytokines, which also initiate liver regeneration. Hepatocyte proliferation is required for liver regeneration. Zinc regulates cell proliferation, tissue growth, and many mitogenic signaling pathways; we investigated its role in hepatocytes. Wild-type and Zip14−/− mice that underwent partial hepatectomy (70% of liver removed) were used as models of liver regeneration. We also analyzed AML12 hepatocytes that overexpressed Zip14. Proliferation was assessed with proliferating cell nuclear antigen, CD1, and Ki67 markers and along with assays of zinc content was related to protein tyrosine phosphatase 1B (PTP1B) and extracellular signal–regulated kinase 1/2 signaling. Zip14 was up-regulated and hepatic zinc content increased during liver regeneration. Increased hepatic zinc inhibited activity of the phosphatase PTP1B and increased phosphorylation of c-Met, which promoted hepatocyte proliferation. AML12 cells that overexpressed Zip14 increased in zinc content and proliferation; PTP1B was inhibited and phosphorylation of c-Met increased. The increases in hepatic levels of zinc and hepatocyte proliferation that occurred following partial hepatectomy were not observed in Zip14−/− mice. The transporter Zip14 mediates hepatic uptake of zinc during liver regeneration and for hepatocyte proliferation. These findings indicate that zinc transporter activity regulates liver tissue growth by sequestering zinc. Reagents that regulate ZIP14 activity might be developed as therapeutics to promote liver regeneration in patients with chronic liver disease.
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影响因子：
1.9
作者：
Greene, AK;Puder, M
通讯作者：
Puder, M
影响因子：
3.6
作者：
Ho Y;Samarasinghe R;Knoch ME;Lewis M;Aizenman E;DeFranco DB
通讯作者：
DeFranco DB
DOI：
10.1073/pnas.0403412101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Borowiak, M;Garratt, AN;Birchmeier, C
通讯作者：
Birchmeier, C
影响因子：
4.8
作者：
Jirakulaporn, T;Muslin, AJ
通讯作者：
Muslin, AJ
影响因子：
6.7
作者：
Moran, DM;Mayes, N;McKillop, IH
通讯作者：
McKillop, IH