Deng Xiaobing, Mercer Stephen E, Sun Chi-Yu, Friedman Eileen
Pathology Department, Upstate Medical University, Syracuse, New York.
Genes Cancer. 2014 Apr;5(1-2):22-30. doi: 10.18632/genesandcancer.1.
Mirk kinase is a gene upregulated and sometimes amplified in pancreatic cancers and in ovarian cancers, but expressed at very low levels in most normal diploid cells except for skeletal muscle. The muscle cell function of Mirk kinase selected for by cancer cells is unknown. It is now shown that Mirk protein is expressed at low levels and is largely nuclear in cycling skeletal muscle C2C12 myoblasts, but is translocated to the cytoplasm and upregulated when myoblasts initiate differentiation, as shown by immunofluorescence staining and by cell fractionation. Either Mirk depletion or Mirk kinase inhibition increased ROS levels in cycling C2C12 myoblasts. However, Mirk protein is localized in the cytoplasm of mature muscle fibers, specifically in the fast twitch fibers of human skeletal muscle where toxic ROS levels are generated by muscle contraction. C2C12 myoblasts at high density in differentiation media fuse to form differentiated postmitotic myotubes that can contract. A Mirk kinase inhibitor induced a dose-dependent increase in ROS in this model for fast twitch fibers of human skeletal muscle. Efficient Mirk depletion in SU86.86 pancreatic cancer cells by an inducible shRNA decreased expression of eight antioxidant genes. Thus both cancer cells and differentiated myotubes utilize Mirk kinase to relieve oxidative stress.
Mirk激酶是一种在胰腺癌和卵巢癌中上调且有时会扩增的基因，但在除骨骼肌外的大多数正常二倍体细胞中表达水平极低。癌细胞选择的Mirk激酶的肌肉细胞功能尚不清楚。现在研究表明，Mirk蛋白在增殖的骨骼肌C2C12成肌细胞中表达水平较低且主要位于细胞核中，但通过免疫荧光染色和细胞分级分离显示，当成肌细胞开始分化时，它会转移到细胞质并上调表达。Mirk缺失或Mirk激酶抑制均会增加增殖的C2C12成肌细胞中的活性氧水平。然而，Mirk蛋白定位于成熟肌纤维的细胞质中，特别是在人类骨骼肌的快肌纤维中，在那里肌肉收缩会产生活性氧毒性水平。处于分化培养基中的高密度C2C12成肌细胞融合形成可收缩的分化后有丝分裂后肌管。在该人类骨骼肌快肌纤维模型中，Mirk激酶抑制剂诱导活性氧呈剂量依赖性增加。通过可诱导的短发夹RNA在SU86.86胰腺癌细胞中有效缺失Mirk会降低八个抗氧化基因的表达。因此，癌细胞和分化的肌管均利用Mirk激酶来减轻氧化应激。
