Uras Iris Z, Scheicher Ruth M, Kollmann Karoline, Glösmann Martin, Prchal-Murphy Michaela, Tigan Anca S, Fux Daniela A, Altamura Sandro, Neves Joana, Muckenthaler Martina U, Bennett Keiryn L, Kubicek Stefan, Hinds Philip W, von Lindern Marieke, Sexl Veronika
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
VetCORE, University of Veterinary Medicine, Vienna, Austria.
Haematologica. 2017 Jun;102(6):995-1005. doi: 10.3324/haematol.2016.159947. Epub 2017 Mar 2.
Mice lacking Cdk6 kinase activity suffer from mild anemia accompanied by elevated numbers of Ter119 cells in the bone marrow. The animals show hardly any alterations in erythroid development, indicating that Cdk6 is not required for proliferation and maturation of erythroid cells. There is also no difference in stress erythropoiesis following hemolysis However, erythrocytes have a shortened lifespan and are more sensitive to mechanical stress , suggesting differences in cytoskeletal architecture. Erythroblasts contain both Cdk4 and Cdk6, while mature erythrocytes apparently lack Cdk4 and their Cdk6 is partly associated with the cytoskeleton. We used mass spectrometry to show that Cdk6 interacts with a number of proteins involved in cytoskeleton organization. erythroblasts show impaired F-actin formation and lower levels of gelsolin, which interacts with Cdk6. We also found that Cdk6 regulates the transcription of a panel of genes involved in actin (de-)polymerization. -deficient cells are sensitive to drugs that interfere with the cytoskeleton, suggesting that our findings are relevant to the treatment of patients with anemia - and may be relevant to cancer patients treated with the new generation of CDK6 inhibitors.
缺乏Cdk6激酶活性的小鼠患有轻度贫血，同时骨髓中Ter119细胞数量增加。这些动物的红系发育几乎没有任何变化，表明红系细胞的增殖和成熟不需要Cdk6。溶血后的应激性红细胞生成也没有差异。然而，红细胞寿命缩短，对机械应激更敏感，提示细胞骨架结构存在差异。成红细胞同时含有Cdk4和Cdk6，而成熟红细胞显然缺乏Cdk4，其Cdk6部分与细胞骨架相关。我们使用质谱法表明Cdk6与许多参与细胞骨架组织的蛋白质相互作用。成红细胞显示F-肌动蛋白形成受损，与Cdk6相互作用的凝溶胶蛋白水平较低。我们还发现Cdk6调节一组参与肌动蛋白（去）聚合的基因的转录。缺乏Cdk6的细胞对干扰细胞骨架的药物敏感，这表明我们的发现与贫血患者的治疗相关——可能也与接受新一代CDK6抑制剂治疗的癌症患者相关。
