Mirk/Dyrk1B in cancer
Mirk/Dyrk1B in cancer
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DOI：
10.1002/jcb.21451
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发表时间：
2007-10-01
影响因子：
4
通讯作者：
Friedman, Eileen
中科院分区：
文献类型：
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作者：
Friedman, Eileen
Mirk/Dyrk1B是由分子内酪氨酸磷酸化激活的丝氨酸/苏氨酸激酶保守家族的成员，在不同组织中介导分化，如骨骼肌中的Mirk和脑中的Dyrk1a等。Mirk在骨骼肌分化中的作用之一是通过细胞周期调节因子阻止处于GO静止状态的循环成肌细胞，而Mirk的另一个作用是限制进入成肌细胞的凋亡。在几种不同类型的癌症中已经观察到了Mirk基因的扩增、Mirk表达的上调和/或该激酶的结构性激活。如果再加上应激条件，如血清饥饿导致静止状态，通过合成的双链RNAi或pSilencer编码的RNAi的RNA干扰耗尽Mirk，可以减少不同癌细胞系的克隆形成，并增强化疗药物诱导的细胞凋亡。应激激活的SAPK激酶MKK3和MKK6通过磷酸化激活MERK。我们的工作假设是，在应对各种压力时，Mirk被这一途径激活，然后作为一个检查点激酶，阻止处于静止状态的受损肿瘤细胞，并允许细胞修复。MIRK的药理抑制作用可能增强化疗药物的抗肿瘤作用。
Mirk/Dyrk1B is a member of a conserved family of serine/threonine kinases which are activated by intramolecular tyrosine phosphorylation, and which mediate differentiation in different tissues-Mirk in skeletal muscle, Dyrk1A in the brain, etc. One role of Mirk in skeletal muscle differentiation is to block cycling myoblasts in the Go quiescent state by modification of cell cycle regulators, while another role of Mirk is to limit apoptosis infusing myoblasts. Amplification of the Mirk gene, upregulation of Mirk expression and/or constitutive activation of this kinase have been observed in several different types of cancer. If coupled with a stress condition such as serum starvation which induces a quiescent state, depletion of Mirk by RNA interference using either synthetic duplex RNAi's or pSilencer-encoded RNAi's have decreased colony formation of different cancer cell lines and enhanced apoptosis induced by chemotherapeutic drugs. Mirk is activated by phosphorylation by the stress-activated SAPK kinases MKK3 and MKK6. Our working hypothesis is that Mirk is activated by this pathway in response to various stresses, and then acts as a checkpoint kinase to arrest damaged tumor cells in a quiescent state and allow cellular repair. Pharmacological inhibition of Mirk may enhance the anti-tumor effect of chemotherapeutic drugs.