Haspin: a newly discovered regulator of mitotic chromosome behavior.
Haspin: a newly discovered regulator of mitotic chromosome behavior.
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DOI：
10.1007/s00412-009-0250-4
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发表时间：
2010-04
期刊：
影响因子：
1.6
通讯作者：
Higgins JM
中科院分区：
文献类型：
--
作者：
Higgins JM
haspins是真核生物蛋白激酶家族的不同成员，其在许多真核生物谱系（包括动物、真菌和植物）中是保守的。最近解决的晶体结构证实，激酶结构域的人haspin具有不寻常的结构特征，稳定的催化活性构象，并创建一个独特的底物结合位点。Haspin主要定位于染色体，并在有丝分裂过程中磷酸化组蛋白H3的苏氨酸-3，特别是在内部着丝粒。这表明haspin通过修饰组蛋白直接调节染色体行为，尽管将来可能会发现其他底物。在人类细胞系中通过RNA干扰耗尽haspin导致有丝分裂中染色体的着丝粒粘附素过早丢失和中期染色体对齐失败，导致纺锤体组装检查点的激活和有丝分裂停滞。Haspin过表达稳定染色体臂的凝聚力。因此，Haspin似乎是有丝分裂着丝粒的凝聚力的保护所必需的。酿酒酵母的haspin同源物Alk 1和Alk 2也参与有丝分裂的调节。在哺乳动物中，haspin在睾丸中以高水平表达，特别是在圆形精子细胞中，因此似乎haspin在减数分裂后的精子发生中具有额外的作用。Haspin目前是许多药物发现工作的主题，并且Haspin抑制剂的未来使用应该为这些激酶的细胞功能提供新的见解，并帮助确定例如靶向Haspin用于癌症治疗的效用。
The haspins are divergent members of the eukaryotic protein kinase family that are conserved in many eukaryotic lineages including animals, fungi, and plants. Recently-solved crystal structures confirm that the kinase domain of human haspin has unusual structural features that stabilize a catalytically active conformation and create a distinctive substrate binding site. Haspin localizes predominantly to chromosomes and phosphorylates histone H3 at threonine-3 during mitosis, particularly at inner centromeres. This suggests that haspin directly regulates chromosome behavior by modifying histones, although it is likely that additional substrates will be identified in the future. Depletion of haspin by RNA interference in human cell lines causes premature loss of centromeric cohesin from chromosomes in mitosis and failure of metaphase chromosome alignment, leading to activation of the spindle assembly checkpoint and mitotic arrest. Haspin overexpression stabilizes chromosome arm cohesion. Haspin, therefore, appears to be required for protection of cohesion at mitotic centromeres. Saccharomyces cerevisiae homologues of haspin, Alk1 and Alk2, are also implicated in regulation of mitosis. In mammals, haspin is expressed at high levels in the testis, particularly in round spermatids, so it seems likely that haspin has an additional role in post-meiotic spermatogenesis. Haspin is currently the subject of a number of drug discovery efforts, and the future use of haspin inhibitors should provide new insight into the cellular functions of these kinases and help determine the utility of, for example, targeting haspin for cancer therapy.
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DOI：
10.1073/pnas.88.20.8895
发表时间：
1991-10-01
影响因子：
11.1
作者：
DOWNES, CS;MULLINGER, AM;JOHNSON, RT
通讯作者：
JOHNSON, RT
DOI：
10.1083/jcb.153.4.865
发表时间：
2001-05-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Adams RR;Maiato H;Earnshaw WC;Carmena M
通讯作者：
Carmena M
影响因子：
9.8
作者：
Hauf S;Roitinger E;Koch B;Dittrich CM;Mechtler K;Peters JM
通讯作者：
Peters JM
影响因子：
2.9
作者：
Garcia, BA;Barber, CM;Hunt, DF
通讯作者：
Hunt, DF
影响因子：
11.4
作者：
de la Barre, AE;Angelov, D;Dimitrov, S
通讯作者：
Dimitrov, S