Proteolysis of MLL family proteins is essential for Taspase1-orchestrated cell cycle progression
Proteolysis of MLL family proteins is essential for Taspase1-orchestrated cell cycle progression
复制标题
DOI：
10.1101/gad.1449406
复制
发表时间：
2006-09-01
影响因子：
10.5
通讯作者：
Hsieh, James J. -D.
中科院分区：
文献类型：
--
作者：
Takeda, Shugaku;Chen, David Y.;Hsieh, James J. -D.
Taspase1被鉴定为苏氨酸内肽酶，在体外裂解混合谱系白血病（MLL），使Hox基因正常表达。为了研究其在体内的功能，我们制造了Taspase1（-/-）小鼠。Taspase1缺乏导致MLL和MLL2的非切割（nc）和同质化转化。值得注意的是，我们的体内研究揭示了Taspase1在细胞周期中的意想不到的作用。Taspase1（-/-）动物体型较小。Taspase1（-/-）小鼠胚胎成纤维细胞（mef）表现出增殖受损，Taspase1的急性缺失导致胸腺细胞显著减少。Taspase1缺乏导致Cyclin Es、As和Bs下调，p16上调（Ink4a）。我们发现MLL和MLL2直接靶向E2Fs表达Cyclin。未裂解前体MLL在体外显示组蛋白H3甲基转移酶活性降低。因此，染色质免疫沉淀分析显示，在Taspase1（-/-）细胞中，Cyclin E1和E2基因的组蛋白H3 K4三甲基化显著降低。此外,MLLnc /数控;2nc/nc MEFs的增殖也受到抑制。我们的数据与一个模型是一致的，在这个模型中，被Taspase1激活的前体MILLs通过E2Fs靶向Cyclins，在K4位点甲基化组蛋白H3，从而导致激活。最后，Taspase1（-/-）细胞对致癌转化具有抗性，并且Taspase1在许多癌细胞系中过表达。因此，Taspase1可以作为癌症治疗的靶点。
Taspase1 was identified as the threonine endopeptidase that cleaves mixed-lineage leukemia (MLL) for proper Hox gene expression in vitro. To investigate its functions in vivo, we generated Taspase1(-/-) mice. Taspase1 deficiency results in noncleavage (nc) of MLL and MLL2 and homeotic transformations. Remarkably, our in vivo studies uncover an unexpected role of Taspase1 in the cell cycle. Taspase1(-/-) animals are smaller in size. Taspase1(-/-) mouse embryonic fibroblasts ( MEFs) exhibit impaired proliferation, and acute deletion of Taspase1 leads to a marked reduction of thymocytes. Taspase1 deficiency incurs down- regulation of Cyclin Es, As, and Bs and up- regulation of p16(Ink4a). We show that MLL and MLL2 directly target E2Fs for Cyclin expression. The uncleaved precursor MLL displays a reduced histone H3 methyl transferase activity in vitro. Accordingly, chromatin immunoprecipitation assays demonstrate a markedly decreased histone H3 K4 trimethylation at Cyclin E1 and E2 genes in Taspase1(-/-) cells. Furthermore, MLLnc/nc;2nc/nc MEFs are also impaired in proliferation. Our data are consistent with a model in which precursor MILLs, activated by Taspase1, target to Cyclins through E2Fs to methylate histone H3 at K4, leading to activation. Lastly, Taspase1(-/-) cells are resistant to oncogenic transformation, and Taspase1 is overexpressed in many cancer cell lines. Thus, Taspase1 may serve as a target for cancer therapeutics.