Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties
Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties
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DOI：
10.1182/blood-2002-04-1015
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发表时间：
2002-11-15
期刊：
影响因子：
20.3
通讯作者：
Ohki, M
中科院分区：
文献类型：
--
作者：
Yokoyama, A;Kitabayashi, I;Ohki, M
MLL（混合系白血病;也ALL-1或HRX）是一种在各种急性白血病中突变的原癌基因。它的产物通常需要在胚胎发生和造血过程中通过分子机制来维持Hox基因的表达，这些机制仍然不清楚。在这里，我们证明了MLL（混合谱系白血病）是蛋白水解加工成2个片段（MLLN和MLLC），显示相反的转录特性，并形成一个分子内MLL复合体在体内。蛋白水解切割发生在共有加工序列（QXD/GZDD，其中X是疏水性氨基酸，Z是丙氨酸或缬氨酸）内的2个氨基酸（D2666和D2718），该序列在TRX（MLL的果蝇同源物）和MLL相关蛋白MLL 2中是保守的，表明加工对MLL功能很重要。加工的MLLN和MLLC通过N-末端（1253-2254个氨基酸）和G-末端（3602-3742个氨基酸）分子内相互作用结构域彼此缔合。MLL加工在翻译后几小时内迅速发生，随后是MLLC的磷酸化。MLLN显示转录抑制活性，而MLLC具有强的转录激活特性。白血病相关MLL融合蛋白缺乏MLL加工位点，不经历切割，并且不能与MLLC相互作用。这些观察结果表明，MLL的翻译后修饰可能参与调节其作为转录因子的活性，并且其功能的这一方面受到致白血病融合的干扰。
MLL (mixed lineage leukemia; also ALL-1 or HRX) Is a proto-oncogene that Is mutated In a variety of acute leukemias. Its product is normally required for the maintenance of Hox gene expression during embryogenesis and hematopoiesis through molecular mechanisms that remain poorly defined. Here we demonstrate that MLL (mixed lineage leukemia) is proteolytically processed Into 2 fragments (MLLN and MLLC) that display opposite transcriptional properties and form an intramolecular MLL complex in vivo. Proteolytic cleavage occurs at 2 amino acids (D2666 and D2718) within a consensus processing sequence (QXD/GZDD, where X Is a hydrophobic amino acid and Z Is an alanine or a valine) that is conserved in TRX, the Drosophila homolog of MLL, and in the MLL-related protein MLL2, suggesting that processing Is important for MLL function. Processed MLLN and MLLC associate with each other via N-terminal (1253-2254 amino acids) and G-terminal (3602-3742 amino acids) intramolecular interaction domains. MLL processing occurs rapidly within a few hours after translation and is followed by the phosphorylation of MLLC. MLLN displays transcriptional repression activity, whereas MLLC has strong transcriptional activation properties. Leukemia-associated MLL fusion proteins lack the MLL processing sites, do not undergo cleavage, and are unable to interact with MLLC. These observations suggest that posttranslational modifications of MLL may participate in regulating its activity as a transcription factor and that this aspect of its function is perturbed by leukemogenic fusions.