The Drosophila Ortholog of MLL3 and MLL4, trithorax related, Functions as a Negative Regulator of Tissue Growth
The Drosophila Ortholog of MLL3 and MLL4, trithorax related, Functions as a Negative Regulator of Tissue Growth
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DOI：
10.1128/mcb.01585-12
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发表时间：
2013-05-01
影响因子：
5.3
通讯作者：
Hariharan, Iswar K.
中科院分区：
文献类型：
--
作者：
Kanda, Hiroshi;Alexander Nguyen;Hariharan, Iswar K.
人类 MLL 基因（MLL1 至 MLL4）及其果蝇直系同源物 trithorax (trx) 和 trithorax 相关 (trr) 编码能够在赖氨酸 4 上甲基化组蛋白 H3 的蛋白质。MLL1 和 MLL2 与 trx 最相似，而 MLL3 和 MLL4 与 trr 关系更密切。一些 MLL 基因在人类癌症中发生突变，但这些蛋白质如何调节细胞增殖尚不清楚。在这里，我们表明，trr 突变细胞比其野生型邻居具有生长优势，并显示出调节生长和细胞分裂的多种蛋白质水平的变化，包括 Notch、Capicua 和细胞周期蛋白 B。trr 突变克隆显示 H3K4 单甲基化水平显着降低，而 H3K4 二甲基化和三甲基化水平没有明显变化。 trr 突变体表型与编码 H3K27 去甲基酶的 Utx 相似，这与 Trr 和 Utx 存在于同一蛋白质复合物中的观察结果一致。与 trr 突变组织表现出的过度生长相反，trx 克隆的代表性不足，表达低水平的抗凋亡蛋白 Diap1，并且 H3K4 甲基化的整体水平仅表现出适度的变化。因此，在果蝇眼成盘中，Trr 可能与 Utx 一起发挥作用，限制组织生长。相反，Trx 似乎可以促进细胞存活。
The human MLL genes (MLL1 to MLL4) and their Drosophila orthologs, trithorax (trx) and trithorax related (trr), encode proteins capable of methylating histone H3 on lysine 4. MLL1 and MLL2 are most similar to trx, while MLL3 and MLL4 are more closely related to trr. Several MLL genes are mutated in human cancers, but how these proteins regulate cell proliferation is not known. Here we show that trr mutant cells have a growth advantage over their wild-type neighbors and display changes in the levels of multiple proteins that regulate growth and cell division, including Notch, Capicua, and cyclin B. trr mutant clones display markedly reduced levels of H3K4 monomethylation without obvious changes in the levels of H3K4 di- and trimethylation. The trr mutant phenotype resembles that of Utx, which encodes a H3K27 demethylase, consistent with the observation that Trr and Utx are found in the same protein complex. In contrast to the overgrowth displayed by trr mutant tissue, trx clones are un-derrepresented, express low levels of the antiapoptotic protein Diap1, and exhibit only modest changes in global levels of H3K4 methylation. Thus, in Drosophila eye imaginal discs, Trr, likely functioning together with Utx, restricts tissue growth. In contrast, Trx appears to promote cell survival.