Physical and genetic interactions link Hox function with diverse transcription factors and cell signaling proteins
Physical and genetic interactions link Hox function with diverse transcription factors and cell signaling proteins
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DOI：
10.1074/mcp.m500256-mcp200
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发表时间：
2006-05-01
影响因子：
7
通讯作者：
Matthews, KS
中科院分区：
文献类型：
--
作者：
Bondos, SE;Tan, XX;Matthews, KS
由Hox同源异型转录因子提供的位置信息与其他转录因子和细胞信号级联以特定的组合整合，以决定背景和基因特异性Hox活性。这些组之间的蛋白质-蛋白质相互作用长期以来一直被假设为调节Hox功能，产生特定的功能。然而，在将相互作用筛选应用于有效的转录因子方面的困难限制了合作伙伴的识别。使用果蝇Hox蛋白Ultrabithorax IB的转录激活缺陷突变体进行的酵母双杂交筛选鉴定了一系列相互作用的蛋白质，主要由转录因子和细胞信号传导途径的组分组成。在噬菌体展示实验中和通过免疫沉淀的一个子集的合作伙伴与野生型Ultrabithorax（UBX）的相互作用进行了确认。体内试验表明，两个Ultrabithorax IB合作伙伴，Armadillo，Wingless/WNT信号调节，和同源结构域蛋白Aristaless，抑制UBX依赖性haltere从默认的翅膀发育途径的发展。因此，转录因子和细胞信号蛋白，细分Hox特异性组织可以改变Hox功能在体内和体外与相应的Hox蛋白相互作用。UBX也可以调节伴侣的功能：UBX伴侣Hairy的异位表达诱导的蛹死亡表型需要UBX的存在。因此，Hox转录因子复合物可以整合各种位置线索，产生环境依赖性Hox功能所需的特异性和多功能性。
Positional information provided by Hox homeotic transcription factors is integrated with other transcription factors and cell signaling cascades in specific combinations to dictate context- and gene-specific Hox activity. Proteinprotein interactions between these groups have long been hypothesized to modulate Hox functions, yielding a context- specific function. However, difficulties in applying interaction screens to potent transcription factors have limited partner identification. A yeast two-hybrid screen using transcription activation-deficient mutants of the Drosophila melanogaster Hox protein Ultrabithorax IB identified an array of interacting proteins, consisting primarily of transcription factors and components of cell signaling pathways. Interactions were confirmed with wild-type Ultrabithorax (UBX) in phage display experiments and by immunoprecipitation for a subset of partners. In vivo assays demonstrated that two Ultrabithorax IB partners, Armadillo, regulated by Wingless/WNT signaling, and the homeodomain protein Aristaless, inhibit UBX-dependent haltere development from the default wing development pathway. Therefore, transcription factors and cell signaling proteins that subdivide Hox-specified tissues can both alter Hox function in vivo and interact with the corresponding Hox protein in vitro. UBX may also modulate partner function: the pupal death phenotype induced by ectopic expression of the UBX partner Hairy required the presence of UBX. Thus, Hox transcription factor complexes may integrate a variety of positional cues, generating the specificity and versatility required for context-dependent Hox function.