C-elegans ISWI and NURF301 antagonize an Rb-like pathway in the determination of multiple cell fates
C-elegans ISWI and NURF301 antagonize an Rb-like pathway in the determination of multiple cell fates
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DOI：
10.1242/dev.02444
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发表时间：
2006-07-15
期刊：
影响因子：
4.6
通讯作者：
Horvitz, H. Robert
中科院分区：
文献类型：
--
作者：
Andersen, Erik C.;Lu, Xiaowei;Horvitz, H. Robert
A类、B类和C类合成多根管（synMuv）基因冗余地负调控秀丽隐杆线虫外阴细胞命运的表达。B和C类synMuv蛋白包括调节染色质并影响其他生物体中转录的蛋白的同源物，类似于Myb-Muv B/dREAM、NuRD和Tip 60/NuA 4复合物的成员。为了确定这些染色质重塑活动如何负调控外阴细胞命运的决定，我们分离了synMuv表型的抑制基因，发现该抑制基因编码C。果蝇ISWI的同源物。梭elegans ISW-1蛋白可能作为核小体重塑因子（NucleosomeRemodelingFactor，NNF）与NNF-1（NNF-301的线虫直系同源物）复合物的一部分，以促进synMuv表型。isw-1和nurf-1突变抑制了由Ras途径过度激活引起的synMuv表型和多根管表型。我们的数据表明，一个类似于Myb-MuvB/dREAM，NuRD和Tip 60/NuA 4的复合物通过拮抗转录和染色质重塑活性来促进外阴细胞命运的表达。由于肿瘤抑制基因和B类synMuv基因lin-35 Rb的无效突变和let-60 Ras的功能获得性突变所引起的表型被isw-1功能的降低所抑制，因此BNF复合物蛋白可能是癌症治疗的有效靶点。
The class A, B and C synthetic multivulva (synMuv) genes act redundantly to negatively regulate the expression of vulval cell fates in Caenorhabditis elegans. The class B and C synMuv proteins include homologs of proteins that modulate chromatin and influence transcription in other organisms similar to members of the Myb-MuvB/dREAM, NuRD and Tip60/NuA4 complexes. To determine how these chromatin-remodeling activities negatively regulate the vulval cell-fate decision, we isolated a suppressor of the synMuv phenotype and found that the suppressor gene encodes the C. elegans homolog of Drosophila melanogaster ISWI. The C. elegans ISW-1 protein likely acts as part of a Nucleosome Remodeling Factor (NURF) complex with NURF-1, a nematode ortholog of NURF301, to promote the synMuv phenotype. isw-1 and nurf-1 mutations suppress both the synMuv phenotype and the multivulva phenotype caused by overactivation of the Ras pathway. Our data suggest that a NURF-like complex promotes the expression of vulval cell fates by antagonizing the transcriptional and chromatin-remodeling activities of complexes similar to Myb-MuvB/dREAM, NuRD and Tip60/NuA4. Because the phenotypes caused by a null mutation in the tumor-suppressor and class B synMuv gene lin-35 Rb and a gain-of-function mutation in let-60 Ras are suppressed by reduction of isw-1 function, NURF complex proteins might be effective targets for cancer therapy.