A gain-of-function allele of cbp-1, the Caenorhabditis elegans ortholog of the mammalian CBP/p300 gene, causes an increase in histone acetyltransferase activity and antagonism of activated Ras
A gain-of-function allele of cbp-1, the Caenorhabditis elegans ortholog of the mammalian CBP/p300 gene, causes an increase in histone acetyltransferase activity and antagonism of activated Ras
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DOI：
10.1128/mcb.25.21.9427-9434.2005
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发表时间：
2005-11-01
影响因子：
5.3
通讯作者：
Han, M
中科院分区：
文献类型：
--
作者：
Eastburn, DJ;Han, M
RTK-Ras-丝裂原活化蛋白激酶（MAPK）信号通路在秀丽隐杆线虫外阴诱导中起关键作用。我们之前已经进行了筛选激活Ras的抑制因子，以确定在该途径的调节中发挥关键作用的因子。ku 258作为抑制由激活的let-60 ras引起的多叶表型的半显性等位基因被分离。我们的遗传学和分子生物学分析表明，ku 258是一个功能获得性等位基因，由C.转录辅激活因子p300/CBP的同源物，cbp-1。遗传数据还表明，cbp-1可能作用于Ras信号通路的下游，但不是主要作用于Wnt信号通路的下游，以负调节外阴细胞命运的特化。cbp-1可能与LIN-1一起发挥作用，LIN-1是Ets转录因子家族成员，是MAPK的靶点之一。体外组蛋白乙酰化试验表明，这两个点突变共同导致重组CBP-1的组蛋白乙酰转移酶（RAT）活性增加7倍。据我们所知，这是在CBP/p300家族蛋白中分离的唯一这样的RAT活性突变，并且该突变可以定义RAT活性在特定发育事件中拮抗Ras功能的负面作用。
An RTK-Ras-mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in vulval induction in Caenorhabditis elegans. We have previously carried out screens for suppressors of activated Ras to identify factors that play critical roles in the regulation of the pathway. ku258 was isolated as a semidominant allelle that suppresses the Multivulva phenotype caused by activated let-60 ras. Our genetic and molecular analyses indicate that ku258 is a gain-of-function allelle resulting from two point mutations in the C. elegans homolog of the transcriptional coactivator p300/CBP, cbp-1. Genetic data also suggest that cbp-1 may act downstream of the Ras signaling pathway, but not primarily downstream of the Wnt signaling pathway, to negatively regulate vulval cell fate specification. cbp-1 may function in concert with LIN-1, an Ets transcription factor family member that is one of the targets of MAPK. In vitro histone acetylation assays have revealed that together, the two point mutations cause a sevenfold increase in the histone acetyltransferase (RAT) activity of recombinant CBP-1. To our knowledge, this is the only such RAT activity mutation isolated in a CBP/p300 family protein, and this mutation may define a negative role of the RAT activity in antagonizing Ras function in a specific developmental event.