DOMINANT FEMINIZING MUTATIONS IMPLICATE PROTEIN-PROTEIN INTERACTIONS AS THE MAIN MODE OF REGULATION OF THE NEMATODE SEX-DETERMINING GENE TRA-1
DOMINANT FEMINIZING MUTATIONS IMPLICATE PROTEIN-PROTEIN INTERACTIONS AS THE MAIN MODE OF REGULATION OF THE NEMATODE SEX-DETERMINING GENE TRA-1
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DOI：
10.1101/gad.9.2.155
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发表时间：
1995-01-15
影响因子：
10.5
通讯作者：
HODGKIN, J
中科院分区：
文献类型：
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作者：
DEBONO, M;ZARKOWER, D;HODGKIN, J
tra-1 基因是秀丽隐杆线虫体细胞性别的终端全局选择器：高 tra-1 活性引发雌性体细胞发育，而低 tra-1 活性引发雄性发育。先前的遗传学研究定义了一系列负面相互作用的基因，这些基因可调节 tra-1 活性以响应主要性别决定信号。在这里，我们通过研究 tra-1 的罕见功能获得（gf）突变来研究这一调控级联的最后一步，该突变指导雌性体细胞发育，而与上游性别决定信号无关。这些突变似乎消除了男性组织中 tra-1 的负调控。我们鉴定了与其中 29 个突变相关的病变，并发现所有这些突变都会影响 tra-1 基因的两种蛋白质产物中存在的一小段氨基酸残基。二十六个等位基因与单个非保守氨基酸取代相关。两个等位基因影响 tra-1 RNA 剪接并生成省略部分或全部编码这段短片段的外显子的信息。这些结果表明，tra-1 的性调节是通过抑制性蛋白质-蛋白质相互作用在翻译后实现的。 tra-1(gf) 突变改变的氨基酸延伸可能定义了 tra-1 负调节因子的相互作用位点。该延伸段包括糖原合成酶激酶 3 的潜在磷酸化位点，并且可能在人类基因 GLI3 中保守，GLI3 是先前鉴定的 tra-1 的同源物。
The tra-1 gene is the terminal global selector of somatic sex in Caenorhabditis elegans: High tra-1 activity elicits female somatic development while low tra-1 activity elicits male development. Previous genetic studies defined a cascade of negatively interacting genes that regulates tra-1 activity in response to the primary sex-determining signal. Here, we investigate the last step in this regulatory cascade, by studying rare gain-of-function (gf) mutations of tra-1 that direct female somatic development irrespective of the upstream sex-determining signal. These mutations appear to abolish negative regulation of tra-1 in male tissues. We identify the lesions associated with 29 of these mutations and find that all affect a short stretch of amino acid residues present in both protein products of the tra-1 gene. Twenty-six alleles are associated with single nonconservative amino acid substitutions. Two alleles affect tra-1 RNA splicing and generate messages that omit part or all of the exon encoding this short stretch. These results suggest that sexual regulation of tra-1 is achieved post-translationally, by an inhibitory protein-protein interaction. The amino acid stretch altered by the tra-1(gf) mutations may define a site of interaction for negative regulators of tra-1. The stretch includes a potential phosphorylation site for glycogen synthase kinase 3 and may be conserved in the human gene GLI3, a homolog of tra-1 identified previously.