Novel Splice Variants of sFlt1 are Upregulated in Preeclampsia
Novel Splice Variants of sFlt1 are Upregulated in Preeclampsia
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DOI：
10.1016/j.placenta.2008.12.010
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发表时间：
2009-03-01
期刊：
影响因子：
3.8
通讯作者：
Maynard, S. E.
中科院分区：
文献类型：
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作者：
Heydarian, M.;McCaffrey, T.;Maynard, S. E.
可溶性fms样酪氨酸激酶-1（sFlt 1）是Flt 1的截短剪接变体，在先兆子痫中上调。在本研究中，我们试图表征sFlt的独特C-末端。通过生物信息学分析，我们确定了两个新的sFlt 1剪接变异体和两个先前描述的sFlt 1剪接变异体。新变体与先前描述的sFlt1_v1至外显子13相同，但随后分叉至由新外显子15（sFlt1_v2和sFlt1_v3）或外显子14的延伸（sFlt1_v4）组成的独特3'末端。定量PCR结果显示，子痫前期患者胎盘中sFlt基因4种变异体中有3种表达上调。对从胎盘血清中纯化的sFlt 1的质谱分析证实了sFlt 1_v1蛋白的存在，以及包含源自外显子14的序列的额外变体。靶向每个变体的siRNA实验证实，四种变体中的三种显著促进细胞滋养层细胞体外总sFlt 1表达。这些发现提供了证据表明，人类胎盘表达sFlt 1剪接变异体家族，其中至少有三种表达为蛋白质，并且似乎在先兆子痫中整体上调。(C)2008爱思唯尔有限公司保留所有权利。
Soluble fms-like tyrosine kinase-1 (sFlt1) is a truncated splice variant of Flt1 which is upregulated in preeclampsia. in this study we sought to characterize the unique C-terminus of sFlt. Through bioinformatic analyses, we identified two novel sFlt1 splice variants and two previously described sFlt1 splice variants. The novel variants are identical to the previously described sFlt1_v1 through exon 13, but then diverge to unique 3' termini consisting of a novel exon 15 (sFlt1_v2 and sFlt1_v3) or an extension of exon 14 (sFlt1_v4). Quantitative PCR showed that three out of four sFlt variants were upregulated in placenta of women with preeclampsia. Mass spectrometry analysis of sFlt1 purified from placental serum confirmed the presence of sFlt1_v1 protein, and an additional variant which includes sequence derived from exon 14. siRNA experiments targeting each variant confirmed that three of the four variants contribute significantly to total sFlt1 expression by cytotrophoblasts in vitro. These findings provide evidence that human placenta expresses a family of sFlt1 splice variants, at least three of which are expressed as proteins, and which appear to be globally upregulated in preeclampsia. (C) 2008 Elsevier Ltd. All rights reserved.