Characterization of conserved tandem donor sites and intronic motifs required for alternative splicing in corticosteroid receptor genes.
Characterization of conserved tandem donor sites and intronic motifs required for alternative splicing in corticosteroid receptor genes.
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DOI：
10.1210/en.2009-0346
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发表时间：
2009-11
期刊：
影响因子：
4.8
通讯作者：
Norman M
中科院分区：
文献类型：
--
作者：
Rivers C;Flynn A;Qian X;Matthews L;Lightman S;Ray D;Norman M
来自串联供体位点的选择性剪接事件导致在糖皮质激素(GR)和盐皮质激素(MR)受体的DNA结合区域编码额外氨基酸的mRNA变体。我们现在发现这两种剪接变体的表达在哺乳动物中广泛保守，为它们的功能意义提供了强有力的证据。MR串联剪接位点(小鼠MR+12供体位点+5位的A)保守的一个例外被预测会减少U1小核RNA结合。与这一预测一致，我们无法在该物种中检测到MR+12变异。GR串联剪接位点保守的一个例外是鸭嘴兽GRγ供体位点+3位的A，它被预测为增强U1SnRNA的结合，意外地与来自内源基因的变体以及微型基因的表达减少有关。研究发现，在GR和MR基因中都存在一个内含子嘧啶基序，这对下游供体位点的使用是至关重要的，而TIA1/TIAL1RNA结合蛋白的过度表达导致GRγ和MR+12的比例显著增加。这些结果为复杂的剪接机制的保守性提供了显著的证据，该机制涉及随机剪接体结合以外的过程，并确定了一种允许调控变异表达的机制。
Alternative splicing events from tandem donor sites result in mRNA variants coding for additional amino acids in the DNA binding domain of both the glucocorticoid (GR) and mineralocorticoid (MR) receptors. We now show that expression of both splice variants is extensively conserved in mammalian species, providing strong evidence for their functional significance. An exception to the conservation of the MR tandem splice site (an A at position +5 of the MR+12 donor site in the mouse) was predicted to decrease U1 small nuclear RNA binding. In accord with this prediction, we were unable to detect the MR+12 variant in this species. The one exception to the conservation of the GR tandem splice site, an A at position +3 of the platypus GRγ donor site that was predicted to enhance binding of U1 snRNA, was unexpectedly associated with decreased expression of the variant from the endogenous gene as well as a minigene. An intronic pyrimidine motif present in both GR and MR genes was found to be critical for usage of the downstream donor site, and overexpression of TIA1/TIAL1 RNA binding proteins, which are known to bind such motifs, led to a marked increase in the proportion of GRγ and MR+12. These results provide striking evidence for conservation of a complex splicing mechanism that involves processes other than stochastic spliceosome binding and identify a mechanism that would allow regulation of variant expression.
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影响因子：
4.5
作者：
Chern, Tzu-Ming;van Nimwegen, Erik;Kai, Chikatoshi;Kawai, Jun;Carninci, Piero;Hayashizaki, Yoshihide;Zavolan, Mihaela
通讯作者：
Zavolan, Mihaela
影响因子：
4.8
作者：
Hislop, JN;Everest, HM;McArdle, CA
通讯作者：
McArdle, CA
影响因子：
3.5
作者：
BRANDON, DD;MARKWICK, AJ;LORIAUX, DL
通讯作者：
LORIAUX, DL
影响因子：
11.4
作者：
KONIG, H;PONTA, H;HERRLICH, P
通讯作者：
HERRLICH, P
影响因子：
64.5
作者：
Hammes, A;Guo, JK;Schedl, A
通讯作者：
Schedl, A