Dysbindin regulates the transcriptional level of myristoylated alanine-rich protein kinase C substrate via the interaction with NF-YB in mice brain.
Dysbindin regulates the transcriptional level of myristoylated alanine-rich protein kinase C substrate via the interaction with NF-YB in mice brain.
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DOI：
10.1371/journal.pone.0008773
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发表时间：
2010-01-19
期刊：
影响因子：
3.7
通讯作者：
Tohyama M
中科院分区：
文献类型：
--
作者：
Okuda H;Kuwahara R;Matsuzaki S;Miyata S;Kumamoto N;Hattori T;Shimizu S;Yamada K;Kawamoto K;Hashimoto R;Takeda M;Katayama T;Tohyama M
越来越多的证据表明，Dtnbp1(Dybindin)是精神分裂症的关键易感基因。利用酵母双杂交筛选系统，我们检测了与debindin相互作用的候选蛋白，发现其中一个是转录因子NF-YB。我们用免疫沉淀法(IP)证明了异型结合蛋白-核因子-YB的相互作用。DNA芯片用于筛选差异结合蛋白或NF-YB下调的细胞中基因的表达变化，染色质IP和Reporter分析证实这些基因参与了肉豆蔻酰化的富含丙氨酸的蛋白激酶C底物(MARCKS)的转录。用表现出行为异常的SDY突变小鼠和野生型DBA2J小鼠研究Marcks的表达。我们揭示了dybindin和NF-YB之间的相互作用。DNA芯片显示MARCKS在差异结合蛋白基因敲除细胞和NF-YB基因敲除细胞中的表达均增加，染色质IP显示这两种蛋白在MARCKS启动子区域相互作用。报告分析结果表明，在Marcks转录水平上，dybindin与NF-YB之间的相互作用是通过CCAAT基序参与的，CCAAT基序是一个NF-YB结合序列。与野生型小鼠相比，SDY突变小鼠的Marcks表达增加。这些结果提示MARCKS的异常表达可能通过异常结合蛋白的功能障碍而导致神经传递障碍和突触发生异常。我们的结果将为神经元发育的机制和精神分裂症的发病机制提供新的见解。
An accumulating body of evidence suggests that Dtnbp1 (Dysbindin) is a key susceptibility gene for schizophrenia. Using the yeast-two-hybrid screening system, we examined the candidate proteins interacting with Dysbindin and revealed one of these candidates to be the transcription factor NF-YB. We employed an immunoprecipitation (IP) assay to demonstrate the Dysbindin-NF-YB interaction. DNA chips were used to screen for altered expression of genes in cells in which Dysbindin or NF-YB was down regulated, while Chromatin IP and Reporter assays were used to confirm the involvement of these genes in transcription of Myristoylated alanine-rich protein kinase C substrate (MARCKS). The sdy mutant mice with a deletion in Dysbindin, which exhibit behavioral abnormalities, and wild-type DBA2J mice were used to investigate MARCKS expression. We revealed an interaction between Dysbindin and NF-YB. DNA chips showed that MARCKS expression was increased in both Dysbindin knockdown cells and NF-YB knockdown cells, and Chromatin IP revealed interaction of these proteins at the MARCKS promoter region. Reporter assay results suggested functional involvement of the interaction between Dysbindin and NF-YB in MARCKS transcription levels, via the CCAAT motif which is a NF-YB binding sequence. MARCKS expression was increased in sdy mutant mice when compared to wild-type mice. These findings suggest that abnormal expression of MARCKS via dysfunction of Dysbindin might cause impairment of neural transmission and abnormal synaptogenesis. Our results should provide new insights into the mechanisms of neuronal development and the pathogenesis of schizophrenia.
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DOI：
10.1073/pnas.111134598
发表时间：
2001-06-05
影响因子：
11.1
作者：
Egan, MF;Goldberg, TE;Weinberger, DR
通讯作者：
Weinberger, DR
影响因子：
3.3
作者：
Gurtner, A;Manni, I;Piaggio, G
通讯作者：
Piaggio, G
影响因子：
3.5
作者：
Burdick, KE;Lencz, T;Malhotra, AK
通讯作者：
Malhotra, AK
影响因子：
17.7
作者：
Fanous, AH;van den Oord, EJ;Kendler, KS
通讯作者：
Kendler, KS
影响因子：
4.8
作者：
Benson, MA;Newey, SE;Blake, DJ
通讯作者：
Blake, DJ