Eya4 Induces Hypertrophy via Regulation of p27kip1
Eya4 Induces Hypertrophy via Regulation of p27kip1
复制标题
Eya4 通过调节 p27kip1 诱导肥大
DOI：
10.1161/circgenetics.115.001134
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Ritter O
中科院分区：
文献类型：
--
作者：
Williams T;Hundertmark M;Nordbeck P;Voll S;Arias-Loza PA;Oppelt D;Mühlfelder M;Schraut S;Elsner I;Seidlmayer L;Heinze B;Hahner S;Heinze K;Schönberger J;Jakob PM;Ritter O
BackgroundE 193，一个杂合截断突变在人类转录辅因子的眼睛缺失4（Eya 4），导致听力障碍，其次是扩张性cardiomyopathy.Methods和ResultsIn这项研究中，我们首先显示Eya 4和E193改变p27 kip 1在体外的表达，这表明Eya 4是一个负调节p27。接下来，我们产生了Eya 4或E193心脏特异性过表达的转基因小鼠。荧光素酶和染色质免疫沉淀试验证实Eya 4和E193以矛盾的方式结合和调节p27表达。与野生型同窝仔相比，Eya 4-中下游分子酪蛋白激酶-2 α和组蛋白去乙酰化酶2的活性和磷酸化状态显著升高，但在E193-过表达动物中显著降低。磁共振成像和血液动力学分析表明Eya 4过表达导致在基线条件下已经发生的年龄依赖性肥大发展，没有明显的功能影响，而E193动物发生扩张性心肌病，如在人类E193患者中所见。两种心脏表型在压力超负荷时均加重。最后，我们鉴定了一个新的杂合截短Eya 4突变E215，结论Eya 4/Six 1通过p27/casein kinase-2α/casein kinase-2组蛋白去乙酰化酶2，并表明该转录复合物和信号级联中突变导致心肌病的发展。
BackgroundE193, a heterozygous truncating mutation in the human transcription cofactor Eyes absent 4 (Eya4), causes hearing impairment followed by dilative cardiomyopathy.Methods and ResultsIn this study, we first show Eya4 and E193 alter the expression of p27kip1in vitro, suggesting Eya4 is a negative regulator of p27. Next, we generated transgenic mice with cardiac-specific overexpression of Eya4 or E193. Luciferase and chromatin immunoprecipitation assays confirmed Eya4 and E193 bind and regulate p27 expression in a contradictory manner. Activity and phosphorylation status of the downstream molecules casein kinase-2α and histone deacetylase 2 were significantly elevated in Eya4- but significantly reduced in E193-overexpressing animals compared with wild-type littermates. Magnetic resonance imaging and hemodynamic analysis indicate Eya4-overexpression results in an age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 animals develop onset of dilative cardiomyopathy as seen in human E193 patients. Both cardiac phenotypes were aggravated on pressure overload. Finally, we identified a new heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein as seen with E193.ConclusionsOur results implicate Eya4/Six1 regulates normal cardiac function via p27/casein kinase-2α/histone deacetylase 2 and indicate that mutations within this transcriptional complex and signaling cascade lead to the development of cardiomyopathy.
登录
查看更多内容
影响因子：
10.5
作者：
Heanue, TA;Reshef, R;Tabin, CJ
通讯作者：
Tabin, CJ
影响因子：
4.8
作者：
Ritter, O;Schuh, K;Neyses, L
通讯作者：
Neyses, L
使用表型增强子陷阱鉴定果蝇眼睛发育所需的基因。
DOI：
--
发表时间：
1997
影响因子：
11.1
作者：
F. Pignoni;B. Hu;Zipursky Sl
通讯作者：
Zipursky Sl
影响因子：
3.3
作者：
Q. T. Bui;J. Zimmerman;H. Liu;N. Bonini
通讯作者：
Q. T. Bui;J. Zimmerman;H. Liu;N. Bonini
影响因子：
37.8
作者：
Eom, Gwang Hyeon;Cho, Young Kuk;Kook, Hyun
通讯作者：
Kook, Hyun