MECP2 表达和活性的调控
中文名称
通路描述
MECP2 基因的转录受启动子及第一个内含子的甲基化调节，但负责甲基转移酶的机制尚不清楚。MECP2 mRNA 的翻译受微 RNA miR-132 的负向调节。miR-132 的转录受 BDNF 信号调节，通过未知机制进行。MECP2 与其他蛋白质和 DNA 的结合受翻译后修饰调节，其中磷酸化研究最为深入。由神经元膜去极化激活的钙依赖性蛋白激酶 PKA 和 CaMK IV 磷酸化 MECP2 的丝氨酸残基 T308（对应较长剪接异构体 MECP2_e1 中的苏氨酸 T320）。T308 的磷酸化与神经元活动相关，并抑制 MECP2 与核受体共抑制复合物 (NCoR/SMRT) 的结合。在静息神经元中，MECP2 在丝氨酸残基 S80 处被磷酸化，导致其与染色质的结合减少。核丝氨酸/苏氨酸蛋白激酶 HIPK2 磷酸化 MECP2 的丝氨酸残基 S80 (Bracaglia et al. 2009)。在由活动诱导的神经元中，神经元膜去极化导致 MECP2 S80 去磷酸化，并发生丝氨酸 S423 的磷酸化（对应小鼠 Mecp2 苏氨酸 S421）。CaMK IV 是磷酸化 MECP2 于 S423 的激酶之一。MECP2 在 S423 处的磷酸化增加其与染色质的结合 (Zhou et al. 2006, Tao et al. 2009, Qiu et al. 2012)。AURKB 在分裂的成体神经元前体细胞中磷酸化 MECP2 的丝氨酸残基 S423 (Li et al. 2014)。除了与 NCoR/SMRT 共抑制复合物结合外，MECP2 还结合 SIN3A 共抑制复合物。该相互作用涉及 MECP2 的转录抑制域和 SIN3A 的氨基末端 HDAC 相互作用域 (HID) 的一部分。HDAC1 和 HDAC2 是共免疫沉淀与 MECP2 的 SIN3A 共抑制复合物的一部分 (Nan et al. 1998)。虽然 MECP2 在靶基因上结合 SIN3A 与转录抑制相关，但在 CREB1 上结合则与转录激活相关 (Chahrour et al. 2008, Chen et al. 2013)。MECP2 的功能可能因结合 FOXG1 而受到影响，FOXG1 是 Rett 综合征中除 MECP2 和 CDKL5 外的另一个基因突变 (Dastidar et al. 2012)，以及 HTT (亨廷顿蛋白) (McFarland et al. 2013)。MECP2 的亚核定位可能因结合 Lamin B 受体 (LBR) 而受到影响 (Guarda et al. 2009)。
英文描述
Regulation of MECP2 expression and activity Transcription of the MECP2 gene is known to be regulated by methylation of the promoter and the first intron, but the responsible methyltransferases are not known (Nagarajan et al. 2008, Franklin et al. 2010, Liyanage et al. 2013).Translation of MECP2 mRNA is negatively regulated by the microRNA miR-132. Transcription of miR-132 is regulated by BDNF signaling, through an unknown mechanism (Klein et al. 2007, Su et al. 2015).Binding of MECP2 to other proteins and to DNA is regulated by posttranslational modifications, of which phosphorylation has been best studied. Calcium dependent protein kinases, PKA and CaMK IV, activated by neuronal membrane depolarization, phosphorylate MECP2 at threonine residue T308 (corresponding to T320 in the longer MECP2 splicing isoform, MECP2_e1). Phosphorylation at T308 correlates with neuronal activity and inhibits binding of MECP2 to the nuclear receptor co-repressor complex (NCoR/SMRT) (Ebert et al. 2013). In resting neurons, MECP2 is phosphorylated at serine residue S80, which results in a decreased association of MECP2 with chromatin. Nuclear serine/threonine protein kinase HIPK2 phosphorylates MECP2 on serine residue S80 (Bracaglia et al. 2009). In activity-induced neurons, upon neuronal membrane depolarization, MECP2 S80 becomes dephosphorylated, and MECP2 acquires phosphorylation on serine S423 (corresponding to mouse Mecp2 serine S421). CaMK IV is one of the kinases that can phosphorylate MECP2 on S423. Phosphorylation of MECP2 at S423 increases MECP2 binding to chromatin (Zhou et al. 2006, Tao et al. 2009, Qiu et al. 2012). AURKB phosphorylates MECP2 at serine residue S423 in dividing adult neuronal progenitor cells (Li et al. 2014).Besides binding to the NCoR/SMRT co-repressor complex (Lyst et al. 2013, Ebert et al. 2013), MECP2 binds the SIN3A co-repressor complex. This interaction involves the transcriptional repressor domain of MECP2 and the amino terminal part of the HDAC interaction domain (HID) of SIN3A. HDAC1 and HDAC2 are part of the SIN3A co-repressor complex that co-immunoprecipitates with MECP2 (Nan et al. 1998). While binding of MECP2 to SIN3A at target genes is associated with transcriptional repression, binding to CREB1 at target genes is associated with transcriptional activation (Chahrour et al. 2008, Chen et al. 2013). Function of MECP2 can be affected by binding to FOXG1, another gene mutated in Rett syndrome besides MECP2 and CDKL5 (Dastidar et al. 2012), and HTT (Huntingtin) (McFarland et al. 2013). The subnuclear localization of MECP2 may be affected by binding to the Lamin B receptor (LBR) (Guarda et al. 2009).
所含基因
30 个基因