RUNX1 表达与活性的调控
中文名称
通路描述
在转录水平上，RUNX1转录因子的表达由两个替代启动子调控：一个位于 P2 下游 7 kb 以上的远端启动子 P1，以及一个位于 P2 近端的启动子 P2。在发育过程中，小鼠的 Runx1 基因在造血细胞生成时优先从近端 P2 启动子转录；而在完全分化的造血祖细胞中，则优先从远端 P1 启动子转录。在人类 T 细胞中，RUNX1 在整个发育过程中优先从 P1 启动子转录，而发育中的自然杀伤细胞则优先从 P2 启动子转录；发育中的 B 细胞则从两个启动子转录低水平的 RUNX1。RUNX1 由不同启动子转录的 mRNA 在 5'UTR 和 RUNX1 的剪接异构体方面存在差异，但不同异构体的功能尚未完全阐明。在斑马鱼造血过程中，RUNX1 表达增加是由 NOTCH 信号通路介导的，但尚未证明 NOTCH 直接转录调控 RUNX1。RUNX1 转录也增加是由 WNT 信号通路介导的，TCF7 和 TCF4 结合 RUNX1 启动子，RUNX1 由 TCF 结合元件（TBE）介导的转录在 WNT3A 处理中受到 TCF4 的占位性突变体的抑制。在发育中的小鼠卵巢中，Runx1 表达由 Wnt4 信号通路正调控。小鼠造血干细胞和祖细胞研究表明，RUNX1 可能是 HOXB4 的直接转录靶标。最近鉴定了 RUNX1 内含子 5 中保守的顺式作用元件。在急性髓系白血病（AML）中，RUNX1 易位（8;21）导致的 RUNX1-ETO 融合蛋白表达，其 RUNX1 断裂点位于内含子 5 中，靠近这些尚未完全表征的顺式作用元件。在翻译水平上，RUNX1 的表达由各种微 RNA 调控，它们结合到 RUNX1 mRNA 的 3'UTR 并抑制其翻译，通过内切酶和非内切酶机制。靶向 RUNX1 的微 RNA 包括 miR-378、miR-302b、miR-18a、miR-675、miR-27a、miR-17、miR-20a、miR106 和 miR-215。在翻译后水平上，RUNX1 的活性由翻译后修饰和结合辅因子调控。SRC 家族激酶在 RUNX1 的多个酪氨酸残基上磷酸化 RUNX1，位于 RUNX1 的负调控域中，涉及 RUNX1 的自抑制。RUNX1 酪氨酸磷酸化与 RUNX1 与 GATA1 的结合减少以及 RUNX1 与 SWI/SNF 复合物的结合增加相关，导致 RUNX1 介导的 T 细胞和巨核细胞分化受到抑制。SHP2（PTPN11）酪氨酸磷酸酶结合 RUNX1 并使其去磷酸化。RUNX1 与 CBFB 的复合物形成对于 RUNX1 的转录活性是必要的。CCND3 和可能还有其他两个 Cyclin D 家族成员 CCND1 和 CCND2 与 RUNX1 的结合抑制其与 CBFB 的结合，而结合 CDK6 干扰 RUNX1 与 DNA 的结合而不影响 RUNX1:CBFB 复合物的形成。RUNX1 与 PML 的结合在 RUNX1 的亚核靶向中发挥作用。RUNX1 的活性和蛋白水平在细胞周期中有所不同。RUNX1 蛋白水平从 G1 到 S 期和从 S 期到 G2 期增加，RUNX1 mRNA 水平没有增加。CDK1 介导的 RUNX1 在 G2/M 过渡期的磷酸化涉及 RUNX1 转录激活能力的减少，并可能通过有丝分裂促进复合物促进 RUNX1 蛋白降解。
英文描述
Receptor Mediated Mitophagy Mitochondrial autophagy in mammalian cells was first observed in glucagon-stimulated hepatocytes. The mechanisms of mitophagy in mammalian cells remain unclear. Oxidative stress and mPTP are involved in the initiation of mitophagy. Receptor mediated mitophagy links both cellular differentiation signals and markers of mitochondrial function to LC3 and Atg32, scaffold proteins important for cargo selection and autophagosome formation. These scaffold proteins recruit other autophagy proteins to form the autophagosomes; destroying and recycling mitochondria.
Mitophagy receptors have to meet at least three criteria: 1) it must be mitochondrially localized, 2) it must interact with LC3/ ATG8 in response to a certain stimulus, and 3) it must have a consensus sequence of W/F/YxxL/I known as the LIR motif. This tetrapeptide sequence is present in several Atg8 or LC3-binding partners that are important for selective autophagy.
FUNDC1-mediated mitophagy is inhibited by its phosphorylation at the Tyr 18 position in the LIR motif by Src kinase under normoxia conditions. Upon hypoxia stimulation, Src is inactivated and FUNDC1 at the Tyr 18 position is dephosphorylated by an unknown phosphatase, resulting in an increase of the interaction between FUNDC1 and LC3-II, leading to the selective incorporation and autophagic removal of the mitochondrion.
The outer mitochondrial membrane protein NIX/BNIP3L is involved in autophagic turnover of mitochondria in reticulocytes, a process essential for red blood cell maturation [43]. The mechanism through which NIX senses signals from red blood cell differentiation is unclear. Phosphorylation of serine residues 17 and 24 flanking the BNIP3 LIR promotes binding to specific LC3 family members LC3B and GATE-16 and increases lysosomal destruction of mitochondria.
Mitophagy receptors have to meet at least three criteria: 1) it must be mitochondrially localized, 2) it must interact with LC3/ ATG8 in response to a certain stimulus, and 3) it must have a consensus sequence of W/F/YxxL/I known as the LIR motif. This tetrapeptide sequence is present in several Atg8 or LC3-binding partners that are important for selective autophagy.
FUNDC1-mediated mitophagy is inhibited by its phosphorylation at the Tyr 18 position in the LIR motif by Src kinase under normoxia conditions. Upon hypoxia stimulation, Src is inactivated and FUNDC1 at the Tyr 18 position is dephosphorylated by an unknown phosphatase, resulting in an increase of the interaction between FUNDC1 and LC3-II, leading to the selective incorporation and autophagic removal of the mitochondrion.
The outer mitochondrial membrane protein NIX/BNIP3L is involved in autophagic turnover of mitochondria in reticulocytes, a process essential for red blood cell maturation [43]. The mechanism through which NIX senses signals from red blood cell differentiation is unclear. Phosphorylation of serine residues 17 and 24 flanking the BNIP3 LIR promotes binding to specific LC3 family members LC3B and GATE-16 and increases lysosomal destruction of mitochondria.
所含基因
11 个基因