应用基因打靶产生磷酸脂酶C-γ 1（PLC-γ 1）基因的定位突变导致小鼠在胚胎发生早期死亡
摘要
在哺乳动物细胞中目前存在约10种不同的磷酸脂酶C(phospho-lipase C，PLC)，它们共有三个家族：PLC-β，PLC-γ和PLC-δ。PLC参与第二信使的产生，即将磷酸脂酰肌醇二磷酸(phosphatidylinositol4，5-diphosphate，PIP2)分解为第二信使二酰基甘油(diacylglyceroI，DAG)和肌醇三磷酸(inositol 1，4，5-trisphosphate，IP3)。PLC-β(共有四种同功酶)的活性由G蛋白介导的受体调节；而目前对于PLC-δ的功能及活性调节机制尚不了解。在PLC家族中，只有PLC-γ含有SH2和SH3结构域(domain)，而且可被生长因子酪氨酸受体所激活。这些生长因子包括表皮生长因子EGF(epidermal growth factor)和血小板生长因子PDGF(platelet-derived growth factor)。当受体与其配体结合并被激活后，PLC-γ1则与激活的受体偶联，继而在这些受体酪氨酸激酶的催化下，其酪氨酸残基被磷酸化了。由此活化的PLC-γ1从胞质转移到质膜上，并催化PIP2的降解。此外，PCL-γ1亦可因B或T细胞受体的激活而被激活，包括非受体的胞质酪氨酸激酶也可激活PLC-γ1的活性。
PLC-γ有两种同功酶：PLC-γ1和PLC-γ2，它们具有非常相似的结构特征和很高的同源性。然而PLC-γ1和PLC-γ2却有着不同的表达形式和不同的染色体定位。有证据表明，PLC-γ1可能通过受体酪氨酸激酶参与细胞的增殖和分化调控；在某些人类肿瘤组织中已检测到PLC-γ1的过渡表达和扩增现象。然而，也有一些实验结果表明，激活PLC-γ1在某些特定的条件下未必能参与细胞的有丝分裂和分化调节。上述这些研究并未涉及到有关PLC-γ1与SH2和SH3结合蛋白的相互作用的非催化功能。为探讨PLC-γ1在生长和发育中的生物学功能，我们应用基因的同源重组原理，以基因打靶技术选择性地在体内破坏了PLC-γ1基因，而保留PLC-γ2基因的完整性。
In mammalian cells there are approximately ten phospholipase (PLC) enzymes, including PLC-β, PLC-γ and PLC-δ, which mediate the hydrolysis of phosphatidylinositol 4,5-diphosphate (PIP2) to the second messenger molecules inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Four PLC-β isozymes are regulated by G protein-mediated receptors, while, regulation of the four -δ isozymes is not understood. PLC-γ is the only PLC isoform which has SH2 and SH3 domains, and is activated by several growth factor tyrosine kinase receptors, for example epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Following the activation of receptor kinases by ligand binding, PLC-γ1 associates with activated receptors, and in turn is phosphorylated on tyrosine residues by these receptor tyrosine kinases. The activated PLC-γ1 then
translocates to the membrane, and causes the hydrolysis of PIP2. PLC-γ1 activation also
follows the activation of Rand T cell receptor and involves the activation of cytoplasmic
tyrosine kinases, which are non-receptor tyrosine kinases.
There are two PLC-γ isotypes, PLC-γ1 and PLC-γ2. They have a similar structural organization and high sequence homology, but different patterns of expression and chromosome location. There is evidence that PLC-γ1 may participate in cellular growth and differentiation mediated by receptor tyrosine kinases. Overexpression and amplification of PLC-γ1 has been detected in certain human cancers. However, some observations have indicated that activation of PLC-γ1 seems to be not obligatory for mitogenesis and differentiation under certain conditions. However, these studies do not rule out non-catalytic activities of PLC-γ1, such as the interaction with SH2 and SH3 binding proteins. In order to address the biological function of PLC-γ1 in growth and
PLC-γ有两种同功酶：PLC-γ1和PLC-γ2，它们具有非常相似的结构特征和很高的同源性。然而PLC-γ1和PLC-γ2却有着不同的表达形式和不同的染色体定位。有证据表明，PLC-γ1可能通过受体酪氨酸激酶参与细胞的增殖和分化调控；在某些人类肿瘤组织中已检测到PLC-γ1的过渡表达和扩增现象。然而，也有一些实验结果表明，激活PLC-γ1在某些特定的条件下未必能参与细胞的有丝分裂和分化调节。上述这些研究并未涉及到有关PLC-γ1与SH2和SH3结合蛋白的相互作用的非催化功能。为探讨PLC-γ1在生长和发育中的生物学功能，我们应用基因的同源重组原理，以基因打靶技术选择性地在体内破坏了PLC-γ1基因，而保留PLC-γ2基因的完整性。
In mammalian cells there are approximately ten phospholipase (PLC) enzymes, including PLC-β, PLC-γ and PLC-δ, which mediate the hydrolysis of phosphatidylinositol 4,5-diphosphate (PIP2) to the second messenger molecules inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Four PLC-β isozymes are regulated by G protein-mediated receptors, while, regulation of the four -δ isozymes is not understood. PLC-γ is the only PLC isoform which has SH2 and SH3 domains, and is activated by several growth factor tyrosine kinase receptors, for example epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Following the activation of receptor kinases by ligand binding, PLC-γ1 associates with activated receptors, and in turn is phosphorylated on tyrosine residues by these receptor tyrosine kinases. The activated PLC-γ1 then
translocates to the membrane, and causes the hydrolysis of PIP2. PLC-γ1 activation also
follows the activation of Rand T cell receptor and involves the activation of cytoplasmic
tyrosine kinases, which are non-receptor tyrosine kinases.
There are two PLC-γ isotypes, PLC-γ1 and PLC-γ2. They have a similar structural organization and high sequence homology, but different patterns of expression and chromosome location. There is evidence that PLC-γ1 may participate in cellular growth and differentiation mediated by receptor tyrosine kinases. Overexpression and amplification of PLC-γ1 has been detected in certain human cancers. However, some observations have indicated that activation of PLC-γ1 seems to be not obligatory for mitogenesis and differentiation under certain conditions. However, these studies do not rule out non-catalytic activities of PLC-γ1, such as the interaction with SH2 and SH3 binding proteins. In order to address the biological function of PLC-γ1 in growth and
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