mRNA Polyadenylation
中文名称
通路描述
真核生物 mRNA（除组蛋白 mRNA 外）经历 3'端成熟步骤，包括前体 mRNA 的特定位点内切酶切割以及上游切割片段的多聚腺苷酸化；下游片段被降解。在哺乳动物细胞中，前体 mRNA 切割位点由至少四个序列元件决定。1) 中央且最保守的信号是 AAUAAA 或其近旁变体，位于切割位点上游约 20 个核苷酸处。2) 切割位点优选序列为 CA。3) GU-或 G 丰富的下游元件很重要。4) AAUAAA 上游的序列（如 UGUA）也可贡献。大多数蛋白质编码基因具有多个多聚腺苷酸化位点（PASs），产生不同的蛋白质异构体或 mRNA 异构体，这些异构体在 3'非翻译区（UTR）长度上不同，进而影响其与 RNA 结合蛋白和微小 RNA 的相互作用。通过不同使用 PASs 形成 mRNA 异构体的过程称为替代多聚腺苷酸化（APA）。APA 在所有真核生物中普遍存在，哺乳动物中超过 70% 的蛋白质编码 mRNA 受 APA 影响。在哺乳动物细胞中，有超过二十种核心蛋白质组成不同的复合物专门负责切割和多聚腺苷酸化（CP）反应。通过亲和纯化和质谱分析鉴定出的约 80 种蛋白质属于 3'加工复合物。其中一些蛋白质可能参与 3'加工与转录及其他过程的偶联。中央复合物是多聚腺苷酸化特异性因子（CPSF）。CPSF 负责前体 mRNA 切割，其与 AAUAAA 序列的结合对于切割和多聚腺苷酸化至关重要，且多聚腺苷酸化依赖于 AAUAAA。CPSF 复合物被认为由七个蛋白质组成：CPSF1（CPSF160）、CPSF2（CPSF100）、CPSF3（CPSF73）、CPSF4（CPSF30）、FIP1L1（FIP1）、WDR33 和 SYMPK（对称蛋白）。SYMPK 被认为是一种支架因子，因为它与 CPSF 复合物和 CSTF 复合物相互作用。切割刺激因子（CSTF）复合物由三个亚基组成：CSTF1、CSTF2 和 CSTF3，并识别下游元件。切割因子 I（CF I）复合物识别 UGUA 上游元件。CF I 复合物是一个异四聚体，由 NUDT21（CPSF5）的同二聚体和 CPSF6 与 CPSF7 的异二聚体或同源二聚体组成。切割因子 II（CF II）复合物是两个亚基 CLP1 和 PCF11 的异二聚体。CF II 的功能研究尚不充分。有观点认为 CF II 通过与远端 G 丰富序列元件相互作用来识别切割/多聚腺苷酸化底物。poly(A)聚合酶生成 poly(A)尾，也可参与切割。尽管 CPSF 和 poly(A)聚合酶足以进行 AAUAAA 依赖性多聚腺苷酸化，但核 poly(A)-结合蛋白 1（PABPN1）刺激 poly(A)尾延伸，对于合成适当长度的 poly(A)尾至关重要。哺乳动物中存在三种相关的 poly(A)聚合酶：PAPOLA、PAPOLB 和 PAPOLG。PAPOLA（也称为 PAP 或 poly(A)聚合酶 alpha 或 PAPII）被认为是 mRNA 多聚腺苷酸化的经典 poly(A)聚合酶。PAPOLG，通常称为 poly(A)聚合酶 gamma，定位于细胞核，并与 3'加工复合物共免疫沉淀。PAPOLG 在氨基酸水平上与人类 PAPOLA 共享 60%的序列同源性。PAPOLG 表现出真正的 poly(A)聚合酶的基本特性，即对 ATP 的特异性以及 CPSF/AAUAAA 依赖性多聚腺苷酸化活性。催化参数表明其催化效率与 PAPOLA 相似。PAPOLG 和 PAPOLA 具有相似的组织和功能域结构。PAPOLG 在 C 末端含有 U1A 蛋白结合区域，而 PAPOLA 可被 U1A 蛋白抑制。PAPOLG 也可能在小 RNA 的单聚腺苷酸化中发挥作用。PAPOLB（也称为 TPAP 或 poly(A)聚合酶 beta）是一种胞质 poly(A)聚合酶，特异性表达于睾丸。PAPOLB 被认为通过调节转录因子在转录后和翻译后水平上调节生殖细胞形态发生。哺乳动物中还存在另一种核 poly(A)聚合酶 TUT1（也称为 STAR-PAP 或 STPAP），它优先多聚腺苷酸化氧化应激诱导的 pre-mRNA。
英文描述
Signaling by FGFR3 in disease The FGFR3 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically.
Activating mutations in FGFR3 are associated with the development of a range of skeletal dysplasias that result in dwarfism (reviewed in Webster and Donoghue, 1997; Burke et al, 1998; Harada et al, 2009). The most common form of human dwarfism is achondroplasia (ACH), which is caused by mutations G380R and G375C in the transmembrane domain of FGFR3 that are thought to promote ligand-independent dimerization (Rousseau et al, 1994; Shiang et al, 1994; Bellus et al, 1995a) Hypochondroplasia (HCH) is a milder form dwarfism that is the result of mutations in the tyrosine kinase domain of FGFR3 (Bellus et al, 1995b). Two neonatal lethal conditions, thanatophoric dysplasia type I and II (TDI and TDII) are also the result of mutations in FGFR3; TDI arises from a range of mutations that either result in the formation of unpaired cysteine residues in the extracellular region that promote aberrant ligand-independent dimerization or by mutations that introduce stop codons (Rousseau et al, 1995; Rousseau et al, 1996, D'Avis et al,1998). A single mutation, K650E in the second tyrosine kinase domain of FGFR3 is responsible for all identified cases of TDII (Tavormina et al, 1995a, b). Other missense mutations at the same K650 residue give rise to Severe Achondroplasia with Developmental Disorders and Acanthosis Nigricans (SADDAN) syndrome (Tavormina et al, 1999; Bellus et al, 1999). The severity of the phenotype arising from many of the activating FGFR3 mutations has recently been shown to correlate with the extent to which the mutations activate the receptor (Naski et al, 1996; Bellus et al, 2000)
In addition to mutations that cause dwarfism syndromes, a Pro250Arg mutation in the conserved dipeptide between the IgII and IgIII domains has been identified in an atypical craniosynostosis condition (Bellus et al, 1996; Reardon et al, 1997). This mutation, which is paralogous to mutations seen in FGFR1 and 2 in Pfeiffer and Apert Syndrome, respectively, results in an increase in ligand-binding affinity for the receptor (Ibrahimi et al, 2004b).
Of all the FGF receptors, FGFR3 has perhaps the best established link to the development in cancer. 50% of bladder cancers have somatic mutations in the coding sequence of FGFR3; of these, more than half occur in the extracellular region at a single position (S249C) (Cappellen et al, 1999; Naski et al, 1996; di Martino et al, 2009, Sibley et al, 2001). Activating mutations are also seen in the juxta- and trans-membrane domains, as well as in the kinase domain (reviewed in Weshe et al, 2011). As is the case for the other receptors, many of the activating mutations that are seen in FGFR3-related cancers mimic the germline FGFR3 mutations that give rise to autosomal skeletal disorders and include both ligand-dependent and independent mechanisms (reviewed in Webster and Donoghue, 1997; Burke et al, 1998). In addition to activating mutations, the FGFR3 gene is subject to a translocation event in 15% of multiple myelomas (Avet-Loiseau et al, 1998; Chesi et al, 1997). This chromosomal rearrangement puts the FGFR3 gene under the control of the highly active IGH promoter and promotes overexpression and constitutive activation of FGFR3. In a small proportion of multiple myelomas, the translocation event is accompanied by activating mutations in the FGFR3 coding sequence (Chesi et al, 1997).
More recently, a number of fusion proteins of FGFR3 have been identified in various cancers (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; Wu et al, 2013; Wang et al, 2014; Yuan et al, 2014; reviewed in Parker et al, 2014). The most common fusion protein is TACC3, a coiled coil protein involved in mitotic spindle assembly. FGFR3 fusion proteins are constitutively active and appear to contribute to proliferation and tumorigenesis through activation of the ERK and AKT signaling pathways (reviewed in Parker et al, 2014).
Activating mutations in FGFR3 are associated with the development of a range of skeletal dysplasias that result in dwarfism (reviewed in Webster and Donoghue, 1997; Burke et al, 1998; Harada et al, 2009). The most common form of human dwarfism is achondroplasia (ACH), which is caused by mutations G380R and G375C in the transmembrane domain of FGFR3 that are thought to promote ligand-independent dimerization (Rousseau et al, 1994; Shiang et al, 1994; Bellus et al, 1995a) Hypochondroplasia (HCH) is a milder form dwarfism that is the result of mutations in the tyrosine kinase domain of FGFR3 (Bellus et al, 1995b). Two neonatal lethal conditions, thanatophoric dysplasia type I and II (TDI and TDII) are also the result of mutations in FGFR3; TDI arises from a range of mutations that either result in the formation of unpaired cysteine residues in the extracellular region that promote aberrant ligand-independent dimerization or by mutations that introduce stop codons (Rousseau et al, 1995; Rousseau et al, 1996, D'Avis et al,1998). A single mutation, K650E in the second tyrosine kinase domain of FGFR3 is responsible for all identified cases of TDII (Tavormina et al, 1995a, b). Other missense mutations at the same K650 residue give rise to Severe Achondroplasia with Developmental Disorders and Acanthosis Nigricans (SADDAN) syndrome (Tavormina et al, 1999; Bellus et al, 1999). The severity of the phenotype arising from many of the activating FGFR3 mutations has recently been shown to correlate with the extent to which the mutations activate the receptor (Naski et al, 1996; Bellus et al, 2000)
In addition to mutations that cause dwarfism syndromes, a Pro250Arg mutation in the conserved dipeptide between the IgII and IgIII domains has been identified in an atypical craniosynostosis condition (Bellus et al, 1996; Reardon et al, 1997). This mutation, which is paralogous to mutations seen in FGFR1 and 2 in Pfeiffer and Apert Syndrome, respectively, results in an increase in ligand-binding affinity for the receptor (Ibrahimi et al, 2004b).
Of all the FGF receptors, FGFR3 has perhaps the best established link to the development in cancer. 50% of bladder cancers have somatic mutations in the coding sequence of FGFR3; of these, more than half occur in the extracellular region at a single position (S249C) (Cappellen et al, 1999; Naski et al, 1996; di Martino et al, 2009, Sibley et al, 2001). Activating mutations are also seen in the juxta- and trans-membrane domains, as well as in the kinase domain (reviewed in Weshe et al, 2011). As is the case for the other receptors, many of the activating mutations that are seen in FGFR3-related cancers mimic the germline FGFR3 mutations that give rise to autosomal skeletal disorders and include both ligand-dependent and independent mechanisms (reviewed in Webster and Donoghue, 1997; Burke et al, 1998). In addition to activating mutations, the FGFR3 gene is subject to a translocation event in 15% of multiple myelomas (Avet-Loiseau et al, 1998; Chesi et al, 1997). This chromosomal rearrangement puts the FGFR3 gene under the control of the highly active IGH promoter and promotes overexpression and constitutive activation of FGFR3. In a small proportion of multiple myelomas, the translocation event is accompanied by activating mutations in the FGFR3 coding sequence (Chesi et al, 1997).
More recently, a number of fusion proteins of FGFR3 have been identified in various cancers (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; Wu et al, 2013; Wang et al, 2014; Yuan et al, 2014; reviewed in Parker et al, 2014). The most common fusion protein is TACC3, a coiled coil protein involved in mitotic spindle assembly. FGFR3 fusion proteins are constitutively active and appear to contribute to proliferation and tumorigenesis through activation of the ERK and AKT signaling pathways (reviewed in Parker et al, 2014).
所含基因
17 个基因