Misfolding, Aggregation, and Disordered Segments in c-Abl and p53 in Human Cancer.
Misfolding, Aggregation, and Disordered Segments in c-Abl and p53 in Human Cancer.
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DOI：
10.3389/fonc.2015.00097
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发表时间：
2015
影响因子：
4.7
通讯作者：
Silva JL
中科院分区：
文献类型：
--
作者：
de Oliveira GA;Rangel LP;Costa DC;Silva JL
目前对导致癌症的分子机制的理解不足以解释与肿瘤发生过程相关的蛋白质功能的丧失或获得。其中，超过100个癌基因，20-30个肿瘤抑制基因和数百个参与DNA修复和复制的基因在过去25年中被发现在癌症的起源中发挥作用。丝氨酸、苏氨酸或酪氨酸残基的磷酸化是细胞生长和发育中的关键步骤，并且通过蛋白激酶的严格调节来实现。磷酸化在真核生物信号转导中起着重要作用，因为在我们的基因中发现了2%的激酶结构域。激酶控制机制的失调具有灾难性的后果，通常导致功能的获得、细胞转化和癌症。c-Abl激酶蛋白是抗癌斗争中研究最多的靶标之一，也是药物开发的热点，因为它参与了几种实体瘤，是慢性髓细胞性白血病的标志。肿瘤抑制剂具有相反的效果。它们在维持基因组完整性方面的基本作用使它们成为DNA的监护人。在肿瘤抑制因子中，p53是研究最多的。p53蛋白已被证明是一种转录因子，其识别并结合特异性DNA应答元件并激活基因转录。电离辐射或其他诱变事件引发的应激导致p53磷酸化和细胞周期停滞、衰老或程序性细胞死亡。p53基因是癌症中最常见的突变基因。DNA结合结构域中的突变分别根据取代是发生在DNA接触位点还是发生在蛋白质核心而被分类为I类或II类。肿瘤相关的p53突变通常导致蛋白质功能的丧失，但最近的研究也表明功能获得性突变。突变型p53的朊病毒样聚集与功能丧失、显性负性和功能获得效应相关。在目前的审查中，我们专注于最新的见解c-Abl和p53蛋白的蛋白质结构和功能，这将为我们提供指导，以了解这些错误折叠的肿瘤相关蛋白的功能的丧失和获得。
The current understanding of the molecular mechanisms that lead to cancer is not sufficient to explain the loss or gain of function in proteins related to tumorigenic processes. Among them, more than 100 oncogenes, 20–30 tumor-suppressor genes, and hundreds of genes participating in DNA repair and replication have been found to play a role in the origins of cancer over the last 25 years. The phosphorylation of serine, threonine, or tyrosine residues is a critical step in cellular growth and development and is achieved through the tight regulation of protein kinases. Phosphorylation plays a major role in eukaryotic signaling as kinase domains are found in 2% of our genes. The deregulation of kinase control mechanisms has disastrous consequences, often leading to gains of function, cell transformation, and cancer. The c-Abl kinase protein is one of the most studied targets in the fight against cancer and is a hotspot for drug development because it participates in several solid tumors and is the hallmark of chronic myelogenous leukemia. Tumor suppressors have the opposite effects. Their fundamental role in the maintenance of genomic integrity has awarded them a role as the guardians of DNA. Among the tumor suppressors, p53 is the most studied. The p53 protein has been shown to be a transcription factor that recognizes and binds to specific DNA response elements and activates gene transcription. Stress triggered by ionizing radiation or other mutagenic events leads to p53 phosphorylation and cell-cycle arrest, senescence, or programed cell death. The p53 gene is the most frequently mutated gene in cancer. Mutations in the DNA-binding domain are classified as class I or class II depending on whether substitutions occur in the DNA contact sites or in the protein core, respectively. Tumor-associated p53 mutations often lead to the loss of protein function, but recent investigations have also indicated gain-of-function mutations. The prion-like aggregation of mutant p53 is associated with loss-of-function, dominant-negative, and gain-of-function effects. In the current review, we focused on the most recent insights into the protein structure and function of the c-Abl and p53 proteins that will provide us guidance to understand the loss and gain of function of these misfolded tumor-associated proteins.
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影响因子：
11.4
作者：
Blagosklonny, MV;Fojo, T;Neckers, LM
通讯作者：
Neckers, LM
p53核心结构域是低pH值的熔融球体：部分展开的结构的功能含义。
DOI：
10.1074/jbc.m109.075861
发表时间：
2010-01-22
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bom AP;Freitas MS;Moreira FS;Ferraz D;Sanches D;Gomes AM;Valente AP;Cordeiro Y;Silva JL
通讯作者：
Silva JL
DOI：
10.1038/nsb0901-730
发表时间：
2001-09-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Ahn, J;Prives, C
通讯作者：
Prives, C
影响因子：
4.8
作者：
Brasher, BB;Van Etten, RA
通讯作者：
Van Etten, RA
影响因子：
30.8
作者：
Barilá, D;Superti-Furga, G
通讯作者：
Superti-Furga, G