de Oliveira Guilherme A P, Rangel Luciana P, Costa Danielly C, Silva Jerson L
Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil ; Faculdade de Farmácia, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
Front Oncol. 2015 Apr 29;5:97. doi: 10.3389/fonc.2015.00097. eCollection 2015.
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.
目前对于导致癌症的分子机制的理解，尚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。在过去25年中，已发现100多个癌基因、20 - 30个肿瘤抑制基因以及数百个参与DNA修复和复制的基因在癌症起源中发挥作用。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，通过蛋白激酶的严格调控来实现。磷酸化在真核生物信号传导中起主要作用，因为在我们2%的基因中发现了激酶结构域。激酶控制机制的失调会产生灾难性后果，常常导致功能获得、细胞转化和癌症。c - Abl激酶蛋白是抗癌研究中研究最多的靶点之一，也是药物开发的热点，因为它参与多种实体瘤，是慢性粒细胞白血病的标志。肿瘤抑制因子则具有相反的作用。它们在维持基因组完整性方面的基本作用使其成为DNA的守护者。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，可识别并结合特定的DNA反应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会导致p53磷酸化以及细胞周期停滞、衰老或程序性细胞死亡。p53基因是癌症中最常发生突变的基因。DNA结合结构域中的突变根据取代分别发生在DNA接触位点还是蛋白质核心中，分为I类或II类。与肿瘤相关的p53突变通常导致蛋白质功能丧失，但最近的研究也表明存在功能获得性突变。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有关。在本综述中，我们重点关注了c - Abl和p53蛋白的蛋白质结构和功能的最新见解，这些见解将为我们理解这些错误折叠的肿瘤相关蛋白的功能丧失和获得提供指导。
