CCAR1 and CCAR2 as gene chameleons with antagonistic duality: Preclinical, human translational, and mechanistic basis.
CCAR1 and CCAR2 as gene chameleons with antagonistic duality: Preclinical, human translational, and mechanistic basis.
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DOI：
10.1111/cas.14579
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发表时间：
2020-10
期刊：
影响因子：
5.7
通讯作者：
Dashwood RH
中科院分区：
文献类型：
--
作者：
Johnson GS;Rajendran P;Dashwood RH
细胞周期和凋亡调节因子1（CCAR 1）和细胞周期和凋亡调节因子2（CCAR 2）已成为生理学和病理生理学中的关键参与者，在DNA损伤反应、核受体功能和Wnt信号传导等活动中发挥关键作用。关于CCAR 1和CCAR 2作为肿瘤促进剂或抑制剂的功能双重性存在矛盾的报道，表明CCAR 1和CCAR 2具有基因变色龙的特征。我们在此综述了CCAR 1和CCAR 2的机制，临床前和人类翻译发现，基于来自人类研究的可用RNA和蛋白质表达数据，癌症基因组图谱（TCGA）数据挖掘，基因敲除小鼠模型和基于细胞的测定。多种因素导致CCAR 1和CCAR 2的不同活性，包括组织类型、突变/遗传背景、蛋白质-蛋白质相互作用、通过翻译后修饰的动态调节和可变RNA剪接。在肿瘤促进和抑制的背景下，一系列蛋白质伴侣与CCAR 1和CCAR 2相互作用，包括β-连环蛋白、雄激素受体、p21 Cip 1/Waf 1、肿瘤蛋白p53（p53）、沉默调节蛋白1和组蛋白脱乙酰酶3。癌症中常见的遗传变化，如TP 53突变，也是癌症患者生存结局的关键决定因素。本文旨在为进一步研究CCAR 1和CCAR 2作为代谢、衰老和癌症的潜在主调节因子提供动力。细胞周期和凋亡调节因子1（CCAR 1）和CCAR 2已成为生理学和病理生理学中的关键参与者，在Wnt信号传导、核受体功能、脂肪形成和DNA损伤反应中发挥重要作用。由于蛋白质伴侣的多样性，包括β-连环蛋白、雄激素受体、p21、p53、沉默调节蛋白1和组蛋白脱乙酰酶3，文献报道存在CCAR 1和CCAR 2作为肿瘤促进剂或抑制剂的功能双重性。在癌症中经常发现的遗传变化，如TP 53突变，也是患者生存结果的关键决定因素，并影响CCAR 1和CCAR 2作为代谢、衰老和癌症的主要调节因子的作用。
Cell Cycle and Apoptosis Regulator 1 (CCAR1) and Cell Cycle and Apoptosis Regulator 2 (CCAR2) have emerged as key players in physiology and pathophysiology, with critical roles in the DNA damage response, nuclear receptor function, and Wnt signaling, among other activities. Contradictory reports exist on the functional duality of CCAR1 and CCAR2 as either tumor promoters or suppressors, suggesting that CCAR1 and CCAR2 have the hallmarks of gene chameleons. We review herein the mechanistic, preclinical, and human translational findings for CCAR1 and CCAR2, based on available RNA and protein expression data from human studies, The Cancer Genome Atlas (TCGA) data mining, gene knockout mouse models, and cell‐based assays. Multiple factors contribute to the divergent activities of CCAR1 and CCAR2, including tissue type, mutation/genetic background, protein‐protein interactions, dynamic regulation via posttranslational modifications, and alternative RNA splicing. An array of protein partners interact with CCAR1 and CCAR2 in the context of tumor promotion and suppression, including β‐catenin, androgen receptor, p21Cip1/Waf1, tumor protein p53 (p53), sirtuin 1, and histone deacetylase 3. Genetic changes frequently found in cancer, such as TP53 mutation, also serve as critical determinants of survival outcomes in cancer patients. This review seeks to provide the impetus for further investigation into CCAR1 and CCAR2 as potential master regulators of metabolism, aging, and cancer. Cell cycle and apoptosis regulator 1 (CCAR1) and CCAR2 have emerged as key players in physiology and pathophysiology, with important roles in Wnt signaling, nuclear receptor function, adipogenesis, and the DNA damage response. Due to the diverse array of protein partners, including beta‐catenin, androgen receptor, p21, p53, sirtuin 1, and histone deacetylase 3, literature reports exist on the functional duality of CCAR1 and CCAR2 as either tumor promoters or suppressors. Genetic changes frequently found in cancer, such as TP53 mutation, also serve as critical determinants of patient survival outcomes and impact the roles of CCAR1 and CCAR2 as master regulators of metabolism, aging, and cancer.
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