文章：

癌症中的bHLH-PAS蛋白

bHLH–PAS proteins in cancer

原文发布日期：2013-11-22

DOI: 10.1038/nrc3621

类型: Review Article

开放获取: 否

要点：

1. The basic HLH (helix–loop–helix)–PER–ARNT–SIM (bHLH–PAS) family of transcriptional regulators are characterized by an amino-terminal bHLH domain and PAS domains that are involved in dimerization, DNA binding and signal transduction.
2. The PAS domain is an evolutionarily conserved protein fold, which is often capable of binding to ligands or relaying signals. PAS domains also have important roles in mediating or restricting protein–protein interactions.
3. bHLH–PAS factors have diverse roles, which include sensing and responding to environmental pollutants (through the aryl hydrocarbon receptor (AHR)), hypoxic sensing (through hypoxia-inducible factor 1α (HIF1α) and HIF2α), circadian rhythm formation (through circadian locomotor output cycles kaput (CLOCK), neuronal PAS2 (NPAS2), brain muscle ARNT-like 1 (BMAL1), period circadian protein homologue 1 (PER1) and PER2), transactivation (through nuclear receptor co-activators (NCOAs)) of hormone signalling via nuclear receptors, appetite control (through single-minded homologue 1 (SIM1)), neurogenesis (through SIM1, SIM2 and NPAS3) and synapse formation (through NPAS4).
4. bHLH–PAS proteins, including AHR, HIFs and NCOAs, have important links with cancer and cancer metabolism. This has been shown using many mouse models and expression studies of human cancers.
5. Crosstalk between various bHLH–PAS family members can occur directly through competition for common partner proteins or DNA elements (for example, between HIF and SIM). This might promote tumour survival when these factors are misregulated.
6. Metabolites (kynurenine and NAD⁺) and oncometabolites (benzo[a]pyrene derivatives and (R)-2-hydroxyglutarate) can modulate or mediate the activity of several bHLH–PAS proteins (including the AHR, the HIFs and circadian rhythm factors CLOCK, BMAL1 and PER2) that have direct relevance to cancer.
7. bHLH–PAS structural resolution and high-throughput activity screens have facilitated the identification of small-molecule modifiers of bHLH–PAS factor activities, which may be useful as cancer therapeutics.

要点翻译：

1. 基本的螺旋-环-螺旋（bHLH）-PER-ARNT-SIM（bHLH-PAS）转录调控因子家族的特征是：其氨基末端具有bHLH结构域和PAS结构域，这些结构域参与二聚化、DNA结合及信号转导。
2. PAS结构域是一种进化上保守的蛋白质折叠形式，通常能够结合配体或传递信号。该结构域在介导或限制蛋白质-蛋白质相互作用中也具有重要作用。
3. bHLH-PAS因子功能多样，包括：通过芳香烃受体（AHR）感知并响应环境污染物；通过缺氧诱导因子1α（HIF1α）和HIF2α进行缺氧感知；通过昼夜运动输出周期蛋白（CLOCK）、神经元PAS2（NPAS2）、脑肌ARNT样蛋白1（BMAL1）、周期昼夜蛋白同源物1（PER1）和PER2参与昼夜节律形成；通过核受体共激活因子（NCOA）介导核受体激素信号的转录激活；通过单意同源物1（SIM1）调控食欲；通过SIM1、SIM2和NPAS3参与神经发生；通过NPAS4调控突触形成。
4. bHLH-PAS蛋白（包括AHR、HIF和NCOA）与癌症及癌症代谢存在重要关联。多项小鼠模型和人类癌症表达研究已证实这一点。
5. 不同bHLH-PAS家族成员可通过竞争共同伴侣蛋白或DNA元件（例如HIF与SIM之间）直接发生交叉对话。当这些因子调控异常时，这种相互作用可能促进肿瘤存活。
6. 代谢物（犬尿氨酸和NAD+）和癌代谢物（苯并[a]芘衍生物与(R)-2-羟基戊二酸）可调节或介导多种与癌症直接相关的bHLH-PAS蛋白（包括AHR、HIF、昼夜节律因子CLOCK、BMAL1和PER2）的活性。
7. bHLH-PAS结构解析和高通量活性筛选促进了bHLH-PAS因子小分子调节剂的发现，这些调节剂可能具有作为癌症治疗药物的潜力。

英文摘要：

Mammalian basic HLH (helix–loop–helix)–PER–ARNT–SIM (bHLH–PAS) proteins are heterodimeric transcription factors that sense and respond to environmental signals (such as pollutants) or to physiological signals (for example, hypoxia and circadian rhythms) through their two PAS domains. PAS domains form a generic three-dimensional fold, which commonly contains an internal cavity capable of small-molecule binding and outer surfaces adept at protein–protein interactions. These proteins are important in several pro-tumour and antitumour pathways and their activities can be modulated by both natural metabolites and oncometabolites. Recently determined structures and successful small-molecule screening programmes are now providing new opportunities to discover selective agonists and antagonists directed against this multitasking family of transcription factors.

摘要翻译： 

哺乳动物碱性HLH（螺旋-环-螺旋）-PER-ARNT-SIM（bHLH-PAS）蛋白是异源二聚体转录因子，通过其两个PAS结构域感知并响应环境信号（如污染物）或生理信号（如缺氧和昼夜节律）。PAS结构域形成一种通用的三维折叠，通常包含一个可结合小分子的内腔，以及擅长蛋白-蛋白相互作用的外表面。这些蛋白在多种促瘤和抗肿瘤通路中发挥重要作用，其活性可被天然代谢物和肿瘤代谢物共同调控。最新解析的结构以及成功的小分子筛选项目，正为发现针对这一多任务转录因子家族的选择性激动剂和拮抗剂提供新机遇。

原文链接：

bHLH–PAS proteins in cancer