Scrib复合物和Par复合物——从细胞极性调控到肿瘤发生

上皮细胞和组织发生癌变时,通常会伴随细胞极性丧失和组织结构紊乱的现象。然而,极性丧失对肿瘤发生的贡献却一直存在争论。随着控制上皮细胞顶-底极性分子机制的逐步揭示,人们发现,这一极性机制与肿瘤发生联系紧密。上皮细胞顶-底极性的确立主要依赖于顶膜区Par复合物与底侧膜区Scrib复合物之间的拮抗。当Scrib复合物活性下调或Par复合物活性上调时,两复合物间的这种相互制约的平衡就会被打破,从而导致肿瘤发生。本文主要综述Scrib复合物和Par复合物如何参与上皮细胞顶-底极性的建立,以及两者间的互作与肿瘤发生的关系。     

细胞极性蛋白复合物PAR/aPKC的研究进展

不对称细胞分裂是动物发育过程中用以调控细胞分化的一种进化上保守的基本模式。极性的祖细胞通过不对称分裂产生两个不同命运的子细胞,这一过程涉及细胞命运决定因子的不对称分布、纺锤体的旋转定位等,而这些过程都必须依赖特定细胞极性的存在才能得以正常进行。简要综述了高度保守的蛋白复合物PAR／aPKC在细胞极性建立和维持中的重要作用,以及它如何调控纺锤体定位和命运决定因子不对称分配,并讨论了在该领域的一些新发现和研究进展。     

上皮细胞极性的建立和维持

细胞极性是生物中广泛存在的一个特征。上皮细胞是构成表皮、腺体、气管和消化道等组织的一类特化细胞。上皮细胞通常沿顶端-基底端轴向发生极化,形成紧密连接、粘附连接等胞间结构,同时细胞膜、细胞骨架和中心体、内膜系统、细胞核等也发生不对称分布,使细胞能行使分泌、吸收和屏障等多种重要的生理功能。有许多分子参与上皮细胞极性的建立和维持,其中最主要的是3个极性复合物,即Par-aPKC复合物,Scribble(Lg1-Dlg-Scrib)复合物和Crb(Crb-Pals-PATJ)复合物,三者共同配合发挥功能。     

肠道细菌与癌症关系的研究进展

人类与大量细菌、真菌和病毒共同生存、进化了数百万年,已初步从分子水平了解了极少数特定细菌与癌症之间的病原学关系。随着二代测序技术的逐步成熟,将进一步推动对微生物尤其是肠道细菌的深入研究,从而解析细菌与癌症之间的分类学和代谢组学关系。本文主要综述了肿瘤组织及其周边微环境中的细菌以直接和（或）免疫调节方式介导肿瘤发生发展的机制。     

蛋白质-核酸复合物界面氨基酸与核苷酸偏好性分析

蛋白质-核酸相互作用机制到目前还不是很清楚,尤其是蛋白质与RNA的相互作用。目前,可得到的蛋白质-核酸复合物结构数据不断增多,作者收集了Protein Data Bank数据库中所有的蛋白质-核酸复合物结构数据,对复合物中结合残基和结合核苷酸的偏好性进行了统计分析。发现：1）不同功能的蛋白质-核酸复合物间的结合残基数量存在显著差异;2）在蛋白 质-DNA和蛋白质-RNA复合物界面,碱性氨基酸都是最受欢迎的;3）氨基酸的极性大小及方向在决定它是否与RNA分子进行结合时起到重要的作用,同时发现氨基酸侧链形成的空间位阻会影响氨基酸残基与RNA分子的相互作用;4）随着定义结合残基距离阈值的增大,其氨基酸使用的特异性降低,而受欢迎与不受欢迎的氨基酸种类均没有变化。     

蛋白质与极性配体复合物的绝对结合自由能计算

介绍了用分子动力学模拟与热力学积分法相结合,模拟蛋白质与配体的绝对结合自由能的方法.通过分子转换法,使蛋白质分子（包括水分子）与配体小分子之间的相互作用逐渐减弱 （或增强）至完全消失（或完全出现）. 运用体约束方法,计算了配体与受体结合后平动、转动自由度的丧失即熵效应所引起的自由能变化.以胰蛋白酶双突变体（D189G/G226D）与极性配体苯甲脒为例,研究了蛋白质活性部位与极性配体的相互作用对结合自由能的影响,该复合物绝对结合自由能的模拟结果(－15.5 kJ/mol)与实验值(－10.5 kJ/mol)相近.     

蛋白质折叠速率与其氨基酸序列极性的关系

以大肠杆菌60个蛋白酶以及几种常见病毒（SARS病毒、艾滋病病毒、丙型肝炎病毒及乙型肝炎病毒）各蛋白质序列中的所有α-螺旋和β-折叠片段为研究对象,计算了各片段的折叠速率和平均极性,分别在各物种的α-螺旋和β-折叠两类二级结构片段中分析了二者的相关性。得到结论：不论是大肠杆菌中的蛋白酶还是病毒蛋白,其中的两类氨基酸片段的平均极性与折叠速率都是极显著相关的：对于所有的α片段,二者呈线性正相关,而对于所有的β片段,二者成线性负相关。结果证实了在蛋白质折叠中,氨基酸的极性起着重要的作用。     

乳制品与癌症患病风险关系的研究进展

综述现有的流行病学研究、实验室研究和Meta分析,并分析乳制品及其中各种成分对癌症发病风险的影响。目前的Meta分析和WCRF/AICR报告得出,乳制品和乳腺癌、卵巢癌的发病率无关联,而过量乳制品是前列腺癌的危险因素,适量乳制品对结肠癌可能有保护作用;乳制品中增加癌症风险的成分可能是饱和脂肪、激素和环境污染物,起保护作用的一般为维生素D、乳糖、乳酸菌和某些不饱和脂肪酸。因此,按照《中国居民膳食指南（2016）》的推荐量（300g/d）摄入乳制品是安全并有益的;国家也应加强对乳制品行业的管制,防止过量的激素和污染物对民众健康和行业形象产生不良影响。     

光合生物色素-蛋白质复合物的多样性

通过对近年来放氧型光合生物有关研究结果的概括分析,提出放氧型光合生物光系统Ⅰ、光系统Ⅱ及捕光色素-蛋白质复合物具有多样性,并根据其PSⅠ复合物的77 K荧光发射特点,指出放氧型光合生物光合系统中的能量传递方式也可能存在多样性.     

上皮极性蛋白的研究进展

极性蛋白（polarity protein）是指具有识别功能并且能够调节细胞极性的一类蛋白质,它们在许多生理和病理过程如细胞增殖、细胞凋亡、细胞迁移、损伤修复、上皮－间充质转化（epithelial—mesenchymal transition,EMT）中具有重要作用,也在肿瘤的发生和发展过程中起到重要作用。本文拟从上述几个方面对上皮相关极性蛋白的生物学功能做以综述,以期为疾病诊断和治疗提供新的思路。     

Epithelial Cell Polarity Determinant CRB3 in Cancer Development

Cell polarity, which is defined as asymmetry in cell shape, organelle distribution and cell function, is essential in numerous biological processes, including cell growth, cell migration and invasion, molecular transport, and cell fate. Epithelial cell polarity is mainly regulated by three conserved polarity protein complexes, the Crumbs (CRB) complex, partitioning defective (PAR) complex and Scribble (SCRIB) complex. Research evidence has indicated that dysregulation of cell polarity proteins may play an important role in cancer development. Crumbs homolog 3 (CRB3), a member of the CRB complex, may act as a cancer suppressor in mouse kidney epithelium and mouse mammary epithelium. In this review, we focus on the current data available on the roles of CRB3 in cancer development.     

Reinterpreting polarity and cancer: The changing landscape from tumor suppression to tumor promotion

Cell polarity is a fundamental property used to generate asymmetry and structure in all cells. Cancer is associated with loss of cell and tissue structure. While observations made in model system such as Drosophila, identify polarity regulators as tumor suppressors that cause inappropriate cell division, studies in mammalian epithelia do not always support such a causative contribution. Our analysis of published cancer dataset shows that many polarity genes, including PARD6B, SCRIB, PRKCI, DLG1, DLG2, DLG5 and LLGL2, are frequently amplified in multiple cancers raising the possibility that mammalian epithelia may have evolved to use polarity proteins in multiple ways where they may have tumor promoting functions. In this review, we reinterpret the published results and propose a modified perspective for the role of polarity regulators in cancer biology. In addition to the traditional form of cell polarity, which is involved establishment of maintenance of normal cell structure and asymmetry, we propose that some mammalian polarity proteins also regulate subcellular polarity (intracellular asymmetry), which can improve cellular fitness to carry out functions such as proliferation, apoptosis, stress adaptation, stemness and organelle biology. Here, we define subcellular polarity and discuss evidence that supports a role for subcellular polarity in biology.     

PAR3beta,a novel homologue of the cell polarity protein PAR3, localizes to tight junctions

The cell polarity protein PAR3, conserved from the nematode to the vertebrate, forms a complex with PAR6 and atypical protein kinase C (aPKC), and the protein complex occurs at the tight junctions in mammalian epithelial cells. Here we have cloned human cDNA for a novel PAR3 homologue, designated PAR3beta, whose messages are present in a variety of tissues and most abundantly expressed in the adult and fetal kidneys. The encoded protein of 1,205 amino acids contains a region homologous to the aPKC-binding domain of PAR3alpha, another human homologue previously identified, and three PDZ domains; the first PDZ domain of PAR3alpha is considered to interact with PAR6. Unexpectedly, in contrast to other PAR3s found in various species, PAR3beta is incapable of binding to any isotypes of PAR6 or aPKC. Nevertheless PAR3beta, expressed intrinsically or extrinsically, localizes to the tight junctions, indicating that the localization does not require the ternary complex formation.     

C. elegans Brat homologs regulate PAR protein-dependent polarity and asymmetric cell division

The evolutionary conserved PAR proteins control polarization and asymmetric division in many organisms. Recent work in Caenorhabditis elegans demonstrated that nos-3 and fbf-1/2 can suppress par-2(it5ts) lethality, suggesting that they participate in cell polarity by regulating the function of the anterior PAR-3/PAR-6/PKC-3 proteins. In Drosophila embryos, Nanos and Pumilio are homologous to NOS-3 and FBF-1/2 respectively and control cell polarity by forming a complex with the tumor suppressor Brat to inhibit Hunchback mRNA translation. In this study, we investigated the possibility that Brat could control cell polarity and asymmetric cell division in C. elegans. We found that disrupting four of the five C. elegans Brat homologs (Cebrats) individually results in suppression of par-2(it5ts) lethality, indicating that these genes are involved in embryonic polarity. Two of the Cebrats, ncl-1 and nhl-2, partially restore the localization of PAR proteins at the cortex. While mutations in the four Cebrat genes do not severely impair polarity, they display polarity-associated defects. Surprisingly, these defects are absent from nos-3 mutants. Similarly, while nos-3 controls PAR-6 protein levels, this is not the case for any of the Cebrats. Our results, together with results from Drosophila, indicate that Brat family members function in generating cellular asymmetries and suggest that, in contrast to Drosophila embryos, the C. elegans homologs of Brat and Nanos could participate in embryonic polarity via distinct mechanisms.     

PAR-dependent and geometry-dependent mechanisms of spindle positioning

During intrinsically asymmetric division, the spindle is oriented onto a polarized axis specified by a group of conserved PAR proteins. Extrinsic geometric asymmetry generated by cell shape also affects spindle orientation in some systems, but how intrinsic and extrinsic mechanisms coexist without interfering with each other is unknown. In some asymmetrically dividing cells of the wild-type Caenorhabditis elegans embryo, nuclear rotation directed toward the anterior cortex orients the forming spindle. We find that in such cells, a PAR-dependent mechanism dominates and causes rotation onto the polarized axis, regardless of cell shape. However, when geometric asymmetry is removed, free nuclear rotation in the center of the cell is observed, indicating that the anterior-directed nature of rotation in unaltered embryos is an effect of cell shape. This free rotation is inconsistent with the prevailing model for nuclear rotation, the specialized cortical site model. In contrast, in par-3 mutant embryos, a geometry-dependent mechanism becomes active and causes directed nuclear rotation. These results lead to the model that in wild-type embryos both PAR-3 and PAR-2 are essential for nuclear rotation in asymmetrically dividing cells, but that PAR-3 inhibits geometry-dependent rotation in nonpolarized cells, thus preventing cell shape from interfering with spindle orientation.     

PAR-6 levels are regulated by NOS-3 in a CUL-2 dependent manner in Caenorhabditiselegans

The PAR proteins have an essential and conserved function in establishing polarity in many cell types and organisms. However, their key upstream regulators remain to be identified. In C. elegans, regulators of the PAR proteins can be identified by their ability to suppress the lethality of par-2 mutant embryos. Here we show that a nos-3 loss of function mutant suppresses the lethality of par-2 mutants by regulating PAR-6 protein levels. The suppression requires the activity of the sex determination genes fem-1/2/3 and of the cullin cul-2. FEM-1 is a substrate-specific adaptor for a CUL-2-based ubiquitin ligase (CBC^FEM-1). Interestingly, we find that CUL-2 is required for the regulation of PAR-6 levels and that PAR-6 physically interacts with FEM-1. Our data strongly suggest that PAR-6 levels are regulated by the CBC^FEM-1 ubiquitin ligase thereby uncovering a novel role for the FEM proteins and cullin-dependent degradation in regulating PAR proteins and polarity processes.     

PAR‐3 controls endothelial planar polarity and vascular inflammation under laminar flow

Impaired cell polarity is a hallmark of diseased tissue. In the cardiovascular system, laminar blood flow induces endothelial planar cell polarity, represented by elongated cell shape and asymmetric distribution of intracellular organelles along the axis of blood flow. Disrupted endothelial planar polarity is considered to be pro‐inflammatory, suggesting that the establishment of endothelial polarity elicits an anti‐inflammatory response. However, a causative relationship between polarity and inflammatory responses has not been firmly established. Here, we find that a cell polarity protein, PAR‐3, is an essential gatekeeper of GSK3β activity in response to laminar blood flow. We show that flow‐induced spatial distribution of PAR‐3/aPKCλ and aPKCλ/GSK3β complexes controls local GSK3β activity and thereby regulates endothelial planar polarity. The spatial information for GSK3β activation is essential for flow‐dependent polarity to the flow axis, but is not necessary for flow‐induced anti‐inflammatory response. Our results shed light on a novel relationship between endothelial polarity and vascular homeostasis highlighting avenues for novel therapeutic strategies.