FOXO 蛋白的修饰与细胞凋亡和癌变

Fox 蛋白家族是 2000 年才发布统一命名的蛋白质家族 . 由于其在生物体内所起的重要作用,已迅速成为生命科学研究的热点 . 目前,已经发现其家族成员有 100 多种,其中, FOXO 亚家族在动物细胞的凋亡中起重要作用 . 细胞凋亡与动物的长寿、繁殖、代谢、肿瘤发生及免疫有重要关系,对 Forkhead (Fox) 蛋白分子的命名进行了回顾、对其分类与结构特征进行了总结,并重点对 FOXO 的化学修饰、活性调节及其在细胞凋亡和肿瘤发生中的作用进行了综述 .     

Identification and characterization of members of the FKHR (FOX O) subclass of winged-helix transcription factors in the mouse

Genetic alterations of FKHR (FOXO1), AF6q21 (FOXO2), and AFX (FOXO4), closely related members of the forkhead family of DNA binding proteins, in human cancers has suggested they play a role in the regulation of cellular differentiation or proliferation. In order to elucidate the function of this gene subfamily during mammalian development, we have identified and characterized three novel mouse genes; Fkhr1 (Foxo1), Fkhr2 (Foxo3), and Afxh (Foxo4), which are closely related to the human FKHR (Foxo1), AF6q21 (FOXO2), and AFX (FOXO4) genes, respectively. The genes are each expressed both during development and in the adult with distinct patterns ranging from ubiquitous [Fkhr2 (Foxo3)] to tissue-specific [Afxh (Foxo4)]. Selection of high-affinity DNA-binding sites from a pool of degenerate oligonucleotides demonstrated that the proteins encoded by these genes recognize a core sequence [(T/A) (A/T) A A C A] similar to that recognized by other forkhead domain-containing proteins. We have also identified additional FKHR-related genes expressed during development in both the chick and zebrafish. Further characterization will provide insight into the roles of members of the FKHR subfamily of forkhead-related genes during both normal and neoplastic development.     

The roles of FOX proteins in virus-associated cancers

Forkhead box (FOX) proteins play a crucial role in regulating the expression of genes involved in multiple biological processes, such as metabolism, development, differentiation, proliferation, apoptosis, migration, invasion, and longevity. Deregulation of FOX proteins is commonly associated with cancer initiation, progression, and chemotherapeutic drug resistance in many human tumors. FOX proteins deregulate through genetic events and the perturbation of posttranslational modification. The purpose of the present review is to describe the deregulation of FOX proteins by oncoviruses. Oncoviruses utilize various mechanisms to deregulate FOX proteins, including alterations in posttranslational modifications, cellular localization independently of posttranslational modifications, virus-encoded miRNAs, activation or suppression of a series of cell signaling pathways. This deregulation can affect proliferation, metastasis, chemotherapy resistance, and immunosuppression in virus-induced cancers and help to chronic viral infection, development of gluconeogenic responses, and inflammation. Since the PI3K/Akt/mTOR signaling pathway is the upstream FOXO, suppressing it can cause FOXO function to return, and this can be one of the reasons for patients to recover from the infection of the viruses used to treat these inhibitors. Hence, FOX proteins could serve as prognosis markers and target therapy specifically in cancers caused by oncoviruses.     

Variations on the topic of the "histone code"

Histones are the fundamental structural proteins intimately associated with eukaryotic DNA to form a highly ordered and condensed nucleoproteic complex termed chromatin. They are the targets of various posttranslational modifications including acetylation, methylation, phosphorylation and ubiquitination that modulate the structure/function of chromatin. The combinatorial nature of histone modifications is hypothesized to define a "histone code" that considerably extends the information potential of the genetic code, giving rise to epigenetic information. Moreover, most core histones consist of several nonallelic variants that can mark specific loci and could play an important role in establishment and maintenance of epigenetic memory. Here we will briefly present our current knowledge about histone posttranslational modifications and their implications in the regulation of epigenetic information. We will next describe core histone variants, insisting on their mode of incorporation into chromatin to discuss their epigenetic function and inheritance.     

The solution structure of the forkhead box‐O DNA binding domain of Brugia malayi DAF‐16a

Brugia malayi is a parasitic nematode that causes lymphatic filariasis in humans. Here the solution structure of the forkhead DNA binding domain of Brugia malayi DAF‐16a, a putative ortholog of Caenorhabditis elegans DAF‐16, is reported. It is believed to be the first structure of a forkhead or winged helix domain from an invertebrate. C. elegans DAF‐16 is involved in the insulin/IGF‐I signaling pathway and helps control metabolism, longevity, and development. Conservation of sequence and structure with human FOXO proteins suggests that B. malayi DAF‐16a is a member of the FOXO family of forkhead proteins. Proteins 2014; 82:3490–3496. © 2014 Wiley Periodicals, Inc.     

Structures and interactions of the core histone tail domains

The core histone tail domains are "master control switches" that help define the structural and functional characteristics of chromatin at many levels. The tails modulate DNA accessibility within the nucleosome, are essential for stable folding of oligonucleosome arrays into condensed chromatin fibers, and are important for fiber-fiber interactions involved in higher order structures. Many nuclear signaling pathways impinge upon the tail domains, resulting in posttranslational modifications that are likely to alter the charge, structure, and/or interactions of the core histone tails or to serve as targets for the binding of ancillary proteins or other enzymatic functions. However, currently we have only a marginal understanding of the molecular details of core histone tail conformations and contacts. Here we review data related to the structures and interactions of the core histone tail domains and how these domains and posttranslational modifications therein may define the structure and function of chromatin.