锌α2糖蛋白生物学功能

锌α2糖蛋白(zinc alpha-2 glycoprotein,ZAG)是一种42 kD可溶性蛋白,广泛存在于人体液中.自从ZAG被发现以来,有许多关于其结构及功能的报道.最初ZAG被认为与生殖及脂代谢有关,后又发现ZAG具有载体蛋白、核糖核酸酶的活性等功能.ZAG也参与免疫控制、细胞黏着、调节黑色素生成等.近年来,多项研究表明,ZAG与促进骨骼肌合成、抑制肿瘤细胞增殖、诊断早期癌症、抗糖尿病有关.本文从ZAG分子结构出发,对ZAG生物学功能的研究进展进行综述.     

脂肪细胞因子锌α 2-糖蛋白的研究进展

锌α 2-糖蛋白（ZAG）是一种广泛存在于人体内的可溶性糖蛋白,是Ι类主要组织相容性复合物（MHC-Ι）家族中的一员。ZAG被认为是不同类型癌可能的生物标志物,由于它的氨基酸序列与脂质动员因子（LMF）高度同源,因此它被认为是一个新的脂肪因子。它的表达受多种因素调控,在人体内能够发挥重要的功能。ZAG刺激脂肪细胞的脂质分解,并导致一些高分化癌症中脂肪的大量损失。本文主要从ZAG的基因结构、分布和功能等方面进行论述。     

Crystallographic studies of ligand binding by Zn-alpha2-glycoprotein

Zn-alpha2-glycoprotein (ZAG) is a 41 kDa soluble protein that is present in most bodily fluids. The previously reported 2.8 A crystal structure of ZAG isolated from human serum demonstrated the structural similarity between ZAG and class I major histocompatibility complex (MHC) molecules and revealed a non-peptidic ligand in the ZAG counterpart of the MHC peptide-binding groove. Here we present crystallographic studies to explore further the nature of the non-peptidic ligand in the ZAG groove. Comparison of the structures of several forms of recombinant ZAG, including a 1.95 A structure derived from ZAG expressed in insect cells, suggests that the non-peptidic ligand in the current structures and in the structure of serum ZAG is a polyethylene glycol (PEG), which is present in the crystallization conditions used. Further support for PEG binding in the ZAG groove is provided by the finding that PEG displaces a fluorophore-tagged fatty acid from the ZAG binding site. From these results we hypothesize that our purified forms of ZAG do not contain a bound endogenous ligand, but that the ZAG groove is capable of binding hydrophobic molecules, which may relate to its function.     

Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed and secreted by human (SGBS) adipocytes

Zinc-alpha2-glycoprotein (ZAG), a lipid mobilizing factor, is expressed in mouse adipose tissue and is markedly upregulated in mice with cancer cachexia. We have explored whether ZAG is expressed and secreted by human adipocytes, using SGBS cells, and examined the regulation of ZAG expression. ZAG mRNA was detected by RT-PCR in mature human adipocytes and in SGBS cells post-, but not pre-, differentiation to adipocytes. Relative ZAG mRNA levels increased rapidly after differentiation of SGBS cells, peaking at day 8 post-induction. ZAG protein was evident in differentiated adipocytes (by day 3) and also detected in the culture medium (by day 6) post-induction. The PPARgamma agonist rosiglitazone induced a 3-fold increase in ZAG mRNA level, while TNF-alpha led to a 4-fold decrease. Human adipocytes express and secrete ZAG, with ZAG expression being regulated particularly through TNF-alpha and the PPARgamma nuclear receptor. ZAG is a novel adipokine, which may be involved in the local regulation of adipose tissue function.     

A molecular semiotic view of biology. Interferon and 'homeokine' as symbols.

A term "homeokine" was introduced as a generic name covering cytokines and protein hormones which serve the purpose of intercellular communication within the animal body for homeostasis and ontogenetic development. The homeokine system, in its complex way of functioning, seems to be analogous to another communication system, human language. Individual homeokine molecules are likened to words; they have meanings and are viewed as symbols, representing those conditions or events inside and outside the body which are relevant to homeostasis. Extending this view, any protein and other molecule can be considered to take on the character of sign, when integrated into a purposive system of higher hierarchy, because the molecule then represents a meaning relative to the system as a whole that is lacking in the isolated state. Living systems with their biological macromolecules as semantic units are constructed upon the principle of double articulation, just like human languages with words as the semantic units. The structure and function of a molecule (of protein and any other substance) are associated with each other, with various degrees of arbitrariness, as are the expression and the content of a sign in general. Namely the activities or the sign functions of biological molecules are determined by the organized system they belong to, and not vice versa.     

CIAPIN1基因与肿瘤

细胞因子诱导的凋亡抑制因子1(cytokine induced apoptosis inhibitor1,CIAPIN1)是最新发现的一个细胞因子依赖性抗凋亡分子,并已经被证实是独立于Bcl家族、胱天蛋白酶(caspase)家族等之外的Ras信号转导通路中的另一个调节分子。CIAPIN1广泛分布于胎儿和成人的正常组织中,特别在分化型组织和活性代谢组织中具有很高的表达水平,但是在某些癌症发生时表达受到抑制。通过基因转染、RNA干扰等技术手段研究CIAPIN1与肿瘤发生、发展的关联,揭示了CIAPIN1表达水平的改变与肿瘤进展具有相关性,CIAPIN1有望成为一个新的肿瘤治疗靶分子。     

A characterization of the MADS-box gene family in maize

Studies on distantly related dicot plant species have identified homeotic genes that specify floral meristem identity and determine the fate of floral organ primordia. Most of these genes belong to a family characterized by the presence of a structural motif, the MADS-box, which encodes a protein domain with DNA-binding properties. As part of an effort to understand how such genes may have been recruited during the evolution of flowers with different organ types such as those found in maize, two members of this gene family in maize, ZAG1 and ZAG2, have been characterized previously. Here, the isolation and characterization of four new members of this gene family, designated ZAP1, ZAG3, ZAG4 and ZAG5, are described and the genetic map position of these and 28 additional maize MADS-box genes is determined. The first new member of this family appears to be the Zea mays ortholog of the floral homeotic gene APETALA1 (AP1) and has been designated ZAP1. One of these genes, ZAG4, is unusual in that its deduced protein sequence includes the MADS domain but lacks the K-domain characteristically present in this family of genes. In addition, its copy number and expression varies among different inbreds. A large number of maize MADS-box genes map to duplicated regions of the genome, including one pair characterized here, ZAG3 and ZAG5. These data underscore the complexity of this gene family in maize, and provide the basis for further studies into the regulation of floral organ morphogenesis among the grasses.     

Identification and molecular characterization of ZAG1, the maize homolog of the Arabidopsis floral homeotic gene AGAMOUS.

Recent genetic and molecular studies in Arabidopsis and Antirrhinum suggest that mechanisms controlling floral development are well conserved among dicotyledonous species. To assess whether similar mechanisms also operate in more distantly related monocotyledonous species, we have begun to clone homologs of Arabidopsis floral genes from maize. Here we report the characterization of two genes, designated ZAG1 and ZAG2 (for Zea AG), that were cloned from a maize inflorescence cDNA library by low stringency hybridization with the AGAMOUS (AG) cDNA from Arabidopsis. ZAG1 encodes a putative polypeptide of 286 amino acids having 61% identity with the AGAMOUS (AG) protein. Through a stretch of 56 amino acids, constituting the MADS domain, the two proteins are identical except for two conservative amino acid substitutions. The ZAG2 protein is less similar to AG, with 49% identity overall and substantially less similarity than ZAG1 outside the well-conserved MADS domain. Like AG, ZAG1 RNA accumulates early in stamen and carpel primordia. In contrast, ZAG2 expression begins later and is restricted to developing carpels. Hybridization to genomic DNA with the full-length ZAG1 cDNA under moderately stringent conditions indicated the presence of a large family of related genes. Mapping data using maize recombinant inbreds placed ZAG1 and ZAG2 near two loci that are known to affect maize flower development, Polytypic ear (Pt) and Tassel seed4 (Ts4), respectively. The ZAG1 protein from in vitro translations binds to a consensus target site that is recognized by the AG protein. These data suggest that maize contains a homolog of the Arabidopsis floral identity gene AG and that this gene is conserved in sequence and function.     

New insights into the metastasis-associated 67 kD laminin receptor

The interactions between tumor cells and laminin or other components of the extracellular matrix have been shown to play an important role in tumor invasion and metastasis. These interactions are mediated by different cell surface molecules, including the monomeric 67 kD laminin receptor. This molecule appears to be very peculiar since so far only a full-length gene encoding a 37 kD precursor protein has been isolated and the mechanism by which the precursor reaches the mature form is not understood. Based on clinical data, which clearly demonstrate the importance of the receptor in tumor progression, studies were conducted to define the structure, expression, and function of this laminin receptor as a step toward developing therapeutic strategies that target this molecule. The data suggest that acylation of the precursor is the key mechanism in maturation of the 67 kD form. The function of the membrane receptor is to stabilize the binding of laminin to cell surface integrins, acting as an integrin-accessory molecule, although homology of the gene encoding the receptor precursor with other genes suggests additional functions. Downregulation of the receptor expression on tumor cells might open new therapeutic approaches to decrease tumor aggressiveness. J. Cell. Biochem. 67:155–165, 1997. © 1997 Wiley-Liss, Inc.     

Amyloid precursor-like protein 2 association with HLA class I molecules

Amyloid precursor-like protein 2 (APLP2) is a ubiquitously expressed protein. The previously demonstrated functions for APLP2 include binding to the mouse major histocompatibility complex (MHC) class I molecule H-2K^d and down regulating its cell surface expression. In this study, we have investigated the interaction of APLP2 with the human leukocyte antigen (HLA) class I molecule in human tumor cell lines. APLP2 was readily detected in pancreatic, breast, and prostate tumor lines, although it was found only in very low amounts in lymphoma cell lines. In a pancreatic tumor cell line, HLA class I was extensively co-localized with APLP2 in vesicular compartments following endocytosis of HLA class I molecules. In pancreatic, breast, and prostate tumor lines, APLP2 was bound to the HLA class I molecule. APLP2 was found to bind to HLA-A24, and more strongly to HLA-A2. Increased expression of APLP2 resulted in reduced surface expression of HLA-A2 and HLA-A24. Overall, these studies demonstrate that APLP2 binds to the HLA class I molecule, co-localizes with it in intracellular vesicles, and reduces the level of HLA class I molecule cell surface expression.     

The physiology of lactoferrin.

This paper reviews our current knowledge of the structure and function of the iron-binding protein lactoferrin. In particular, it attempts to relate the various proposed physiological functions of lactoferrin to its most characteristic biochemical properties, i.e. its ability to bind iron and its highly basic nature. The extent to which various physiological functions can be considered as definitely established is critically reviewed, and suggestions for future research are proposed.     

The Oncogenic MicroRNA-21 Inhibits the Tumor Suppressive Activity of FBXO11 to Promote Tumorigenesis

The microRNA miR-21 is overexpressed in most human cancers and accumulating evidence indicates that it functions as an oncogene. Since miRNAs suppress the expression of their target genes, we hypothesized that some miR-21 targets may act as tumor suppressors, and thus their expression would be anticipated to be reduced by the high miR-21 levels observed in various human cancers. By microarray analysis and quantitative PCR we identified and validated FBXO11 (a member of the F-box subfamily lacking a distinct unifying domain) as a miR-21 target gene. FBXO11 is a component of the SKP1-CUL1-F-box ubiquitin ligase complex that targets proteins for ubiquitination and proteosomal degradation. By loss of function and gain of function studies, we show that FBXO11 acts as a tumor suppressor, promotes apoptosis and mediates the degradation of the oncogenic protein BCL6. The critical role that FBXO11 plays in miR-21-mediated tumorigenesis was demonstrated by a rescue experiment, in which silencing FBXO11 in miR-21KD cancer cells restored their high tumorigenicity. Expression of miR-21 and FBXO11 are inversely correlated in tumor tissue, and their expression correlates with patient survival and tumor grade. High FBXO11 expression correlates with better patient survival and lower tumor grade consistent with its tumor suppressor activity. In contrast high miR-21 expression, which correlates with poor patient survival and higher tumor grade, is consistent with its oncogenic activity. Our results identify FBXO11 as a novel miR-21 target gene, and demonstrate that the oncogenic miRNA miR-21 decreases the expression of FBXO11, which normally acts as a tumor suppressor, and thereby promotes tumorigenesis.     

RBM10: Harmful or helpful‐many factors to consider

RBM10 is an RNA binding motif (RBM) protein expressed in most, if not all, human and animal cells. Interest in RBM10 is rapidly increasing and its clinical importance is highlighted by its identification as the causative agent of TARP syndrome, a developmental condition that significantly impacts affected children. RBM10's cellular functions are beginning to be explored, with initial studies demonstrating a tumor suppressor role. Very recently, however, contradictory results have emerged, suggesting a tumor promoter role for RBM10. In this review, we describe the current state of knowledge on RBM10, and address this dichotomy in RBM10 function. Furthermore, we discuss what may be regulating RBM10 function, particularly the importance of RBM10 alternative splicing, and the relationship between RBM10 and its paralogue, RBM5. As RBM10‐related work is gaining momentum, it is critical that the various aspects of RBM10 molecular biology revealed by recent studies be considered moving forward. It is only if these recent advances in RBM10 structure and function are considered that a clearer insight into RBM10 function, and the disease states with which RBM10 mutation is associated, will be gained.     

Fgfbp1 is essential for the cellular survival during zebrafish embryogenesis

Fibroblast growth factor binding protein 1 (FGFBP1) is expressed in various tumors and may serve as a diagnostic marker and/or a therapeutic target. Previous studies suggested FGFBP1 functions as an angiogenic switch molecule by regulating the activity of FGF2, and it was later found to associate with a broad spectrum of FGFs. To study FGFBP1, we used zebrafish, in which the function of extracellular matrix protein can be easily studied in intact tissues or organisms. When Fgfbp1 expression was knocked down, morphants manifested massive cell death and structural abnormalities. Cell death was most prominent in the brain and the neural tube, but not limited to those regions. These findings suggest that the primary function of Fgfbp1 may be to sustain cellular survival throughout embryogenesis. For comparison, the expression of fgf2 was limited to the early stage of embryogenesis and fgf2 morphants showed more severe phenotype, with high morbidity before reaching 14-somites. Taken together, our work reveals the physiologic function of Fgfbp1, and that its function could be exerted in a Fgf2-independent manner.     

Endoplasmic reticulum protein 29 (ERp29): An emerging role in cancer

The endoplasmic reticulum protein 29 (ERp29) is a molecule that facilitates processing and transport of proteins in the early secretory pathway. Structural and functional analyses have suggested a biological role as a putative chaperone in the endoplasmic reticulum. The N-terminal domain of ERp29 resembles the thioredoxin domain of protein disulfide isomerase, but lacks its redox-active function due to the absence of an active motif consisting of double cysteines. In the context of carcinogenesis, the role of ERp29 in cancer progression has not been fully elucidated. However, recent studies indicate that high expression of ERp29 inversely correlates to tumor progression. In addition, over-expression of ERp29 significantly inhibits proliferation and suppresses tumorigenesis by modulating ER stress signaling and the mesenchymal-epithelial transition in breast cancer cells. In this review, we summarize the biological properties of ERp29 and its novel function as a tumor suppressor.     

Stage-dependent increase of orosomucoid and zinc-alpha2-glycoprotein in urinary bladder cancer

Identification and characterization of biomarkers in body fluids such as serum or urine serve as a basis for early detection of diseases, particularly of cancer. Performing 2-DE with subsequent MS analyses, conventional immunoblotting and immunohistochemistry we identified two proteins, orosomucoid (ORM) and human zinc-alpha(2)-glycoprotein (ZAG), which were increased in the urine samples of patients with bladder cancer in comparison to the urine samples of healthy volunteers. The highest amount of both proteins was found in invasive bladder cancer stages such as pT2-3. Immunohistochemical studies showed ORM in inflammatory cells but also in endothelial cells of blood vessels within or adjacent to the tumor area and in part of the tumor cells. ZAG was prominent in tumor cells at the tumor invasion front. Additionally, ZAG was localized at the luminal surface of normal urothelium, which switches to the basal side when a superficial papillary tumor was observed. These results show that we have been able to identify two new proteins that may be related to the development of superficial bladder cancer and to its switch to an invasive phenotype.