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The cyclophilins
Ping Wang, Joseph Heitman
Genome Biology , 2005, DOI: 10.1186/gb-2005-6-7-226
Abstract: The terms 'cyclophilin' and 'peptidyl-prolyl isomerase' (PPIase) are almost synonymous today, but the identification of the first protein that showed PPIase activity over 20 years ago [1] was independent of the purification of cyclophilin A (CypA) from bovine thymocytes as an intracellular protein with a high affinity for the immunosuppressive drug cyclosporin A (CsA) [2]. It was not until five years later that the 18 kDa protein with PPIase activity and CypA were found to be one and the same [3,4]. Along with the discoveries of other PPIase proteins (immunophilins), such as the parvulins and the FK-506-binding proteins (FKBPs, which bind the immunosuppressant drug FK-506), additional cyclophilins have subsequently been identified and the cyclophilins were found to constitute a protein family. All cyclophilins share a common domain of approximately 109 amino acids, the cyclophilin-like domain (CLD), surrounded by domains unique to each member of the family that are associated with subcellular compartmentalization and functional specialization [5,6].Cyclophilins have been found in mammals, plants, insects, fungi, and bacteria; they are structurally conserved throughout evolution and all have PPIase activity. There are 7 major cyclophilins in humans - hCypA (also called hCyp-18a, 18 denotes molecular mass of 18 kDa), hCypB (also called hCyp-22/p, 22 kDa), hCypC, hCypD, hCypE, hCyp40 (40 kDa), and hCypNK (first identified from human natural killer cells) - and a total of 16 unique proteins [7,8]. Drosophila has at least 9 cyclophilins [7] and the plant Arabidopsis thaliana has 29 putative cyclophilins [9], whereas 8 cyclophilins, Cpr1-Cpr8, have been found in Saccharomyces cerevisiae (reviewed in [6]). Little is known about the genomic structure of human cyclophilin genes; they are generally not linked to each other in the genome.What is peptidyl-prolyl isomerization and why does it require a catalyst? The peptide bond has a partial double-bond character, and like all
Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications  [PDF]
Nida Iqbal,Naveed Iqbal
Molecular Biology International , 2014, DOI: 10.1155/2014/852748
Abstract: Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Dimerization of the receptor results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways leading to cell proliferation and tumorigenesis. Amplification or overexpression of HER2 occurs in approximately 15–30% of breast cancers and 10–30% of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. HER2 overexpression has also been seen in other cancers like ovary, endometrium, bladder, lung, colon, and head and neck. The introduction of HER2 directed therapies has dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers; however, the results have been proved disappointing in other HER2 overexpressing cancers. This review discusses the role of HER2 in various cancers and therapeutic modalities available targeting HER2. 1. Introduction The human epidermal growth factor receptor (HER) family of receptors plays a central role in the pathogenesis of several human cancers. They regulate cell growth, survival, and differentiation via multiple signal transduction pathways and participate in cellular proliferation and differentiation. The family is made up of four main members: HER-1, HER-2, HER-3, and HER-4, also called ErbB1, ErbB2, ErbB3, and ErbB4, respectively [1]. All four HER receptors comprise a cysteine-rich extracellular ligand binding site, a transmembrane lipophilic segment, and an intracellular domain with tyrosine kinase catalytic activity [2]. Epidermal growth factor receptor (EGFR, ErbB1, and HER1)—the first receptor tyrosine kinase, was discovered by Carpenter and coworkers at Vanderbilt University, USA, in 1978 [3]. ErbB stands for its origin in the Erb-b gene responsible for avian erythroblastosis virus. The neu oncogene (also known as HER2, ErbB2, or p185) was discovered by a group of scientists at Massachusetts Institute of Technology, Rockefeller, and Harvard University [4, 5]. The HER2 receptor is a 1255 amino acid, 185?kD transmembrane glycoprotein located at the long arm of human chromosome 17 (17q12) [6]. HER2 is expressed in many tissues and its major role in these tissues is to facilitate excessive/uncontrolled cell growth and tumorigenesis [7–9]. 2. Function The HER receptors exist as monomers on the cell surface. Upon ligands binding to their extracellular domains, HER proteins undergo dimerization and transphosphorylation of
Lack of functional and expression homology between human and mouse aldo-keto reductase 1C enzymes: implications for modelling human cancers
Pedro Veli?a, Nicholas J Davies, Pedro P Rocha, Heinrich Schrewe, Jonathan P Ride, Chris M Bunce
Molecular Cancer , 2009, DOI: 10.1186/1476-4598-8-121
Abstract: In this study, we have characterized and compared the four human (AKR1C1,-1C2, -1C3 and -1C4) and the eight murine (AKR1C6, -1C12, -1C13, -1C14, -1C18, -1C19, -1C20 and -1C21) isoforms in their phylogeny, substrate preference and tissue distribution. We have found divergent evolution between human and murine AKR1C enzymes that was reflected by differing substrate preference. Murine enzymes did not perform the 11β-ketoreduction of prostaglandin (PG) D2, an activity specific to human AKR1C3 and important in promoting leukemic cell survival. Instead, murine AKR1C6 was able to perform the 9-ketoreduction of PGE2, an activity absent amongst human isoforms. Nevertheless, reduction of the key steroids androstenedione, 5α-dihydrotestosterone, progesterone and estrone was found in murine isoforms. However, unlike humans, no AKR1C isoforms were detected in murine prostate, testes, uterus and haemopoietic progenitors.This study exposes significant lack of phylogenetic and functional homology between human and murine AKR1C enzymes. Therefore, we conclude that mice are not suitable to model the role of AKR1C in human cancers and leukemia.Aldo-keto reductases (AKRs) are a large superfamily of ~37 kDa enzymes present in bacteria, protozoa, fungi, plants and animals [1-3]. In spite of their highly conserved (α/β)8-barrel structure, AKRs perform the NAD(P)H-dependent reduction of carbonyl groups in a wide variety of substrates and therefore have diverse physiological roles [3]. To date, more than 150 proteins have been assigned to the superfamily, currently divided into 15 families (AKR1-AKR15) listed at the AKR homepage http://www.med.upenn.edu/akr/ webcite[2].In recent years, members of the AKR1C subfamily have been implicated in the development of human cancers due to their ability to modify steroid hormones and prostaglandins (PGs) [4-7] (Fig. 1). Four AKR1C isoforms exist in humans (AKR1C1-AKR1C4) and their respective genes are clustered on chromosome 10p14 (Fig. 2b) [5,8]. In
Target Cell Cyclophilins Facilitate Human Papillomavirus Type 16 Infection  [PDF]
Malgorzata Bienkowska-Haba equal contributor,Hetalkumar D. Patel equal contributor,Martin Sapp
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000524
Abstract: Following attachment to primary receptor heparan sulfate proteoglycans (HSPG), human papillomavirus type 16 (HPV16) particles undergo conformational changes affecting the major and minor capsid proteins, L1 and L2, respectively. This results in exposure of the L2 N-terminus, transfer to uptake receptors, and infectious internalization. Here, we report that target cell cyclophilins, peptidyl-prolyl cis/trans isomerases, are required for efficient HPV16 infection. Cell surface cyclophilin B (CyPB) facilitates conformational changes in capsid proteins, resulting in exposure of the L2 N-terminus. Inhibition of CyPB blocked HPV16 infection by inducing noninfectious internalization. Mutation of a putative CyP binding site present in HPV16 L2 yielded exposed L2 N-terminus in the absence of active CyP and bypassed the need for cell surface CyPB. However, this mutant was still sensitive to CyP inhibition and required CyP for completion of infection, probably after internalization. Taken together, these data suggest that CyP is required during two distinct steps of HPV16 infection. Identification of cell surface CyPB will facilitate the study of the complex events preceding internalization and adds a putative drug target for prevention of HPV–induced diseases.
Cyclophilins as Modulators of Viral Replication  [PDF]
Stephen D. Frausto,Emily Lee,Hengli Tang
Viruses , 2013, DOI: 10.3390/v5071684
Abstract: Cyclophilins are peptidyl‐prolyl cis/trans isomerases important in the proper folding of certain proteins. Mounting evidence supports varied roles of cyclophilins, either positive or negative, in the life cycles of diverse viruses, but the nature and mechanisms of these roles are yet to be defined. The potential for cyclophilins to serve as a drug target for antiviral therapy is evidenced by the success of non-immunosuppressive cyclophilin inhibitors (CPIs), including Alisporivir, in clinical trials targeting hepatitis C virus infection. In addition, as cyclophilins are implicated in the predisposition to, or severity of, various diseases, the ability to specifically and effectively modulate their function will prove increasingly useful for disease intervention. In this review, we will summarize the evidence of cyclophilins as key mediators of viral infection and prospective drug targets.
Current use and potential role of bevacizumab in the treatment of gastrointestinal cancers
Jia Li, Muhammad Wasif Saif
Biologics: Targets and Therapy , 2009, DOI: http://dx.doi.org/10.2147/BTT.S5874
Abstract: rrent use and potential role of bevacizumab in the treatment of gastrointestinal cancers Review (5639) Total Article Views Authors: Jia Li, Muhammad Wasif Saif Published Date September 2009 Volume 2009:3 Pages 429 - 441 DOI: http://dx.doi.org/10.2147/BTT.S5874 Jia Li, Muhammad Wasif Saif Yale Cancer Center, Yale School of Medicine, New Haven CT, USA Abstract: Angiogenesis is essential for cancer growth and metastasis. Vascular endothelial growth factor (VEGF) is a key modulator of angiogenesis. In addition, overexpression of VEGF is correlated with advanced disease and poor prognosis. Bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody, is the first anti-angiogenic agent approved by Food and Drug Administration for use in treatment of human solid cancers. Although bevacizumab has received most attention for first-line treatment of advanced colorectal and nonsmall-cell lung cancer, there is a rapidly growing body of evidence for its efficacy in treatment of a number of other solid tumors. We present the current status and potential use of bevacizumab therapy in gastrointestinal cancers.
Current use and potential role of bevacizumab in the treatment of gastrointestinal cancers
Jia Li,Muhammad Wasif Saif
Biologics: Targets and Therapy , 2009,
Abstract: Jia Li, Muhammad Wasif SaifYale Cancer Center, Yale School of Medicine, New Haven CT, USAAbstract: Angiogenesis is essential for cancer growth and metastasis. Vascular endothelial growth factor (VEGF) is a key modulator of angiogenesis. In addition, overexpression of VEGF is correlated with advanced disease and poor prognosis. Bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody, is the first anti-angiogenic agent approved by Food and Drug Administration for use in treatment of human solid cancers. Although bevacizumab has received most attention for first-line treatment of advanced colorectal and nonsmall-cell lung cancer, there is a rapidly growing body of evidence for its efficacy in treatment of a number of other solid tumors. We present the current status and potential use of bevacizumab therapy in gastrointestinal cancers.Keywords: advanced colon cancer, angiogenesis, bevacizumab, chemotherapy, metastatic, targeted therapy, vascular endothelial growth factor, gastric cancer, pancreatic cancer, hepatocellular cancer
Targeted mTOR in Human Gynecologic Cancers  [PDF]
Yi-Jen Chen
Journal of Cancer Molecules , 2007,
Abstract: The protein mammalian Target of Rapamycin (mTOR) is a conserved Serine/Threonine kinase that regulates cell growth and metabolism in response to environmental cues. When growth conditions are favorable, TOR is active and cells maintain a robust rate of ribosome biogenesis, translation initiation, and nutrient import. Aberrant high activity of mTOR complexes appears to be an underlying cause of human gynecologic cancers. In patients with advanced or recurrent gynecologic cancer survival is greatly diminished. At this time the focus of future research should be on the use of novel targeted agents. mTOR inhibition represents a promising treatment strategy for endometrial and breast cancer. The tumor growth-inhibitory properties of rapamycin were recognized early, although it was initially clinically developed for its immunosuppressive properties. Because rapamycin has an undesirable pharmaceutical profile, including poor water-solubility, some analogues of rapamycin, such as CCI-799 (tensirolimus), RAD001 (everolimus) and AP23573 (ARIAD), have been developed with improved pharmaceutical properties. mTOR inhibition by theses agents has shown remarkable anti-tumor activity against human gynecologic malignancies in vitro and in vivo, and these drugs are currently under evaluation in Phase I-II clinical trials. Moreover, mTOR inhibitors enhances chemosensitivity of paclitaxel and cisplatin in ovarian and cervical cancer cells. mTOR inhibitors may have a major role for the management of malignancies characterized by increased activity of the mTOR pathway. mTOR is an exciting target, and future research will determine the optimal use of agents directed at this pathway.
Mitochondrial DNA Instability and Metabolic Shift in Human Cancers  [PDF]
Hsin-Chen Lee,Yau-Huei Wei
International Journal of Molecular Sciences , 2009, DOI: 10.3390/ijms10020674
Abstract: A shift in glucose metabolism from oxidative phosphorylation to glycolysis is one of the biochemical hallmarks of tumor cells. Mitochondrial defects have been proposed to play an important role in the initiation and/or progression of various types of cancer. In the past decade, a wide spectrum of mutations and depletion of mtDNA have been identified in human cancers. Moreover, it has been demonstrated that activation of oncogenes or mutation of tumor suppressor genes, such as p53, can lead to the upregulation of glycolytic enzymes or inhibition of the biogenesis or assembly of respiratory enzyme complexes such as cytochrome c oxidase. These findings may explain, at least in part, the well documented phenomena of elevated glucose uptake and mitochondrial defects in cancers. In this article, we review the somatic mtDNA alterations with clinicopathological correlations in human cancers, and their potential roles in tumorigenesis, cancer progression, and metastasis. The signaling pathways involved in the shift from aerobic metabolism to glycolysis in human cancers are also discussed.
Clinical Relevance of KRAS in Human Cancers
Sylwia Jan ík,Ji í Drábek,Danuta Radzioch,Marián Hajdúch
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/150960
Abstract: The KRAS gene (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is an oncogene that encodes a small GTPase transductor protein called KRAS. KRAS is involved in the regulation of cell division as a result of its ability to relay external signals to the cell nucleus. Activating mutations in the KRAS gene impair the ability of the KRAS protein to switch between active and inactive states, leading to cell transformation and increased resistance to chemotherapy and biological therapies targeting epidermal growth factor receptors. This review highlights some of the features of the KRAS gene and the KRAS protein and summarizes current knowledge of the mechanism of KRAS gene regulation. It also underlines the importance of activating mutations in the KRAS gene in relation to carcinogenesis and their importance as diagnostic biomarkers, providing clues regarding human cancer patients' prognosis and indicating potential therapeutic approaches.
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