Review Article
PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis
- Simon M. Schultze, Brian A. Hemmings, Markus Niessen, Oliver Tschopp
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- Published online by Cambridge University Press:
- 19 January 2012, e1
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New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications.
Neuronal receptors as targets for the action of amyloid-beta protein (Aβ) in the brain
- Aarti N. Patel, Jack H. Jhamandas
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- 20 January 2012, e2
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Accumulation of neurotoxic soluble amyloid-beta protein (Aβ) oligomers in the brains of patients with Alzheimer disease (AD) and their role in AD pathogenesis have emerged as topics of considerable interest in recent years. Soluble Aβ oligomers impair synaptic and neuronal function, leading to neurodegeneration that is clinically manifested by memory and cognitive dysfunction. The precise mechanisms whereby Aβ oligomers cause neurotoxicity remain unknown. Emerging insights into the mechanistic link between neuronal receptors and soluble Aβ oligomers highlight the potential role of these receptors in Aβ-mediated neurotoxicity in AD. The current review focuses on studies describing interactions between soluble Aβ oligomers and neuronal receptors, and their role in AD pathogenesis. Furthermore, these studies provide insight into potential therapies for AD using compounds directed at putative target receptors for the action of Aβ in the central nervous system. We focus on interactions of Aβ with subtypes of acetylcholine and glutamatergic receptors. Additionally, neuronal receptors such as insulin, amylin and receptor for advanced glycation end products could be potential targets for soluble Aβ-oligomer-mediated neurotoxicity. Aβ interactions with other receptors such as the p75 neurotrophin receptors, which are highly expressed on cholinergic basal forebrain neurons lost in AD, are also highlighted.
RNA therapy for polyglutamine neurodegenerative diseases
- Lauren M. Watson, Matthew J. A. Wood
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- 31 January 2012, e3
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Polyglutamine neurodegenerative diseases result from the expansion of a trinucleotide CAG repeat, encoding a polyglutamine tract in the disease-causing protein. The process by which each polyglutamine protein exerts its toxicity is complex, involving a variety of mechanisms including transcriptional dysregulation, proteasome impairment and mitochondrial dysfunction. Thus, the most effective and widely applicable therapies are likely to be those designed to eliminate production of the mutant protein upstream of these deleterious effects. RNA-based approaches represent promising therapeutic strategies for polyglutamine diseases, offering the potential to suppress gene expression in a sequence-specific manner at the transcriptional and post-transcriptional levels. In particular, gene silencing therapies capable of discrimination between mutant and wildtype alleles, based on disease-linked polymorphisms or CAG repeat length, might prove crucial in cases where a loss of wild type function is deleterious. Novel methods, such as gene knockdown and replacement, seek to eliminate the technical difficulties associated with allele-specific silencing by avoiding the need to target specific mutations. With a variety of RNA technologies currently being developed to target multiple facets of polyglutamine pathogenesis, the emergence of an effective therapy seems imminent. However, numerous technical obstacles associated with design, discrimination and delivery must be overcome before RNA therapy can be effectively applied in the clinical setting.
Molecular mechanisms underlying chemical liver injury
- Xinsheng Gu, Jose E. Manautou
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- Published online by Cambridge University Press:
- 03 February 2012, e4
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The liver is necessary for survival. Its strategic localisation, blood flow and prominent role in the metabolism of xenobiotics render this organ particularly susceptible to injury by chemicals to which we are ubiquitously exposed. The pathogenesis of most chemical-induced liver injuries is initiated by the metabolic conversion of chemicals into reactive intermediate species, such as electrophilic compounds or free radicals, which can potentially alter the structure and function of cellular macromolecules. Many reactive intermediate species can produce oxidative stress, which can be equally detrimental to the cell. When protective defences are overwhelmed by excess toxicant insult, the effects of reactive intermediate species lead to deregulation of cell signalling pathways and dysfunction of biomolecules, leading to failure of target organelles and eventual cell death. A myriad of genetic factors determine the susceptibility of specific individuals to chemical-induced liver injury. Environmental factors, lifestyle choices and pre-existing pathological conditions also have roles in the pathogenesis of chemical liver injury. Research aimed at elucidating the molecular mechanism of the pathogenesis of chemical-induced liver diseases is fundamental for preventing or devising new modalities of treatment for liver injury by chemicals.
MicroRNA-181a – a tale of discrepancies
- Aliaa M. Seoudi, Yasmine A. Lashine, Ahmed I. Abdelaziz
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- 21 February 2012, e5
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MicroRNAs (miRNAs) are short noncoding RNAs that act as post-transcriptional regulators. The low complementarity required between the sequences of a miRNA and its target mRNA enables a single miRNA to act on a large range of targets. Thus miRNAs have an intersecting complex effect that spans a multiplicity of pathways and processes. In this review, the different roles of a vital miRNA, miR-181a, in physiological and pathological developments are collated in an attempt to highlight the intersections of such processes and to show how the deregulation of miR-181a could in one context drive malignancy, whereas in another it can lead to autoimmunity. Such deregulation could be related to the faulty levels of one of its own targets, p53, which was recently reported to control an array of miRNAs, one of which is miR-181a. This sheds light on a hidden loop of chaos behind chronic diseases such as autoimmunity and cancer.
T-cell-receptor-like antibodies – generation, function and applications
- Rony Dahan, Yoram Reiter
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- 24 February 2012, e6
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Tumour and virus-infected cells are recognised by CD8+ cytotoxic T cells that, in response, are activated to eliminate these cells. In order to be activated, the clonotypic T-cell receptor (TCR) needs to encounter a specific peptide antigen presented by the membrane surface major histocompatibility complex (MHC) molecule. Cells that have undergone malignant transformation or viral infection present peptides derived from tumour-associated antigens or viral proteins on their MHC class I molecules. Therefore, disease-specific MHC–peptide complexes are desirable targets for immunotherapeutic approaches. One such approach transforms the unique fine specificity but low intrinsic affinity of TCRs to MHC–peptide complexes into high-affinity soluble antibody molecules endowed with a TCR-like specificity towards tumour or viral epitopes. These antibodies, termed TCR-like antibodies, are being developed as a new class of immunotherapeutics that can target tumour and virus-infected cells and mediate their specific killing. In addition to their therapeutic capabilities, TCR-like antibodies are being developed as diagnostic reagents for cancer and infectious diseases, and serve as valuable research tools for studying MHC class I antigen presentation.
Mechanisms of disease: the endocrinology of ectopic pregnancy
- Andrew W. Horne, Hilary O.D. Critchley
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- 02 March 2012, e7
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Ectopic pregnancy is defined as a pregnancy implanted outside the uterus, and >98% implant in the Fallopian tube. It has a major clinical and socioeconomic impact worldwide. The diagnosis of ectopic pregnancy is often difficult and resource intensive owing to a lack of accurate biomarkers, and there is a need for improved medical management of ectopic pregnancy using new or adjuvant treatments. The aetiology of ectopic pregnancy is uncertain, but tubal implantation is probably due to retention of the embryo in the Fallopian tube owing to impaired embryo-tubal transport and alterations in the tubal microenvironment. This comprehensive review of the literature supporting current understanding of the endocrinology of Fallopian tube biology and tubal implantation focuses on genes expressed in the Fallopian tube regulated by oestrogen and progesterone and discusses their potential functions. It concludes with a discussion of how advances in this field are enabling the development of novel biomarkers and could lead to the identification of potential new treatments for ectopic pregnancy.
InTERTesting association between telomerase, mTOR and phytochemicals
- Tabetha Sundin, Patricia Hentosh
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- 29 March 2012, e8
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Telomeres are stretches of repeated DNA sequences located at the ends of chromosomes that are necessary to prevent loss of gene-coding DNA regions during replication. Telomerase – the enzyme responsible for immortalising cancer cells through the addition of telomeric repeats – is active in ~90% of human cancers. Telomerase activity is inhibited by various phytochemicals such as isoprenoids, genistein, curcumin, epigallocatechin-3-gallate, resveratrol and others. Human TERT (telomerase reverse transcriptase – the rate-limiting component of telomerase), heat shock protein 90, Akt, p70 S6 kinase (S6K) and mammalian target of rapamycin (mTOR) form a physical and functional complex with one another. The inclusion of Akt, mTOR and S6K in the TERT complex is compelling evidence to support mTOR-mediated control of telomerase activity. This review will define the role of mTOR, the master regulator of protein translation, in telomerase regulation and provide additional insights into the numerous ways in which telomerase activity is hindered by phytochemicals.
Opioid receptor heteromers in analgesia
- Cristina M. Costantino, Ivone Gomes, Steven D. Stockton, Jr, Maribel P. Lim, Lakshmi A. Devi
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- 10 April 2012, e9
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Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation.
Antiangiogenic and anticancer molecules in cartilage
- Debabrata Patra, Linda J. Sandell
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- 23 April 2012, e10
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Cartilage is one of the very few naturally occurring avascular tissues where lack of angiogenesis is the guiding principle for its structure and function. This has attracted investigators who have sought to understand the biochemical basis for its avascular nature, hypothesising that it could be used in designing therapies for treating cancer and related malignancies in humans through antiangiogenic applications. Cartilage encompasses primarily a specialised extracellular matrix synthesised by chondrocytes that is both complex and unique as a result of the myriad molecules of which it is composed. Of these components, a few such as thrombospondin-1, chondromodulin-1, the type XVIII-derived endostatin, SPARC (secreted protein acidic and rich in cysteine) and the type II collagen-derived N-terminal propeptide (PIIBNP) have demonstrated antiangiogenic or antitumour properties in vitro and in vivo preclinical trials that involve several complicated mechanisms that are not completely understood. Thrombospondin-1, endostatin and the shark-cartilage-derived Neovastat preparation have also been investigated in human clinical trials to treat several different kinds of cancers, where, despite the tremendous success seen in preclinical trials, these molecules are yet to show success as anticancer agents. This review summarises the current state-of-the-art antiangiogenic characterisation of these molecules, highlights their most promising aspects and evaluates the future of these molecules in antiangiogenic applications.
FGFR3 targeting strategies for achondroplasia
- Melanie B. Laederich, William A. Horton
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- 23 April 2012, e11
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Mutations that exaggerate signalling of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) give rise to achondroplasia, the most common form of dwarfism in humans. Here we review the clinical features, genetic aspects and molecular pathogenesis of achondroplasia and examine several therapeutic strategies designed to target the mutant receptor or its signalling pathways, including the use of kinase inhibitors, blocking antibodies, physiologic antagonists, RNAi and chaperone inhibitors. We conclude by discussing the challenges of treating growth plate disorders in children.
Molecular pathogenesis of malignant mesothelioma
- Philip A. Rascoe, Daniel Jupiter, Xiaobo Cao, James E. Littlejohn, W. Roy Smythe
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- 24 May 2012, e12
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Malignant mesothelioma is a rare, highly aggressive cancer arising from mesothelial cells that line the pleural cavities. Approximately 80% of mesothelioma cases can be directly attributed to asbestos exposure. Additional suspected causes or co-carcinogens include other mineral fibres, simian virus 40 (SV40) and radiation. A mesothelioma epidemic in Turkey has demonstrated a probable genetic predisposition to mineral fibre carcinogenesis and studies of human tissues and animal models of mesothelioma have demonstrated genetic and epigenetic events that contribute to the multistep process of mineral fibre carcinogenesis. Several growth factors and their receptors have a significant role in the oncogenesis, progression and resistance to therapy of mesothelioma. Epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF) have been shown as targets for therapy based on promising preclinical data. However, clinical trials of tyrosine kinase inhibitors in mesothelioma have been disappointing. Bcl-XL is an important antiapoptotic member of the Bcl-2 family and is overexpressed in several solid tumours, including mesothelioma. Reduction of Bcl-XL expression in mesothelioma induces apoptosis and engenders sensitisation to cytotoxic chemotherapeutic agents. Pharmacological inhibitors of antiapoptotic Bcl-2 family members continue to undergo refinement and have shown promise in mesothelioma.
Epigenetic mechanisms, nuclear architecture and the control of gene expression in trypanosomes
- Sam Alsford, Kelly duBois, David Horn, Mark C. Field
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- 29 May 2012, e13
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The control of gene expression, and more significantly gene cohorts, requires tight transcriptional coordination and is an essential feature of probably all cells. In higher eukaryotes, the mechanisms used involve controlled modifications to both local and global DNA environments, principally through changes in chromatin structure as well as cis-element-driven mechanisms. Although the mechanisms regulating chromatin in terms of transcriptional permissiveness and the relation to developmental programmes and responses to the environment are becoming better understood for animal and fungal cells, it is only just beginning to become clear how these processes operate in other taxa, including the trypanosomatids. Recent advances are now illuminating how African trypanosomes regulate higher-order chromatin structure, and, further, how these mechanisms impact on the expression of major surface antigens that are of fundamental importance to life-cycle progression. It is now apparent that several mechanisms are rather more similar between animal and fungal cells and trypanosomes than it originally appeared, but some aspects do involve gene products unique to trypanosomes. Therefore, both evolutionarily common and novel mechanisms cohabit in trypanosomes, offering both important biological insights and possible therapeutic opportunity.
Calcineurin inhibitors and immunosuppression – a tale of two isoforms
- Clintoria R. Williams, Jennifer L. Gooch
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- Published online by Cambridge University Press:
- 04 July 2012, e14
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Organ transplantation is the state of the art for treating end-stage organ failure. Over 25 000 organ transplants are performed in the USA each year. Survival rates following transplantation are now approaching 90% for 1 year and 75% for 5 years. Central to this success was the introduction of drugs that suppress the immune system and prevent rejection. The most commonly used class of immunosuppressing drugs are calcineurin inhibitors (CNIs). Calcineurin is a ubiquitous enzyme that is important for T-cell function. With more people taking CNIs for longer and longer periods of time the consequences of calcineurin inhibition on other organ systems – particularly the kidney – have become a growing concern. Virtually all people who take a CNI will develop some degree of kidney toxicity and up to 10% will progress to kidney failure. In the past 15 years, research into calcineurin action has identified distinct actions of the two main isoforms of the catalytic subunit of the enzyme. The α-isoform is required for kidney function whereas the β-isoform has a predominant role in the immune system. This review will discuss the current state of knowledge about calcineurin isoforms and how these new insights may reshape post-transplant immunosuppression.
On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes
- Robert Busch, Alessandra De Riva, Andreas V. Hadjinicolaou, Wei Jiang, Tieying Hou, Elizabeth D. Mellins
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- 06 July 2012, e15
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This review discusses mechanisms that link allelic variants of major histocompatibility complex (MHC) class II molecules (MHCII) to immune pathology. We focus on HLA (human leukocyte antigen)-DQ (DQ) alleles associated with celiac disease (CD) and type 1 diabetes (T1D) and the role of the murine DQ-like allele, H2-Ag7 (I-Ag7 or Ag7), in murine T1D. MHCII molecules bind peptides, and alleles vary in their peptide-binding specificity. Disease-associated alleles permit binding of disease-inducing peptides, such as gluten-derived, Glu-/Pro-rich gliadin peptides in CD and peptides from islet autoantigens, including insulin, in T1D. In addition, the CD-associated DQ2.5 and DQ8 alleles are unusual in their interactions with factors that regulate their peptide loading, invariant chain (Ii) and HLA-DM (DM). The same alleles, as well as other T1D DQ risk alleles (and Ag7), share nonpolar residues in place of Asp at β57 and prefer peptides that place acidic side chains in a pocket in the MHCII groove (P9). Antigen-presenting cells from T1D-susceptible mice and humans retain CLIP because of poor DM editing, although underlying mechanisms differ between species. We propose that these effects on peptide presentation make key contributions to CD and T1D pathogenesis.
Features of protein–protein interactions that translate into potent inhibitors: topology, surface area and affinity
- Matthew C. Smith, Jason E. Gestwicki
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- 26 July 2012, e16
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Protein–protein interactions (PPIs) control the assembly of multi-protein complexes and, thus, these contacts have enormous potential as drug targets. However, the field has produced a mix of both exciting success stories and frustrating challenges. Here, we review known examples and explore how the physical features of a PPI, such as its affinity, hotspots, off-rates, buried surface area and topology, might influence the chances of success in finding inhibitors. This analysis suggests that concise, tight binding PPIs are most amenable to inhibition. However, it is also clear that emerging technical methods are expanding the repertoire of ‘druggable’ protein contacts and increasing the odds against difficult targets. In particular, natural product-like compound libraries, high throughput screens specifically designed for PPIs and approaches that favour discovery of allosteric inhibitors appear to be attractive routes. The first group of PPI inhibitors has entered clinical trials, further motivating the need to understand the challenges and opportunities in pursuing these types of targets.
MEK and RAF inhibitors for BRAF-mutated cancers
- Sarah Belden, Keith T. Flaherty
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- Published online by Cambridge University Press:
- 12 October 2012, e17
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The mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of many cancers. Under normal physiologic conditions, the RAS–RAF–mitogen-activated protein kinase kinase (MEK)–mitogen-activated protein kinase (ERK) signalling cascade interaction is initiated by ligation of a receptor-linked tyrosine kinase by its cognate growth factor. It has been demonstrated in many systems that aberrant autocrine or paracrine stimulation of growth factor receptors is pathogenic in large part because of MAPK activation. As one of the key downstream effector pathways of mutated RAS (KRAS, NRAS and HRAS), pharmacologic inhibition of components of the MAPK pathway has been pursued as a means to indirectly inhibit RAS, which remains a technical challenge for direct pharmacologic inhibition. RAF and MEK are the two non-membrane-bound, serine–threonine and tyrosine–threonine kinases, within the pathway that have been most extensively explored as drug targets. The discovery of activating BRAF mutations in cancer clarified which cancer types and subsets of certain cancers are most dependent on activation of the MAPK pathway for growth and survival. Now, with the successful translation of selective BRAF and MEK inhibitors into validated therapies for BRAF mutant melanoma, the field seeks to resolve the role for these agents in cancers harbouring RAS mutations or those driven by aberrant growth factor receptor activation.
Insulin gene therapy from design to beta cell generation
- Ahter D. Sanlioglu, Hasan Ali Altunbas, Mustafa Kemal Balci, Thomas S. Griffith, Salih Sanlioglu
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- 15 October 2012, e18
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Despite the fact that insulin injection can protect diabetic patients from developing diabetes-related complications, recent meta-analyses indicate that rapid and long-acting insulin analogues only provide a limited benefit compared with conventional insulin regarding glycemic control. As insulin deficiency is the main sequel of type-1 diabetes (T1D), transfer of the insulin gene-by-gene therapy is becoming an attractive treatment modality even though T1D is not caused by a single genetic defect. In contrast to human insulin and insulin analogues, insulin gene therapy targets to supplement patients not only with insulin but also with C-peptide. So far, insulin gene therapy has had limited success because of delayed and/or transient gene expression. Sustained insulin gene expression is now feasible using current gene-therapy vectors providing patients with basal insulin coverage, but management of postprandial hyperglycaemia is still difficult to accomplish because of the inability to properly control insulin secretion. Enteroendocrine cells of the gastrointestinal track (K cells and L cells) may be ideal targets for insulin gene therapy, but cell-targeting difficulties have limited practical implementation of insulin gene therapy for diabetes treatment. Therefore, recent gene transfer technologies developed to generate authentic beta cells through transdifferentiation are also highlighted in this review.
Human adipose tissue stem cells: relevance in the pathophysiology of obesity and metabolic diseases and therapeutic applications
- Angelo Cignarelli, Sebastio Perrini, Romina Ficarella, Alessandro Peschechera, Pasquale Nigro, Francesco Giorgino
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- 10 December 2012, e19
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Stem cells are unique cells exhibiting self-renewing properties and the potential to differentiate into multiple specialised cell types. Totipotent or pluripotent stem cells are generally abundant in embryonic or fetal tissues, but the use of discarded embryos as sources of these cells raises challenging ethical problems. Adult stem cells can also differentiate into a wide variety of cell types. In particular, adult adipose tissue contains a pool of abundant and accessible multipotent stem cells, designated as adipose-derived stem cells (ASCs), that are able to replicate as undifferentiated cells, to develop as mature adipocytes and to differentiate into multiple other cell types along the mesenchymal lineage, including chondrocytes, myocytes and osteocytes, and also into cells of endodermal and neuroectodermal origin, including beta-cells and neurons, respectively. An impairment in the differentiation potential and biological functions of ASCs may contribute to the development of obesity and related comorbidities. In this review, we summarise different aspects of the ASCs with special reference to the isolation and characterisation of these cell populations, their relation to the biochemical features of the adipose tissue depot of origin and to the metabolic characteristics of the donor subject and discuss some prospective therapeutic applications.