Trends in Molecular Medicine

Published by Elsevier
Online ISSN: 1471-4914
Publications
Article
The active form of vitamin D, 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], is a secosteroid hormone that regulates calcium and bone metabolism, controls cell proliferation and differentiation, and exerts immunoregulatory activities. This range of functions has been exploited clinically to treat a variety of conditions, from secondary hyperparathyroidism to osteoporosis, to autoimmune diseases such as psoriasis. Recent advances in understanding 1,25(OH)(2)D(3) functions and novel insights into the mechanisms of its immunomodulatory properties suggest a wider applicability of this hormone in the treatment of autoimmune diseases and allograft rejection.
 
Article
MicroRNA molecules (miRNAs) are naturally occurring triggers of the RNA-interference pathway. The first identified miRNA, lin-4, was discovered in Caenorhabditis elegans >20 years ago. What began as a curiosity in this model organism has expanded into almost every area of biology; there are now 326 confirmed miRNA genes in humans and the total is predicted to reach 1000. Each miRNA has the potential to regulate hundreds of mRNAs; therefore, there are likely to be few biological pathways not impacted by miRNA regulation. Recent evidence has suggested that miRNAs might be viable therapeutic targets for a wide range of diseases, including cancer. A recent article by Stoffel and colleagues has demonstrated remarkably effective inhibition of miRNAs in vivo, thus providing an entry point into the promising new arena of miRNA therapeutics.
 
Article
Remodeling of the extracellular matrix--regulated by the matrix metalloproteinases (MMPs) and their endogenous inhibitors--is an important component of disease progression in many chronic disease states. Unchecked MMP activity can result in significant tissue damage, facilitate disease progression and is associated with host responses to pathologic injury, such as angiogenesis. The tissue inhibitors of metalloproteinases (TIMPs) have been shown to regulate MMP activity. However, recent findings demonstrate that an MMP-independent effect of TIMP-2 inhibits the mitogenic response of human microvascular endothelial cells to growth factors. This is the first demonstration of a cell-surface signaling receptor for a member of the TIMP family and suggests that TIMP-2 functions to regulate cellular responses to growth factors. These new findings are integrated in a comprehensive model of TIMP-2 function in tissue homeostasis.
 
Article
Natural FOXP3+CD25+CD4+ regulatory T cells (Tregs) actively suppress pathological and physiological immune responses, contributing to the maintenance of immunological self-tolerance and immune homeostasis. Various molecular and cellular events have been described to explain the mechanism(s) of Treg-mediated suppression. However, none of the proposed mechanisms can explain all aspects of suppression. It is probable that various combinations of several mechanisms are operating, depending on the milieu and the type of immune responses, although there might be a single key mechanism that has a predominant role. Further studies of suppression and search for Treg-specific cell surface molecules are required for potential clinical application to treat and prevent immunological diseases and to control immune responses for the benefit of the host.
 
Article
Ubiquitin-containing cellular inclusions are characteristic of major neurodegenerative diseases and suggest an involvement of the ubiquitin-proteasome system. The frameshifted form of ubiquitin has proved to be a valuable tool for studying the role of the ubiquitin-proteasome system. It is an endogenous reporter for proteasome activity in human pathology but it is also capable of inhibiting proteasomal degradation. Current studies have revealed that the frameshifted form of ubiquitin accumulates in the brains of patients with Alzheimer's disease but not in those with Parkinson's disease.
 
Article
Rapamycin, a valuable drug with diverse clinical applications, inhibits mTOR (mammalian target of rapamycin), which is a protein kinase that controls cell growth by regulating many cellular processes, including protein synthesis and autophagy. The sensitivity of select tumor cells to rapamycin has ignited considerable excitement over its potential as an anti-cancer therapeutic. Recent findings identified a rapamycin-insensitive function of mTOR in regulating a cell-survival pathway that is hyperactive in many cancers, particularly those with elevated PtdIns3K signaling or harboring mutations in the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10). These new findings suggest that targeting this function of mTOR might have broader applications in cancer therapy. In this article, we re-evaluate mTOR signaling, suggesting a more central role for mTOR in cancers with defective PtdIns3K-PTEN signaling and conceptually discuss these implications in the context of drug discovery.
 
Article
Recent studies show that activation of p38 mitogen-activated protein kinase (MAPK) results in cancer cell apoptosis initiated by retinoids, cisplatin and other chemotherapeutic agents. The observation that divergent therapies act through a common signal transduction pathway raises the possibility of developing new anti-cancer agents that lack the side-effects caused by events upstream of p38 MAPK. Here, we review p38-MAPK-mediated tumor cell apoptosis and implications for cancer therapeutics.
 
Article
Antibiotic resistance is a problem that continues to challenge the healthcare sector. In particular, multidrug resistance is now common in familiar pathogens such as Staphylococcus aureus and Mycobacterium tuberculosis, as well as emerging pathogens such as Acinetobacter baumannii. New antibiotics and new therapeutic strategies are needed to address this challenge. Advances in identifying new sources of antibiotic natural products and expanding antibiotic chemical diversity are providing chemical leads for new drugs. Inhibitors of resistance mechanisms and microbial virulence are orthogonal strategies that are also generating new chemicals that can extend the life of existing antibiotics. This new chemistry, coupled with a growing understanding of the mechanisms, origins and distribution of antibiotic resistance, position us to tackle the challenges of antibiotic resistance in the 21st century.
 
Article
Age-related macular degeneration (AMD) is the leading cause of blindness in elderly patients. The more aggressive exudative form is characterized by abnormal blood-vessel development that occurs beneath the retina as a result of choroidal neovascularization (CNV). Vascular endothelial growth factor (VEGF) has emerged as the key mediator of CNV formation; this has led to intensive research on VEGF and the recent approval of anti-VEGF compounds by the US Food and Drug Administration. Despite this successful introduction of anti-angiogenic therapies into the clinical setting, there is still a lack of treatments that definitively reverse damaged vision. Here, we consider the importance of putative molecular targets other than VEGF that might have been underestimated. Emerging cellular mechanisms offer additional opportunities for innovative therapeutic approaches.
 
Article
Post-transcriptional regulation of RNA is an important mechanism for activating and resolving cellular stress responses. Poly(ADP-ribose) polymerase-13 (PARP13), also known as ZC3HAV1 and zinc-finger antiviral protein (ZAP), is an RNA-binding protein that regulates the stability and translation of specific mRNAs, and modulates the miRNA silencing pathway to globally affect miRNA targets. These functions of PARP13 are important components of the cellular response to stress. In addition, the ability of PARP13 to restrict oncogenic viruses and to repress the prosurvival cytokine receptor tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 4 (TRAILR4) suggests that it can be protective against malignant transformation and cancer development. The relevance of PARP13 to human health and disease make it a promising therapeutic target. Copyright © 2015 Elsevier Ltd. All rights reserved.
 
Article
The mammalian target of rapamycin (mTOR) is an unconventional protein kinase that is centrally involved in the control of cancer cell metabolism, growth and proliferation. The mTOR pathway has attracted broad scientific and clinical interest, particularly in light of the ongoing clinical cancer trials with mTOR inhibitors. The mixed clinical results to date reflect the complexity of both cancer as a disease target, and the mTOR signaling network, which contains two functionally distinct mTOR complexes, parallel regulatory pathways, and feedback loops that contribute to the variable cellular responses to the current inhibitors. In this review, we discuss the regulatory pathways that govern mTOR activity, and highlight clinical results obtained with the first generation of mTOR inhibitors to reach the oncology clinics.
 
Article
Adult skeletal muscle contains an abundant and highly accessible population of muscle stem and progenitor cells called satellite cells. The primary function of satellite cells is to mediate postnatal muscle growth and repair. Owing to their availability and remarkable capacity to regenerate damaged muscle, satellite cells and their descendent myoblasts have been considered as powerful candidates for cell-based therapies to treat muscular dystrophies and other neuromuscular diseases. However, regenerative medicine in muscle repair requires a thorough understanding of, and the ability to manipulate, the molecular mechanisms that control the proliferation, self-renewal and myogenic differentiation of satellite cells. Here, we review the latest advances in our current understanding of the quiescence, activation, proliferation and self-renewal of satellite cells and the challenges in the development of satellite cell-based regenerative medicine.
 
Article
Aminopeptidase N (CD13) is a widely expressed ectoenzyme with functions that do not always depend on its enzymatic activity: an aspect that has been overlooked. Numerous CD13-targeting tools have been developed in the last few years. Several of them are already undergoing clinical trials, and there are promising reports on the effectiveness of others in animal models of disease. However, their efficacy might be obscured by their effects on unrecognized functions of CD13, resulting in unexpected complications. The purpose of this review is (i) to discuss the various functions ascribed to CD13 and the possible mechanisms behind them and (ii) to consider some of the questions that need to be answered to achieve a better understanding of the biological relevance of these functions, a more precise interpretation of the results obtained after their manipulation and a more rational design of CD13-targeting agents.
 
Article
Dendritic cells (DCs) are thought to mediate HIV-1 transmission but it is becoming evident that different DC subsets at the sites of infection have distinct roles. In the genital tissues, two different DC subsets are present: the Langerhans cells (LCs) and the DC-SIGN(+)-DCs. Although DC-SIGN(+)-DCs mediate HIV-1 transmission, recent data demonstrate that LCs prevent HIV-1 transmission by clearing invading HIV-1 particles. However, this protective function of LCs is dependent on the function of the C-type lectin Langerin: blocking Langerin function by high virus concentrations enables HIV-1 transmission by LCs. Here, we will discuss the molecular mechanisms involved in HIV-1 transmission and viral clearance. A better understanding of these processes is crucial to understand and develop strategies to combat transmission.
 
Signaling pathways targeted by PP2A inhibitor protein I2PP2A/SET. (a) PP2A inhibition by I2PP2A/SET stimulates BCR-ABL-mediated signaling. (i) BCR-ABL protein stability is negatively regulated by SHP-1-mediated tyrosine dephosphorylation. (ii) In BCR-ABL positive cells, BCR-ABL kinase activity stimulates I2PP2A/SET expression. (iii) I2PP2A/SET inhibits PP2A activity, and (iv) thereby attenuates SHP-1 activity and BCR-ABL tyrosine dephosphorylation. (v) The consequence of I2PP2A/SET expression is stabilization of BCR-ABL and increased activity of indicated downstream signaling pathways. (b) PP2A inhibition by I2PP2A/SET also stimulates activity of the MEK-ERK-MAPK pathway and c-Jun phosphorylation. Question marks denote that the direct target(s) of the I2PP2A/SET inhibited PP2A activity in MEK-ERK and JNK-c-Jun pathways have not been identified. 
PP2A inhibitor CIP2A stabilizes Myc protein. (a) Myc is phosphorylated on threonine 58 (T58) and serine 62 (S62) by GSK-3 and ERK kinases, respectively. (b) PP2A binds to the N-terminus of phosphorylated Myc via B56a. (c) CIP2A directly interacts with Myc and inhibits PP2A-mediated S62 dephosphorylation. Inhibition of S62 dephosphorylation results in Myc protein stabilization. (d) In the absence of CIP2A, PP2A dephosphorylates S62, which targets Myc phosphorylated at T58 for ubiquitination and for proteolytic degradation. 
Article
Reversible protein phosphorylation plays a central role in regulating intracellular signaling. Dysregulation of the mechanisms that regulate phosphorylation plays a direct role in cancer initiation and maintenance. Although abundant evidence supports the role of kinase oncogenes in cancer development, recent work has illuminated the role of specific protein phosphatases in malignant transformation. Protein phosphatase 2A (PP2A) is the major serine-threonine phosphatase in mammalian cells. Inactivation of PP2A by viral oncoproteins, mutation of specific subunits or overexpression of endogenous inhibitors contributes to cell transformation by regulating specific phosphorylation events. Here, we review recent progress in our understanding of how PP2A regulates mitogenic signaling pathways in cancer pathogenesis and how PP2A activity is modulated in human cancers.
 
Article
The study of reactive oxygen species (ROS) and oxidative stress remains a very active area of biological research, particularly in relation to cellular signaling and the role of ROS in disease. In the cerebral circulation, oxidative stress occurs in diverse forms of disease and with aging. Within the vessel wall, ROS produce complex structural and functional changes that have broad implications for regulation of cerebral perfusion and permeability of the blood-brain barrier. These oxidative-stress-induced changes are thought to contribute to the progression of cerebrovascular disease. Here, we highlight recent findings in relation to oxidative stress in the cerebral vasculature, with an emphasis on the emerging role for NADPH oxidases as a source of ROS and the role of ROS in models of disease.
 
Article
Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular and bioinformatic approaches being used to understand the complex epigenetic regulation of gene expression by drugs of abuse. This novel mechanistic insight might open new avenues for improved treatments of drug addiction.
 
Article
Forkhead transcription factors have a 'winged helix' domain and regulate processes that range from cell longevity to cell death. Of the mammalian forkhead family members in the O class, FoxO1, FoxO3a and FoxO4 can fill a crucial void for the treatment of disorders that include aging, cancer, diabetes, infertility, neurodegeneration and immune system dysfunction. Yet, observations that forkhead family members also can compromise clinical utility have fueled controversy and highlight the necessity to further outline the integrated cellular pathways governed by these transcription factors. Here we discuss recent advances that have elucidated the unique cellular pathways and clinical potential of targeting FoxO proteins to develop novel therapeutic strategies and avert potential pitfalls that might be closely intertwined with its benefits for patient care.
 
Article
MicroRNAs (miRNAs) are small noncoding RNAs, approximately 22 nucleotides in length, that repress target messenger RNAs (mRNAs) through an antisense mechanism. The let-7 miRNA was originally discovered in the nematode Caenorhabditis elegans, where it regulates cell proliferation and differentiation, but subsequent work has shown that both its sequence and its function are highly conserved in mammals. Recent results have now linked decreased let-7 expression to increased tumorigenicity and poor patient prognosis. Moreover, during normal development, accumulation of let-7 can be prevented by LIN28, a promoter of pluripotency. Based on these findings, we propose that let-7 regulates 'stemness' by repressing self-renewal and promoting differentiation in both normal development and cancer. A more complete understanding of its function will thus provide insights into these processes and might yield diagnostic and therapeutic advances for cancer treatment.
 
Article
The neurofibromatoses NF1 and NF2 are inherited cancer predisposition syndromes in which affected individuals are prone to development of mostly benign, but occasionally malignant, tumors. The NF1 and NF2 genes function as tumor suppressor genes (negative growth regulators), such that their loss of expression predisposes to tumor formation. Neurofibromin, the protein product of the NF1 gene, acts as a negative regulator of the ras proto-oncogene, to reduce cell growth. Merlin, the NF2 gene product, is involved in regulating cell proliferation and motility, and probably plays a role in integrating multiple cell-signaling pathways. By understanding the function of these tumor suppressors, we have a unique opportunity to develop targeted pharmacotherapeutic interventions for these disorders.
 
Article
Successfully developed target-based therapies have significantly changed cancer treatment. Among many targets, the c-MET receptor tyrosine kinase and its ligand hepatocyte growth factor have recently gained considerable attention. The c-MET pathway is dysregulated in most human malignancies, and regulates tumor formation, progression and dissemination, and numerous c-MET pathway inhibitors are currently being evaluated in the clinic. Although some studies have shown impressive evidence of antitumor activity, the data should be interpreted with caution because of the distinct properties of these agents and diverse patient populations studied. Furthermore, in tumor types where patients might benefit from c-MET inhibition, rational combination treatments might ultimately provide maximal clinical benefit. Here, we review the evidence linking c-MET activation to cancer, and discuss the latest progress, opportunities and challenges in the clinical development of c-MET pathway inhibitors.
 
Article
The p53 tumor suppressor protein has well-established roles in monitoring various types of stress signals by activating specific transcriptional targets that control cell cycle arrest and apoptosis, although some activities are also mediated in a transcription-independent manner. Here, we review the recent advances in our understanding of the wide spectrum of post-translational modifications that act as epigenetic-like codes for modulating specific functions of p53 in vivo and how deregulation of these modifications might contribute to tumorigenesis. We also discuss future research priorities to further understand p53 post-translational modifications and the interpretation of genetic data in appreciation of the increasing evidence that p53 regulates cellular metabolism, autophagy and many unconventional tumor suppressor activities.
 
Article
S-nitrosylation is a ubiquitous redox-related modification of cysteine thiol by nitric oxide (NO), which transduces NO bioactivity. Accumulating evidence suggests that the products of S-nitrosylation, S-nitrosothiols (SNOs), play key roles in human health and disease. In this review, we focus on the reaction mechanisms underlying the biological responses mediated by SNOs. We emphasize reactions that can be identified with complex (patho)physiological responses, and that best rationalize the observed increase or decrease in specific classes of SNOs across a spectrum of disease states. Thus, changes in the levels of various SNOs depend on specific defects in both enzymatic and non-enzymatic mechanisms of nitrosothiol formation, processing and degradation. An understanding of these mechanisms is crucial for the development of an integrated model of NO biology, and for effective treatment of diseases associated with dysregulation of NO homeostasis.
 
Article
Alterations in histone lysine methylation and other epigenetic regulators of gene expression contribute to changes in brain transcriptomes in mood and psychosis spectrum disorders, including depression and schizophrenia. Genetic association studies and animal models implicate multiple lysine methyltransferases and demethylases in the neurobiology of emotion and cognition. Here, we review the role of histone lysine methylation and transcriptional regulation in normal and diseased neurodevelopment and discuss various methyltransferases and demethylases as potential therapeutic targets in the treatment of neuropsychiatric disease.
 
Article
Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. Abnormal filamentous tau deposits constitute a major defining characteristic of several neurodegenerative diseases, including Alzheimer's disease. Although the presence of tau pathology correlates with the symptoms of Alzheimer's disease, there was no genetic evidence linking tau to neurodegeneration until recently. However, since 1998, the identification of more than 25 mutations in the tau gene, associated with frontotemporal dementia and parkinsonism linked to chromosome 17, has demonstrated that tau dysfunction can lead to neurodegeneration and the development of clinical symptoms.
 
Article
Tuberous sclerosis (TSC) is a genetic disorder caused by heterozygous mutations in the TSC1 or TSC2 genes and is associated with autism spectrum disorders (ASD) in 20-60% of cases. In addition, altered TSC/mTOR signaling is emerging as a feature common to a subset of ASD. Recent findings, in animal models, show that restoration of the underlying molecular defect can improve neurological dysfunction in several of these models, even if treatment is initiated in adult animals, suggesting that pathophysiological processes in the mature brain contribute significantly to the overall neurological phenotype in these models. These findings suggest that windows for therapeutic intervention in ASD could be wider than thought previously.
 
Article
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a deficiency of functional SMN protein because of mutations in SMN1. A decrease in SMN activity results in motor neuron cell loss in the spinal cord, leading to a weakness of the proximal muscles responsible for crawling, walking, head/neck control and swallowing as well as the involuntary muscles that control breathing and coughing. Thus, patients present with pulmonary manifestations, paralysis and a shortened lifespan. Gene therapy is emerging as a promising therapeutic strategy for SMA given that the molecular basis for this monogenic disorder is well established. Recent advances and findings from preclinical studies in animal models provide optimism that gene therapy might be an effective therapeutic strategy for treating SMA.
 
Article
Medulloblastomas often activate Hedgehog signaling inappropriately. The finding that mutations in components of this pathway are present only in few tumors suggests that additional genetic or epigenetic lesions can also lead to Hedgehog dysregulation. Chromosome 17p deletion, the most frequently detected genetic lesion in medulloblastoma, has recently been identified as a cause of unrestrained Hedgehog signaling. Such a deletion leads to the loss of REN(KCTD11), a novel Hedgehog antagonist, thus removing a checkpoint of Hedgehog-dependent events during cerebellum development and tumorigenesis. The disruption of additional Hedgehog modulators that map to 17p suggests a rationale for a multitargeted therapeutic strategy aimed at interrupting the cooperative activation of the Hedgehog pathway.
 
Article
Hypoxia inducible factors (HIFs) regulate a variety of genes to prepare cells to adapt and survive under a hypoxic environment. Recently, microRNAs (miRNAs) have emerged as a new class of genes regulated by HIFs in response to hypoxia, of which miR-210 is the most consistently and predominantly upregulated miRNA. Functional studies have demonstrated that miR-210 is a versatile gene that regulates many aspects of hypoxia pathways, both in physiological and malignant conditions. Here, we summarize recent findings on the mechanism of hypoxia regulation of miR-210 expression and its multifaceted biological functions in normal physiological and malignant conditions, and discuss the challenges we face in elucidating the biological functions of miR-210 and exploring its potential use for therapeutics.
 
Article
Caspase-mediated apoptosis is a major hindrance to tumour growth and metastasis. Accordingly, defects in signalling pathways leading to the activation of caspases are common in tumours. Moreover, many tumour cells can unexpectedly survive the activation of caspases. As a result, caspase-independent cell death programmes are gaining increasing interest among cancer researchers. The heterogeneity of cancer cells with respect to their sensitivity to various death stimuli further emphasizes the need for additional death pathways in the therapeutic control of cell death. An understanding of the molecular control of alternative death pathways is beginning to emerge, being comparable with that of the molecular anatomy of apoptosis at the time of the discovery of caspases less than a decade ago. Here, newly discovered triggers and molecular regulators of alternative cell death programmes are reviewed and their potential in future cancer therapy is discussed.
 
Article
DNA vaccines have been widely used in efforts to develop vaccines against various pathogens as well as for cancer, autoimmune diseases and allergy. DNA vaccines offer broad efficacy (particularly for their ability to generate both cellular and humoral immunity), ease of construction and manufacture and the potential for world-wide usage even in low-resource settings. However, despite their successful application in many preclinical disease models, their potency in human clinical trials has been insufficient to provide protective immunity. Nevertheless, two DNA vaccines were recently licensed for use in animals (horse and fish), underscoring the potential of this technology. Here, we describe recent advances in increasing the potency of these vaccines, in understanding their immunological mechanisms, and in their applications and efficacy in clinical trials so far.
 
Article
Mesenchymal stem sells (MSCs) are present in a variety of tissues during human development, and in adults they are prevalent in bone marrow. From that readily available source, MSCs can be isolated, expanded in culture, and stimulated to differentiate into bone, cartilage, muscle, marrow stroma, tendon, fat and a variety of other connective tissues. Because large numbers of MSCs can be generated in culture, tissue-engineered constructs principally composed of these cells could be re-introduced into the in vivo setting. This approach is now being explored to regenerate tissues that the body cannot naturally repair or regenerate when challenged. Moreover, MSCs can be transduced with retroviral and other vectors and are, thus, potential candidates to deliver somatic gene therapies for local or systemic pathologies. Untapped applications include both diagnostic and prognostic uses of MSCs and their descendents in healthcare management. Finally, by understanding the complex, multistep and multifactorial differentiation pathway from MSC to functional tissues, it might be possible to manipulate MSCs directly in vivo to cue the formation of elaborate, composite tissues in situ.
 
Article
Birth defects occur in nearly 5% of all live births and are the major cause of infant mortality and morbidity. Despite the recent progress in molecular and developmental biology, the underlying genetic etiology of most congenital anomalies remains unknown. Heterozygous deletion of the 22q11.2 locus results in the most common human genetic deletion syndrome, known as DiGeorge syndrome, and has served as an entry to understanding the basis for numerous congenital heart and craniofacial anomalies, among many other defects. Extensive human genetic analyses, mouse modeling and studies of developmental molecular cascades involved in 22q11 deletion syndrome are revealing complex networks of signaling and transcriptional events that are essential for normal embryonic development. Armed with this knowledge, we can now begin to consider the multiple genetic "hits" that might contribute to developmental anomalies, some of which could provide targets for in utero prevention of birth defects.
 
Article
Membrane and protein traffic in the secretory and endocytic pathways is mediated by vesicular transport. Recent studies of certain key regulators of vesicular transport, the Rab GTPases, have linked Rab dysfunction to human disease. Mutations in Rab27a result in Griscelli syndrome, caused by defects in melanosome transport in melanocytes and loss of cytotoxic killing activity in Tcells. Other genetic diseases are caused by partial dysfunction of multiple Rab proteins resulting from mutations in general regulators of Rab activity; Rab escort protein-1 (choroideremia), Rab geranylgeranyl transferase (Hermansky-Pudlak syndrome) and Rab GDP dissociation inhibitor-alpha (X-linked mental retardation). In infectious diseases caused by intracellular microorganisms, the function of endocytic Rabs is altered either as part of host defences or as part of survival strategy of the pathogen. The human genome is predicted to contain 60 RAB genes, suggesting that future work could reveal further links between Rab dysfunction and disease.
 
Article
Colorectal cancer is a leading cause of cancer-related deaths throughout the world. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the few agents that are known to inhibit colorectal tumorigenesis. The mechanisms that underlie this effect are poorly understood. Two recent studies have provided some significant insight. Castellone and colleagues showed that prostaglandin E2 modulates the beta-catenin signaling axis, a key pathway for colorectal tumorigenesis. Holla and colleagues showed that prostaglandin E2 might act via a nuclear receptor. These findings shed light on the mechanisms that underlie prostaglandin action, and provide a molecular framework for developing future treatments for colorectal cancer.
 
Article
Most common forms of hair loss (alopecia) are caused by aberrant hair follicle cycling and changes in hair follicle morphology. However, current treatments for alopecia do not specifically target these processes. We are now beginning to identify the molecules and molecular pathways that control normal hair follicle formation, cycling and growth. In parallel, new techniques are being developed for delivering molecules to hair follicles. Here, we outline the characteristics of common hair loss diseases, and discuss ways in which recent advances in hair follicle biology could be translated into effective therapies for these conditions.
 
Article
Nitric-oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs), which consist of an NSAID with an NO-donating moiety covalently attached to it, promise to contribute significantly towards the development of effective chemoprevention strategies against cancer. NO-NSAIDs inhibit the growth of cultured cancer cells 10-6000-fold more potently than their parent NSAIDs and prevent colon cancer in animal tumor models. Clinical data indicate that they are extremely safe. Mechanistically, NO-aspirin, the best-studied NO-NSAID, has pleiotropic effects on cell signaling (it inhibits Wnt signaling, induces nitric oxide synthase and NF-kappaB activation and induces cyclooxygenase-2 expression), and this mechanistic redundancy might be central to its mode of action against cancer. The apparent safety and superior efficacy of NO-NSAIDs makes them promising chemopreventive agents against cancer.
 
Article
Sight-threatening eye diseases can be caused and exacerbated by the aberrant growth of new blood vessels. Recent work indicates that this neovascularization not only is a response to a rise in the local concentration of molecules that induce such angiogenesis but also requires a fall in the levels of endogenous molecules that inhibit angiogenesis. One of the most potent of these endogenous inhibitors is pigment epithelium-derived factor (PEDF), which serves as a survival factor for neuronal components of the eye as well as an essential inhibitor of the growth of ocular blood vessels. Its anti-angiogenic activity is selective in that it is effective against newly forming vessels but spares existing ones, and it is reversible. The molecular basis for this delicate control of endothelial cells is beginning to be understood and strategies to test the ability of PEDF to ameliorate or prevent vessel damage in the eye are developing rapidly.
 
Article
The number of mammalian calpain protease family members has grown to 14 on last count. Overactivation of calpain 1 and calpain 2 (and their small subunit) has long been tied to acute neurological disorders (e.g. stroke and traumatic brain injury) and recently to Alzheimer's disease. Loss-of-function mutations of the calpain 3 gene have now been identified as the cause of limb-girdle muscular dystrophy 2A. Calpain 10 was recently identified as a susceptibility gene for type 2 diabetes, whereas calpain 9 appears to be a gastric cancer suppressor. This review describes our current understanding of the calpain family members and their mechanistic linkages to the aforementioned diseases as well as other emerging pathological conditions.
 
Article
Eradication of advanced prostate cancer still represents an unsolved clinical problem, making the development of alternative treatment approaches highly desirable. Understanding the molecular alterations that distinguish non-progressive from progressive disease would provide mechanistic information for the identification of new therapeutic targets. Recent findings indicate that human tumors have deregulated expression of microRNAs, which have thus been proposed as novel oncogenes or tumor suppressors. A few studies have analyzed the expression profiles or the functional role of microRNAs in prostate cancer, generating largely inconsistent data. Here we review the major issues that have hindered the identification of prostate cancer-related microRNAs, outlining an approach for rational validation of candidates that might be clinically relevant in the management of this disease.
 
Therapeutic strategies for the targeted induction of apoptosis in human cancer cells. (1) Naked monoclonal antibodies (e.g. RituxiMAb and ApolizuMAb) bind to and crosslink their target antigen, which results in activation of the mitochondrial pathway of apoptosis. (2) Galectin-1 binds to carbohydrate moieties on various cell surface-expressed proteins and triggers caspase-independent apoptosis that is characterized by specific release of endonuclease G from the mitochondria. (3) Apoptosis is activated by triggering of death receptors by recombinant forms of the cognate deathinducing ligand. (4) Hypoxia in the tumor microenvironment upregulates the expression of the transcription factor HIF-1α, which protects towards apoptosis. The function of HIF-1α can be specifically inhibited by the small-molecule inhibitor PX-478, whereupon cells undergo apoptosis. (5) The antiapoptotic proteins BCL-2 and BCL-xL shift the balance of mitochondria towards survival. Inhibition of BCL-2, using the antisense ODN genasense, and inhibition of both BCL-2 and BCL-xL, using small molecule inhibitor ABT-737, blocks the anti-apoptotic function of these proteins and thereby shifts the balance towards induction of mitochondrial apoptosis. (6) Inhibition of the proteasome, using the inhibitor bortezomib, deregulates protein homeostasis leading to cell cycle arrest and activation of the mitochondrial apoptotic pathway. (7) Inhibition of the important chaperone molecule HSP90, using 17-AAG, results in proteasomal degradation of regulatory proteins and subsequent cell-cycle arrest and activation of the mitochondrial apoptotic pathway. (8) Inhibition of the XIAP-mediated block on active caspase-9, using SMAC peptides, sensitizes tumor cells towards apoptosis. Inhibition of the XIAP-mediated block on active caspase-3, using small-molecule inhibitors, results in potent activation of apoptosis. (9) Demethylation of cellular DNA, using decitabine, induces growth arrest and concomitant apoptosis. (10) Restoring the balance between histone acetylation and histone deacetylation with histone deacetylase inhibitors such as valproic acid results in increased acetylation,
Target-cell-restricted induction of apoptosis by scFv-death-ligand fusion proteins. Specific binding of scFv-death-ligand fusion proteins to the tumor target antigen results in accretion at the cell surface. Subsequently, apoptosis can be induced in an autocrine manner by binding to the cognate death receptor on the same tumor cells. Alternatively, specific binding of scFv-death ligand to the tumor target antigen on one cell can induce crosslinking of cognate death receptors on a neighboring target antigen-positive tumor cell, resulting in paracrine target cell apoptosis. In addition, paracrine crosslinking of cognate death receptors on a neighboring target antigen negative tumor cell results in bystander cell apoptosis. This bystander effect depends only on the presence of functional cognate death receptors.
Article
Important breakthroughs in cancer therapy include clinical application of antibodies, such as Rituximab, and small inhibitory molecules, such as Iressa and Velcade. In addition, recent reports have indicated the therapeutic potential of physiological pro-apoptotic proteins such as TRAIL and galectin-1. Although unrelated at first glance, each strategy relies on the deliberate and selective induction of apoptosis in malignant cells. Importantly, therapy-resistance in cancer is frequently associated with de-regulation in the mechanisms that control apoptosis. However, cancer cells are often reliant on these molecular aberrations for survival. Therefore, selective induction of apoptosis in cancer cells but not normal cells seems feasible. Here, we review recent progress and prospects of selected novel anti-cancer approaches that specifically target and sensitize cancer cells to apoptosis.
 
Article
The transcription factor nuclear factor (NF)-kappaB is activated in certain cancers and in response to chemotherapy and radiation. The transcriptional activation of genes associated with cell proliferation, angiogenesis, metastasis and suppression of apoptosis appears to lie at the heart of the ability of NF-kappaB to promote oncogenesis and cancer therapy resistance. Supporting these findings are recent experiments, performed in vitro and using xenograft models of cancer, which implicate NF-kappaB inhibition as an important new approach for the treatment of certain hematological malignancies and as an adjuvant approach in combination with chemotherapy or radiation for a variety of cancers. Clinical trials with drugs that block NF-kappaB are currently in progress with promising results. However, as there is currently no drug that blocks specific NF-kappaB activation, conclusions drawn with small-molecule inhibitors must be interpreted carefully.
 
Article
Semaphorins have been classically defined as axonal signalling cues involved in central nervous system (CNS) development, but in adults these molecules are expressed in distinct tissues and exert various functions under several physiological and pathological contexts. Semaphorins capable of modulating the immune system are particularly relevant in autoimmune diseases, especially multiple sclerosis (MS), which is a demyelinating, neurodegenerative disease. In this article, we compile recent insights into the specific roles of semaphorin (sema)3A and sema7A to clarify the details of their possible participation in the inflammatory and neurodegenerative phases of MS.
 
Article
Experimental models indicate that tumor cells in suspension, unlike solid tumor fragments, might be unable to produce life-threatening cancer outgrowth when transferred to animal models, irrespective of the number of cells transferred, although they induce specific immune responses. Human tumor cells cultured in three dimensions display increased pro-angiogenic capacities and resistance to interferons, chemotherapeutic agents or irradiation, as compared with cells cultured in two-dimensional (2D) monolayers. Tumor cells cultured in three dimensions were also shown to be characterized by defective immune recognition by cytotoxic T lymphocytes (CTLs) specific for tumor-associated antigens (TAAs) and by a capacity to inhibit CTL proliferation and dendritic cell (DC) functions. Downregulation of human leukocyte antigen (HLA) or TAA expression and high production of lactic acid might play a role in the elicitation of these effects. Here, we propose that growth in 3D architectures might provide new insights into tumor immunology and could represent an integral missing component in pathophysiological tumor immune escape mechanisms.
 
Article
Adult neural stem cells hold great promise for repair because of their unique location within the central nervous system, their potential to proliferate and to differentiate into all major neural lineages, and their ability to incorporate functionally into the existing neuronal circuitry. However, recruitment of these cells for repair is hampered by the lack of knowledge about the signals that control the generation of a functional neuron from adult neural stem cells. Here, we discuss recent findings on the regulatory mechanisms that underlie neurogenesis from neural stem cells in the adult hippocampus and the implications of these findings for future stem-cell-based repair strategies.
 
Article
Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors that regulate lipid and lipoprotein metabolism, glucose homeostasis and inflammation. The PPAR family consists of three proteins, alpha, beta/delta and gamma. Recent data suggest that PPAR alpha and gamma activation decreases atherosclerosis progression not only by correcting metabolic disorders, but also through direct effects on the vascular wall. PPARs modulate the recruitment of leukocytes to endothelial cells, control the inflammatory response and lipid homeostasis of monocytes/macrophages and regulate inflammatory cytokine production by smooth muscle cells. Experiments using animal models of atherosclerosis and clinical studies in humans strongly support an anti-atherosclerotic role for PPAR alpha and gamma in vivo. Thus, PPARs remain attractive therapeutic targets for the development of drugs used in the treatment of chronic inflammatory diseases such as atherosclerosis. Future research will aim for the development of more potent drugs with co-agonist activity on PPAR alpha, PPAR beta/delta and/or PPAR gamma as well as tissue and target gene-selective PPAR receptor modulators (SPPARMs).
 
Article
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are clinically distinct fatal neurodegenerative disorders. Increasing molecular evidence indicates that both disorders are linked in a continuous spectrum (ALS-FTD spectrum). Neuronal cytoplasmic inclusions consisting of the nuclear TAR DNA-binding protein 43 (TDP-43) are found in the large majority of patients in the ALS-FTD spectrum and dominant mutations in the TDP-43 gene cause ALS. A major unresolved question is whether TDP-43-mediated neuronal loss is caused by toxic gain of function of cytoplasmic aggregates, or by a loss of its normal function in the nucleus. Here we argue that based on recent genetic studies in worms, flies, fish, and rodents, loss of function of TDP-43, rather than toxic aggregates, is the key factor in TDP-43-related proteinopathies.
 
Article
Until a couple of years ago, TAR-DNA-binding protein-43 (TDP-43) was a relatively unknown nuclear protein implicated in transcriptional repression and splicing. Since 2006, when the protein was reported to be present in inclusions in the neurons and/or glial cells of a range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive, tau- and alpha-synuclein-negative inclusions (FTLD-U) and Alzheimer's disease (AD), many reports on the medical aspects of TDP-43 have been published. Here, we summarize the current literature on TDP-43, focusing on recent studies that provide clues to the function of TDP-43. Using this information and database analysis, we also suggest a molecular and cellular model for possible events in normal and diseased neurons in relation to the emerging importance of the function and dysfunction of this protein as a target for basic as well as translational research.
 
Article
Following the induction of DNA damage, a prominent route of cell inactivation is apoptosis. During the last ten years, specific DNA lesions that trigger apoptosis have been identified. These include O6-methylguanine, base N-alkylations, bulky DNA adducts, DNA cross-links and DNA double-strand breaks (DSBs). Repair of these lesions are important in preventing apoptosis. An exception is O6-methylguanine-thymine lesions, which require mismatch repair for triggering apoptosis. Apoptosis induced by many chemical genotoxins is the consequence of blockage of DNA replication, which leads to collapse of replication forks and DSB formation. These DSBs are thought to be crucial downstream apoptosis-triggering lesions. DSBs are detected by ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related) proteins, which signal downstream to CHK1, CHK2 (checkpoint kinases) and p53. p53 induces transcriptional activation of pro-apoptotic factors such as FAS, PUMA and BAX. Many tumors harbor mutations in p53. There are p53 backup systems that involve CHK1 and/or CHK2-driven E2F1 activation and p73 upregulation, which in turn transcribes BAX, PUMA and NOXA. Another trigger of apoptosis upon DNA damage is the inhibition of RNA synthesis, which leads to a decline in the level of critical gene products such as MKP1 (mitogen-activated protein kinase phosphatase). This causes sustained activation of JNK (Jun kinase) and, finally, AP-1, which stimulates death-receptor activation. DNA damage-triggered signaling and execution of apoptosis is cell-type- and genotoxin-specific depending on the p53 (p63 and p73) status, death-receptor responsiveness, MAP-kinase activation and, most importantly, DNA repair capacity. Because most clinical anti-cancer drugs target DNA, increasing knowledge on DNA damage-triggered signaling leading to cell death is expected to provide new strategies for therapeutic interventions.
 
Top-cited authors
Bernd Kaina
  • Johannes Gutenberg University, University Medical Center, Mainz, Germany
Josie Louise Hayes
  • University of California, Berkeley
Sean Lawler
  • Brigham and Women's Hospital
Hozumi Motohashi
  • Tohoku University
Masayuki Yamamoto
  • Tohoku University