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At least 469 records · Page 26Linked to original sources
PubMed2002

Multiparameter analyses of cell cycle regulatory proteins in human breast cancer: a key to definition of separate pathways in tumorigenesis.

Breast cancer is one of the most common cancer forms affecting many women. The disease nevertheless has widely varying behavior and therefore patient outcome, and an important undertaking is to define and understand the molecular mechanisms behind these actions. Defects in the G1/S transition in the cell cycle affect both tumor proliferation and the fidelity of check points responsible for chromosomal integrity and DNA damage response and has lately been shown to represent one of a rather limited set of key aberrations in the transformation process. Many cell cycle regulatory proteins are either oncogenes or suppressor genes or are closely associated to the transformation process. The types of aberrations in the G1/S transition seem to be different in various cancers but are nevertheless often linked to clinical behaviors. In this review the role of multiparameter analyses of cell cycle regulatory proteins in breast cancer will be outlined with special attention to pattern analyses as well as the definition of two contrasting pathways in tumorigenesis defined by either cyclin D1 or cyclin F overexpression.

Breast Neoplasms↗
PubMed2001

Pathways for self-tolerance and the treatment of autoimmune diseases.

Antigen delivers both immunogenic and tolerogenic signals to lymphocytes. The outcome of antigen exposure represents a complex integration of the timing of antigen binding with signals from many other immunogenic and tolerogenic costimulatory pathways. A road map of these signalling pathways is only beginning to be charted, revealing the mechansim of action and limitations of current immunotherapeutic agents and the points of attack for new agents. Ciclosporin and tacrolimus interfere with tolerogenic signals from antigen in addition to blocking immunogenic signals, thus preventing active establishment of tolerance. Corticosteroids inhibit a key immunogenic pathway, NFkappaB, and more specific inhibitors of this pathway may allow tolerance to be actively established while immune responses are blocked. New experimental therapies aim to mimic tolerogenic antigen signals by chronically stimulating antigen receptors with antigen or antibodies to the receptor, or aim to block costimulatory pathways involving CD40 ligand, B7, or interleukin 2. Obtaining the desired response with these strategies is unpredictable because many of these signals have both tolerogenic and immunogenic roles. The cause of autoimune diseases has been determined for several rare monogenic disorders, revealing inherited deficiencies in tolerogenic costimulatory pathways such as FAS. Common autoimmune disorders may have a biochemically related pathogenesis.

Animals↗
PubMed2025

HEPARIN AND DNase I TREAT MYOCARDIAL INJURY IN SEPTIC MICE.

Background: Sepsis is a life-threatening clinical condition often seen in intensive care units, leading to multi-organ dysfunction. Myocardial injury is a prevalent complication, significantly increasing mortality among sepsis patients. Although heparin is used in sepsis management, its specific effects on myocardial injury and the role of neutrophil extracellular traps (NETs) in this context remain insufficiently understood. Aim: This study investigates the role of unfractionated heparin (UFH) combined with DNase I in reducing myocardial injury in a septic mouse model. Methods: A cecal ligation and puncture (CLP)-induced sepsis model was established in C57BL/6 mice to study myocardial injury. The experimental groups included treatments with UFH, UFH with DNase I, and NETs introduction. Myocardial injury was assessed using hematoxylin and eosin staining, enzyme linked immunosorbent assay for injury markers (creatine kinase MB [CK-MB] and lactate dehydrogenase [LDH]), and Western blotting for inflammatory proteins (TNF-α and IL-6). Differential proteomic analysis using data independent acquisition mass spectrometry and pathway enrichment analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) were conducted to identify molecular pathways and key proteins affected by the treatments. Results: Single UFH treatment increased the formation of NETs, upregulated TNF-α and IL-6, and increased CK-MB and LDH, worsening myocardial injury. The combination of UFH and DNase I significantly reduced myocardial injury, suppressing NETs formation and inflammation. Proteomic analysis identified crucial pathways related to NETs, metabolism, and complement and coagulation cascades, with proteins Ccn1 and Tagln highlighted as potential therapeutic targets. Conclusion: UFH combined with DNase I effectively alleviates myocardial injury in septic mice by modulating NETs formation and associated inflammatory processes. This study may provide new insights and options for the early use of heparin in the treatment of septic patients, particularly in cases with a higher risk of myocardial injury.

Animals↗
PubMed2003

An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle.

Skeletal muscle adapts to chronic physical activity by inducing mitochondrial biogenesis and switching proportions of muscle fibers from type II to type I. Several major factors involved in this process have been identified, such as the calcium/calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A (CnA), and the transcriptional component peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha). Transgenic expression of PGC-1alpha recently has been shown to dramatically increase the content of type I muscle fibers in skeletal muscle, but the relationship between PGC-1alpha expression and the key components in calcium signaling is not clear. In this report, we show that the PGC-1alpha promoter is regulated by both CaMKIV and CnA activity. CaMKIV activates PGC-1alpha largely through the binding of cAMP response element-binding protein to the PGC-1alpha promoter. Moreover, we show that a positive feedback loop exists between PGC-1alpha and members of the myocyte enhancer factor 2 (MEF2) family of transcription factors. MEF2s bind to the PGC-1alpha promoter and activate it, predominantly when coactivated by PGC-1alpha. MEF2 activity is stimulated further by CnA signaling. These findings imply a unified pathway, integrating key regulators of calcium signaling with the transcriptional switch PGC-1alpha. Furthermore, these data suggest an autofeedback loop whereby the calcium-signaling pathway may result in a stable induction of PGC-1alpha, contributing to the relatively stable nature of muscle fiber-type determination.

Animals↗
PubMed2026

A genome-wide in vivo screen reveals fitness pathways required for streptococcal infective endocarditis.

Infective endocarditis (IE) is a life-threatening disease most often caused by blood-borne bacteria that infect previously damaged cardiac tissue. Despite the importance of this disease, the genetic basis for IE-associated fitness remains poorly defined. Here, we present the first genome-wide in vivo analysis of bacterial fitness in a vertebrate model of IE. We identified 146 genes in Streptococcus sanguinis required for IE fitness, the majority of which had not previously been linked to endocarditis. These determinants cluster into conserved metabolic, cell envelope, transport, and regulatory pathways, representing a vast reservoir of potential targets for novel antimicrobial intervention. A subset of these genes was examined in Streptococcus mutans; all were found to be essential for IE fitness in this distantly related oral species as well, suggesting broad conservation. Using experimental evolution, we further show that disruption of key fitness pathways triggers reproducible compensatory "bypass" mechanisms. Together, these findings provide a comprehensive, genome-wide map of the bacterial niche-requirements for streptococcal infective endocarditis.

Animals↗
PubMed2025

Cytoplasmic mRNA decay and quality control machineries in eukaryotes.

mRNA degradation pathways have key regulatory roles in gene expression. The intrinsic stability of mRNAs in the cytoplasm of eukaryotic cells varies widely in a gene- and isoform-dependent manner and can be regulated by cellular cues, such as kinase signalling, to control mRNA levels and spatiotemporal dynamics of gene expression. Moreover, specialized quality control pathways exist to rid cells of non-functional mRNAs produced by errors in mRNA processing or mRNA damage that negatively impact translation. Recent advances in structural, single-molecule and genome-wide methods have provided new insights into the central machineries that carry out mRNA turnover, the mechanisms by which mRNAs are targeted for degradation and the general principles that govern mRNA stability at a global level. This improved understanding of mRNA degradation in the cytoplasm of eukaryotic cells is finding practical applications in the design of therapeutic mRNAs.

RNA Stability↗
PubMed2004

Getting to grips with the granulocyte: manipulation of granulocyte behaviour and apoptosis by protein transduction methods.

Human granulocytes clearly play an important role in host defence against invading organisms, however they have also been implicated in the pathogenesis and progression of many chronic inflammatory diseases. In addition, these cells have been paramount in gaining a better understanding of many key-signalling pathways regulating fundamental biological processes. Since granulocytes are terminally differentiated and undergo relatively rapid constitutive apoptosis it has been difficult to manipulate intracellular events by transfection or transduction procedures. It has been shown in recent years that the HIV-TAT protein transduction system can be successfully used in granulocytes to manipulate key signalling mechanisms regulating functional responsiveness and survival. In this paper, we review recent literature highlighting important developments using this system in isolated human granulocytes and in inflammatory process in vivo where these cells play a prominent role.

Apoptosis↗
PubMed2001

Hepatitis C virus core protein enhances the activation of the transcription factor, Elk1, in response to mitogenic stimuli.

Mitogen-activated protein kinase (MAPK) pathways play key roles in cell proliferation, transformation of mammalian cells, and the stress response. We and other investigators showed that hepatitis C virus (HCV) core protein has an oncogenic potential, but its mechanism has remained unknown. We previously demonstrated that the MAPK-extra-cellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway and its downstream target, the serum response element (SRE), is activated in BALB/3T3 cells producing HCV core protein. To elucidate the precise mechanism by which HCV core protein activates the MEK-ERK pathway, we transiently expressed HCV core protein in several cell lines and studied the signal transduction of the pathway, using Gal4-Elk1 luciferase assay, in vitro kinas assay of MAPK, and Western blotting analysis. We discovered that, in the presence of mitogenic signal, HCV core protein enhanced Elk1 activation working downstream of MEK without affecting ERK activity and Elk1 phosphorylation. Our data suggest that HCV core protein may activate Elk1 through a pathway alternative to the typical phosphorylation cascade. These findings might give new insights into the role of HCV in hepatocarcinogenesis.

3T3 Cells↗
PubMed2004

Ras, PI3-kinase and mTOR signaling in cardiac hypertrophy.

Cardiac hypertrophy involves increased mass (growth) of the heart and a cardinal feature of this condition is increased rates of protein synthesis. Several signaling pathways have been implicated in cardiac hypertrophy including the phosphatidylinositol 3-kinase (PI3K) and Ras/Raf/MEK/Erk pathways. PI3K lies upstream of the mammalian target of rapamycin (mTOR), an important positive regulator of protein synthesis and cell growth. However, recent data suggest that, in response to certain hypertrophic agents, signaling via Ras and MEK/Erk, as well as mTOR, is required for activation of protein synthesis, indicating new connections between these key signaling pathways.

Animals↗
PubMed2003

Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis.

In a genome-wide ENU mouse mutagenesis screen a recessive mouse mutation, unmodulated, was isolated with profound defects in humoral immune responses, selective deficits in B cell activation by antigen receptors and T cell costimulation by CD28, and gradual development of atopic dermatitis with hyper-IgE. Mutant B cells are specifically defective in forming connections between antigen receptors and two key signaling pathways for immunogenic responses, NF-kappaB and JNK, but signal normally to calcium, NFAT, and ERK. The mutation alters a conserved leucine in the coiled-coil domain of CARMA-1/CARD11, a member of the MAGUK protein family implicated in organizing multimolecular signaling complexes. These results define Carma-1 as a key regulator of the plasticity in antigen receptor signaling that underpins opposing mechanisms of immunity and tolerance.

Aging↗
PubMed2005

VSV-tumor selective replication and protein translation.

The emergence of vesicular stomatatis virus (VSV) as a potent antitumor agent has made a dissection of the molecular determinants of host-cell permissiveness to this virus an important objective. Such insight would not only enable the intelligent design of future generations of recombinant VSV vectors to combat disease, but may also resolve general features of cellular transformation that may be exploited by this virus, and perhaps other oncolytic viruses. The defective pathways underlining the oncolytic activity of VSV remain to be fully determined but recent data indicates that flaws in innate immune responses, involving the interferon (IFN) system, may commonly occur in tumor cells and thus play a large role in facilitating oncolysis. Aside from the IFN system, however, it is almost certain that other key cellular pathways may be similarly defective and therefore cooperatively contribute towards mediating rapid oncolytic virus activity. Recent data have indicated that defects in cancer cell translational regulation could be one area that may be exploited by VSV. Certainly, all viruses require cellular protein synthesis pathways to facilitate their replication and many have devised numerous mechanisms to ensure that viral mRNAs become translated at the expense of the host. Using VSV as a model, this review will discuss some of the recent developments in the fields of innate immunity and translational regulation that may help explain mechanisms of viral oncolysis.

Immunity, Innate↗
PubMed2005

Targeting programmed cell death pathways with experimental therapeutics: opportunities in high-risk neuroblastoma.

Neuroblastoma is a pediatric solid tumor with high morbidity and mortality in association with particular high-risk biological and clinical features (such as MYCN proto-oncogene amplification or advanced tumor stage). Such high-risk neuroblastomas may be initially responsive to cytoreductive therapies, yet the majority will ultimately demonstrate de novo or acquired chemoresistance leading to tumor progression and death. Insight into the genetic alterations responsible for these phenotypes are beginning to be gained, and subversion of inherent programmed cell death pathways is a common theme. Intact apoptosis pathways protect cells against neoplastic transformation and provide the mechanisms by which cytotoxic agents exert their effects. When these pathways are abolished through alterations in the cell death machinery, they complement deregulated oncogenes to promote tumor initiation and therapy resistance. Currently, therapeutic intensity for high-risk neuroblastoma has been advanced to near-tolerance with only modest gains in survival, and it is likely that further improvements in outcome will require innovative approaches that target key regulatory pathways that potentiate currently available therapies. Efforts to abrogate the cancer cell 'survival bias' engendered by alterations in death pathways are now a major focus in experimental cancer therapeutics, and their application to the problem of high-risk neuroblastoma form the basis of this review. These include agents that activate death receptors (TRAIL-agonists) or restore DISC competency (CDDO, DNA methyltransferase and HDAC inhibitors); reduce pro-survival Bcl2 homologues (Oblimersen sodium [AS-Bcl2], AS-Mcl1) or deliver a pro-apoptotic BH3 protein burden (BH3 peptides, gossypol, ABT737); or repress IAPs (Smac/Diablo peptides, AS-XIAP, AS-Survivin). As our knowledge of apoptosis dysregulation in neuroblastoma evolves, the possibilities for pro-apoptotic therapeutics seems not only promising, but a realistic adjunct to conventional treatments.

Apoptosis↗
PubMed2006

The MAP kinase signal transduction network in Candida albicans.

MAP (mitogen-activated protein) kinase-mediated pathways are key elements in sensing and transmitting the response of cells to environmental conditions by the sequential action of phosphorylation events. In the fungal pathogen Candida albicans, different routes have been identified by genetic analysis, and especially by the phenotypic characterization of mutants altered in the Mkc1, Cek1/2 and Hog1 MAP kinases. The cell integrity (or MKC1-mediated) pathway is primarily involved in the biogenesis of the cell wall. The HOG pathway participates in the response to osmotic stress while the Cek1 pathway mediates mating and filamentation. Their actual functions are, however, much broader and Mkc1 senses several types of stress, while Hog1 is also responsive to other stress conditions and participates in two morphogenetic programmes: filamentation and chlamydospore formation. Furthermore, it has been recently shown that Cek1 participates in a putative pathway involved in the construction of the cell wall and which seems to be operative under basal conditions. As these stimuli are frequently encountered in the human host, they provide a reasonable explanation for the significant reduction in pathogenicity that several signal transduction mutants show in certain animal models of virulence. MAPK pathways therefore represent an attractive multienzymic system for which novel antifungal therapy could be designed.

Adaptation, Physiological↗
PubMed2006

Comparative genomics of metabolic pathways in Mycobacterium species: gene duplication, gene decay and lateral gene transfer.

The genus Mycobacterium comprises significant pathogenic species that infect both humans and animals. One species within this genus, Mycobacterium tuberculosis, is the primary killer of humans resulting from bacterial infections. Five mycobacterial genomes belonging to four different species (M. tuberculosis, Mycobacterium bovis, Mycobacterium leprae and Mycobacterium avium ssp. paratuberculosis) have been sequenced to date and another 14 mycobacterial genomes are at various stages of completion. A comparative analysis of the gene products of key metabolic pathways revealed that the major differences among these species are in the gene products constituting the cell wall and the gene families encoding the acidic glycine-rich (PE/PPE/PGRS) proteins. Mycobacterium leprae has evolved by retaining a minimal gene set for most of the gene families, whereas M. avium ssp. paratuberculosis has acquired some of the virulence factors by lateral gene transfer.

Amino Acids↗
PubMed1998

The role of B7 co-stimulation in activation and differentiation of CD4+ and CD8+ T cells.

The functional significance of B7 co-stimulation in T-cell activation was described first in the context of preventing the induction of anergy. The functions of this pathway are far more complex than initially appreciated in view of the existence of two B7 molecules which have specificities for both CD28 and CTLA-4, which serve to amplify and terminate T-cell responses respectively. Mice lacking B7 co-stimulators and CD28 and CTLA-4 co-stimulatory receptors are helping to clarify the functions of this key immunoregulatory pathway. In this review we will focus on the role of B7 co-stimulation in the activation and differentiation of CD4+ helper cells and CD8+ cytotoxic cells. The contribution of B7 co-stimulation to CD4+ responses depends upon the activation history of the T-cell and the strength of the T-cell antigen receptor signal. B7 co-stimulation contributes to interleukin (IL)-2 production by both naive and previously activated CD4+ T cells. B7 co-stimulation is most critical for the differentiation of naive CD4+ T cells to IL-4 producers, but predominately influences IL-2 production by previously activated CD4+ cells. B7 co-stimulation is important in development of cytotoxic T cells through both effects on T-helper cells and by direct co-stimulation of CD8+ cells.

Animals↗
PubMed2000

Principles of homeostasis in governing virus activation and latency.

The goal of our work is to understand, from the molecular to the organismal level, the principles that drive and sustain lifelong infection by viruses. These infectious agents live in a dynamic equilibrium (homeostasis) with their hosts in which both immune and nonimmune pathways contribute to viral homeostasis. Disruption of these pathways can have dramatic consequences on pathogenesis. Immune responses to infection provide a vital countermeasure by the host but are nonsterilizing. They effect an essential and primary control mechanism for viral growth. Essential nonimmune pathways for effecting control of a viral life cycle relate to the obligate dependency of the virus on its host. For these reasons, we view infections as a highly dynamic interplay that takes place between the pathogen and host. This, in many cases, leads to the establishment of an incurable lifelong infection that remains benign but can become life threatening once key homeostatic pathways are disrupted. We discuss these issues in the context of our studies using cytomegalovirus as a clinically relevant pathogen.

Animals↗
PubMed2005

Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death.

Active Ras and phosphatidylinositol-3-kinase-dependent pathways contribute to the malignant phenotype of glioblastoma multiformes (GBM). Here we show that the Ras inhibitor trans-farnesylthiosalicylic acid (FTS) exhibits profound antioncogenic effects in U87 GBM cells. FTS inhibited active Ras and attenuated Ras signaling to extracellular signal-regulated kinase, phosphatidylinositol-3-kinase, and Akt. Concomitantly, hypoxia-inducible factor 1alpha (HIF-1alpha) disappeared, expression of key glycolysis pathway enzymes and of other HIF-1alpha-regulated genes (including vascular endothelial growth factor and the Glut-1 glucose transporter) was down-regulated, and glycolysis was halted. This led to a dramatic reduction in ATP, resulting in a severe energy crisis. In addition, the expression of E2F-regulated genes was down-regulated in the FTS-treated cells. Consequently, U87 cell growth was arrested and the cells died. These results show that FTS is a potent down-regulator of HIF-1alpha and might therefore block invasiveness, survival, and angiogenesis in GBM.

Cell Death↗
PubMed2006

NPC1L1: evolution from pharmacological target to physiological sterol transporter.

Niemann-Pick C1-like 1 protein (NPC1L1) was recently shown to be the molecular target of the cholesterol absorption inhibitor class of drugs, of which ezetimibe is the first widely used member. Since its discovery, NPC1L1 has also been shown to play a focal physiological role in intestinal absorption of sterols, including plant sterols and cholesterol. Evidence in support of this new metabolic pathway has been garnered not only through human, animal, and cell studies of function but also through the use of human genetics as an approach to study the association of NPC1L1 sequence variation with metabolic and drug-response phenotypes. The example of NPC1L1 shows how the elucidation of a pharmacological target can serve as a means to gain understanding of a key physiological pathway.

Absorption↗