Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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LCK connects NTB-A and SAP signaling in T cells to restimulation-induced cell death
Get PDFSignaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is an adaptor protein required for SLAM family receptor signaling. In T cells, signaling from different SLAM receptors (SLAM-Rs) governs differentiation, effector function, and apoptosis specifically through the self-regulatory program of T cell receptor restimulation-induced cell death (RICD). Indeed, SLAM-R signaling and RICD are impaired in X-linked lymphoproliferative disease (XLP) patients that are deficient for SAP, as well as in SAP-deficient mice. Importantly, defective RICD likely contributes to excessive CD8+ T cell accumulation and severe immunopathology noted in XLP patients upon infection with Epstein-Barr Virus (EBV). It is well established that SAP signaling through different SLAM-Rs is associated with the recruitment of the Src-family kinase FYN. Surprisingly, we recently discovered that FYN has no role in RICD. Instead, our data suggests that SAP enhances the recruitment and activation of LCK to the SLAM family receptor NK, T, and B cell Antigen (NTB-A), and thus amplifies TCR signaling for optimal RICD. In this research highlight we review the role of SAP in T cells and describe our recent findings placing LCK as an important player in SAP-mediated NTB-A signaling for T cell apoptosis
AIMP1 negatively regulates PPARgamma: Implication in adipogenesis
No full textThe regulation mechanism of peroxisome proliferator-activated receptor g (PPARg) known as key determinant in adipogenesis is important for understanding the cause of lipid metabolic disorders and glucose metabolic syndromes. In a recent paper published in Journal of Cell Science, we demonstrated that aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a novel negative regulator of PPARg. Although AIMP1 is originally found as a factor associated with multi-tRNA synthetase complex for translation, it has been shown to play regulatory roles in diverse cellular processes. Now AIMP1 is shown to negatively regulates PPARg-mediated transcription through direct interaction with DNA-binding domain of PPARg and inhibits adipogenesis. These results suggest that AIMP1 functions as a novel inhibitor of PPARg, raising the possible linkage between translation and adipogenesis
B-cell receptor strength and zinc signaling: Unraveling the role of zinc transporter ZIP10 in humoral immunity
No full textThe humoral immune response, alongside cell-mediated immunity, in which B cells play a key role, form the primary arms of the adaptive immune system. Resting mature follicular (FO) B cells in the spleen are essential for antibody-mediated immune responses. They recirculate through the blood, and are activated upon the binding of various diverse cognate antigens to the specific B cell antigen receptor (BCR) on their cell surface. With the help of T cells, the activated FO B cells undergo the germinal center (GC) reaction, which involves massive expansion and immunoglobulin (Ig) class-switch recombination (e.g. IgM to IgG1) to elicit a high-affinity antibody response against the antigens. Zinc (Zn) is essential in immunity, and in both humans and rodents, aberrant Zn homeostasis strongly disrupts the cellularity and functions of immune cells, leading to thymic and splenic atrophy, lymphopenia, and weakened cellular and humoral immunity, which increases the host’s susceptibility to various pathogens. Zn, which is transported by specific members of the Zn-transporter families, SLC39/ZIP and SLC30/ZnT, selectively fine-tunes distinct intracellular signaling events by targeting signaling molecules involved in development, growth, and immunity. Zn controls a wide range of immune signaling cascades that lead to cytokine production, antigen presentation, and the activation of kinases and transcription factors in immune cells, and disrupting the specific Zn transporter?Zn signal axis impairs cellular function. However, how Zn controls immune function, in particular the humoral immune response, is poorly understood. In this research highlight, we review our recent finding that ZIP10-Zn signaling is required in B-cell receptor signaling for the antibody-mediated immune response
Driver or Passenger - Roles of the Glucocorticoid Receptor in Castration Resistance Prostate Cancers
Get PDFProstate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer death in men in North America. With the rate of new cases rising each year, prostate cancer poses a heavy burden on both the economy and society. While the first line of treatment for metastatic prostate cancer is androgen deprivation therapy, it has become evident that tumors eventually become castration resistant. One of the proposed mechanisms by which tumors overcome androgen deprivation therapy is through the expression and activation of glucocorticoid receptors. However, whether the glucocorticoid receptor functions as a key driver for castration resistant progression or a biomarker reflecting androgen receptor activity remains elusive. In our recent study, we utilized tissue microarrays and multiple prostate cancer xenograft and cell models to investigate the roles of the glucocorticoid receptor during castration resistant progression. As a result, we determined that the expression of the glucocorticoid receptor is inversely correlated with androgen receptor activity and is not associated with castration resistant phenotypes. In addition, we identified a negative androgen responsive element in the promoter region of the glucocorticoid receptor gene through chromatin immunoprecipitation analysis combined with DNA sequencing technology. We showed that the androgen receptor interacted directly to this response element to exert suppressive effects on the transcription of the glucocorticoid receptor gene. In conclusion, the expression of the glucocorticoid receptor is negatively regulated by the androgen receptor and can potentially serve as a biomarker to monitor prostate tumor progression
Regulation of ryanodine receptor-mediated calcium signaling by presenilins
Get PDFCa2+ dyshomeostasis is a critical causative mechanism underlying the functional impairment of the central nervous system seen in ‘healthy’ aging [1], specifically in normal brain aging processes in the absence of disease-causing mutations or external causes. It is generally thought that such impairments result from the gradual accumulation of small changes at the molecular level, such as oxidative damage to the structure and function of synapses, that ultimately cause the loss of biological function [2]. Alzheimer’s disease (AD) is a multifactorial pathology directly related to aging and with age as a primary risk factor [3]. Neurons affected by AD have an elevated cytosolic calcium ion concentration [4]. It has not yet been determined if the observed elevation of cytosolic calcium is contributing to or results from AD pathology, but there is mounting evidence in support of the Calcium Hypothesis of brain aging [4-9]. The two presenilin genes found in vertebrates are ubiquitously expressed as the transmembrane proteins presenilin-1 (PS1) and presenilin-2 (PS2), respectively, in the endoplasmic reticulum (ER). They are part of the ?-secretase enzyme complex catalyzing the processing of amyloid precursor protein (APP), which - if aberrant under disease conditions - can result in the generation of neurotoxic amyloid-beta (A?) peptides [10] (Fig. 1). Approximately 80% of the mutations linked to familial AD have been found in PS1 [11] and clinically relevant PS1 mutations exert effects on cytosolic calcium concentrations [10, 12]. While both presenilins affect cytosolic calcium concentrations, the PS1 isoform binds to several proteins essential to the regulation of intracellular calcium signaling, e.g. the inositol 1,4,5-trisphosphate receptor (IP3R) [13], the N-methyl-D-aspartate (NMDA) receptor (NMDAR) [14], and the ryanodine receptor (RyR) [15-17]. Here, the interaction of presenilins with RyRs will be reviewed
ENU-3 is a new player in UNC-6/Netrin directed axon outgrowth and guidance in C. elegans
Get PDFUNC-6/Netrin is an axon guidance cue that works through UNC-40/DCC/Frazzled to attract cells and neurons and through UNC-5 and UNC-40 to repulse cells and neurons during nervous system development. The gene encoding the novel protein ENU-3 was identified in a mutant that enhanced the axon outgrowth defects of the DA and DB classes of motor neurons in a strain lacking functional UNC-5. Mutant ENU-3 also enhanced the axon outgrowth and guidance defects of the ventrally directed processes of the AVM and PVM touch receptor neurons in a strain lacking functional UNC-40. ENU-3 also plays a role in adhesion of axons to the substratum as does UNC-40. The protein is a putative single pass transmembrane protein expressed throughout the nervous system whose possible biochemical roles are currently unknown
Personalized treatment options in Non-small Cell Lung Cancer
Get PDFLung cancer is the leading cause of cancer related death among both men and women worldwide [1-3]. There are two major groups of lung cancer based on the histological features and response to therapy; non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC is also divided to the histological subtypes, and which accounts 80% of lung cancer patients [3, 4] . Despite advances in diagnosis, 5-year survival rates are approximately 15% for all cases [5] . Since EGFR (epidermal growth factor receptors) is overexpressed in more than 80% of NSCLC patients, its overexpression is correlated with poor prognosis and chemoresistance. However, only 10% of EGFR1 overexpressing patients respond to EGFR1 TKI (tyrosine kinase inhibitor) therapy implying that EGFR1 overexpression may not be the main factor responsible for NSCLC development [6, 7]. Therefore, new therapeutic strategies that specifically target other molecular pathways must be considered as alternative options. In this review, we tried to summarize the most recent studies in treatment of NSLC, and made suggestions on the basis of our results and clinical studies
Vascular Senescence in Chronic kidney Disease; Association of Aryl Hydrocarbon Receptor Activated by Indoxyl Sulfate
Get PDFThe impact of chronic kidney disease (CKD) on the occurrence of cardiovascular disease (CVD) is a major concern and this reciprocal relation is currently so called "cardio-renal syndrome". More detailed understanding in its mechanism may have a possibility to reduce the global burden of CVD. Of note, uremic toxins have been known to accumulate in the progression of CKD and play an important role for worsening renal function, on the other hand, recent studies suggest that they also negatively affect cardiovascular system. In this review, we delve into the role of aryl hydrocarbon receptor (AhR) in uremic toxicities, as highlighted in our latest work and give a new insight for the mechanism of cardio-renal syndrome
Stem-cell marker CD34, multidrug resistance proteins P-gp and BCRP in SEGA
Get PDFThe resistance of human malignancy to multiple chemotherapeutic agents remains a major obstacle in cancer therapy due to in part to increased expression of ATP-binding cassette (ABC) transporters gene family, including “multidrug resistance 1”, and “breast cancer resistant protein”. These proteins are differentially expressed during normal hematopoiesis with the highest levels in primitive bone marrow CD34 stem cell population, and similarly, it was also suggested to occur transiently during neurulation. Subependymal Giant Cell Astrocytoma (SEGA) is a periventricular-low-grade tumor usually associated with tuberous sclerosis complex. We previously described that several multidrug-resistance proteins are overexpressed in brain cortical tubers associated with refractory epilepsy; however, they have not been investigated in SEGA. From a previous reported study of 15 brain specimens of SEGA, 6 randomized cases were selected for the immunostaining with specific monoclonal antibodies to multidrug resistance 1, breast cancer resistant protein and CD34 stem-cell marker. Heterogeneous distributions for these markers were detected with differential immunostaining pattern, showing high immunoreactivity in SEGA cells far of vessels, and low or negative expression in SEGA cells near the vessels. This particular expression pattern of both ABCtransporters, and CD34 antigen could identify different stem-cell subset in SEGA
The NOD2 receptor modulates cytokine response but does not alter the clinical outcome of Group B Streptococcus-infected mice
Get PDFThe nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an intracellular receptor capable of sensing bacteria-derived muramyl dipeptide. We investigated the role of NOD2 in the pathogenesis of Group B Streptococcus (GBS) capsular type III, a crucial agent of life-threatening invasive infections, by using an adult NOD2-/- mouse model of infection. We demonstrated that NOD2 is not a key receptor to fight GBS infection and only partially contributes to the inflammatory response. This Research Highlight discusses the findings of this recent study and the investigators’ active research on the involvement of receptors in the interaction between encapsulated bacteria and dendritic cells