Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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Tif1? controls the TGF-? receptor on hematopoietic stem cells: implication in physiological aging
No full textHematopoietic stem cell (HSC) aging has been directly linked to the development of several hematological disorders including myeloproliferative diseases. We recently described that in elderly mice (20-month-old), physiological aging of the hematopoietic system is associated with a decreased expression of the Transcription Intermediary Factor 1? (Tif1?) gene in HSCs. In young mice (4-month-old), deleted for the Tif1? gene in HSCs (Tif1?-/-), the hematopoiesis aging phenotype is intensified. We discovered that Tif1? controls the TGF-b receptor 1 (Tgfbr1) and finely regulates the number of myeloid-restricted HSCs in bone marrow. Altogether, we established that young Tif1?-/- mice develop a phenotype of premature hematopoietic aging, which may explain their tendency to myeloproliferative disease. We identified two populations of HSCs specifically discriminated by Tgfbr1 expression and afforded evidence of the capture of myeloid-restricted (Tgfbr1hi) and myeloid-lymphoid-balanced (Tgfbr1lo) HSC. In conclusion, our study proves that Tif1? can regulate the balance between lymphoid and myeloid HSCs, through a modulation of the TGF-b signaling
Regulation of Androgen Receptor by E3 Ubiquitin Ligases: for More or Less
Get PDFProstate cancer (PCa) primarily depends on androgen receptor (AR) signaling pathway for the initiation and growth as well as recurrence after castration [1]. Androgen deprivation therapy (ADT) effectively alleviates the symptoms of the malignancy to arrest further growth of the primary tumors or the progression of metastasis in patients with the advanced PCa. However, the relapse occurs in many patients after a short period, and PCa cells eventually become insensitive to ADT - termed castration resistant prostate cancer [2, 3]. Tremendous advancements have been achieved to decipher the mechanisms on AR signaling, and ubiquitination machinery contributes to PCa directly or indirectly by either promotion of AR transcriptional activity or degradation of AR protein levels. The recent report reveals that SKP2 is an E3 ubiquitin ligase for AR protein, and SKP2 levels determine AR expression through ubiquitin-mediated proteasomal degradation. Given the pivotal roles of AKT and SKP2 in cancers, the differential mechanisms of AR ubiquitination by various E3 ligases hold valuable significance and beneficial implications for PCa control
The diverse roles of G protein-coupled receptor kinase 2 (GRK2): a focus on regulation of receptor tyrosine kinases (RTKs)
Get PDFThe G protein-coupled receptor (GPCR) kinases (GRKs) are a family of seven serine/threonine kinases that are recruited to and activated by almost all agonist-occupied GPCRs. Upon recruitment and activation, GRK2 inhibits G protein-dependent signaling downstream of GPCRs both directly, for example by sequestering activated G proteins, and indirectly, by promoting the recruitment of ?-arrestins, which sterically hinder further G protein activation and drive receptor internalization. In addition to switching off G protein signaling, GRK2 also initiates a number of G protein-independent signaling pathways downstream of activated GPCRs by recruiting scaffolding proteins or by phosphorylating non-GPCR substrates. Furthermore, it has recently become clear that the GRKs regulate signaling downstream of receptors that belong to families other than the GPCRs, including the transforming growth factor ? (TGF?) receptor and the toll-like receptor TLR4. Here we focus on recent studies demonstrating an important role for GRK2 in regulating signaling in both positive and negative ways downstream of various receptor tyrosine kinases (RTKs), including platelet-derived growth factor (PDGF) receptors, epidermal growth factor (EGF) receptors and insulin-like growth factor 1 (IGF-1) receptors
In vivo neuronal co-expression of mu and delta opioid receptors uncovers new therapeutic perspectives
Get PDFOpioid receptors are G protein coupled receptors that modulate brain function at all levels of neural integration, including autonomous, sensory, emotional and cognitive processing. Mu and delta opioid receptors functionally interact in vivo, but whether interactions occur at circuitry, cellular or molecular level remains unsolved. Also, the notion of receptor crosstalk via mu-delta heteromers is well documented in vitro but in vivo evidence remains scarce. To identify neurons in which receptor interactions could take place, we designed a unique double mutant knock-in mouse line that expresses functional red-fluorescent mu receptors and green-fluorescent delta receptors. We mapped mu and delta receptor distribution and co-localization throughout the nervous system and created the first interactive brain atlas with concomitant mu-delta visualization at subcellular resolution (http://mordor.ics-mci.fr/). Mu and delta receptors co-localize in neurons from subcortical networks but are mainly detected in separate neurons in the forebrain. Also, co-immunoprecipitation experiments indicated physical proximity in the hippocampus, a prerequisite to mu-delta heteromerization. Altogether, data suggest that mu-delta functional interactions take place at systems level for high-order emotional and cognitive processing whereas mu-delta may interact at cellular level in brain networks essential for survival, which has potential implications for innovative drug design in pain control, drug addiction and eating disorders
HGF/Met axis has anti-apoptotic and anti-autophagic function in hypoxic cardiac injury
Get PDFIschaemic heart disease is the main cause of death in western countries. Cardiac tissue is primarily damaged by cardiomyocyte cell death triggered by low oxygen supply to the heart (hypoxia). The current therapeutic approach is coronary angioplastic intervention or thrombolytic treatments to resume blood flow in the ischaemic heart. Unfortunately, reperfusion itself causes a burst of ROS production responsible for cardiomyocyte death and myocardial dysfunction. Indeed, the majority of patients surviving to acute myocardial infarction undergoes progressive heart failure, with 50% mortality at five years from diagnosis. Apoptosis of cardiomyocytes is dangerous both during ischaemia and reperfusion. In line with this concept, we have shown that treatment of H9c2 cardiomyoblasts with cobalt chloride (CoCl2), a chemical mimetic of hypoxia, induces caspase-dependent apoptosis. Unexpectedly, we found that 3-methyladenine, an inhibitor of autophagy initiation, partially prevents CoCl2-mediated cell death, indicating that also autophagy contributes to cardiomyoblast death. Consistently, we found an increase in the autophagic flux in dying cells. Mechanistically, we have shown that CoCl2 upregulates Redd1, Bnip3 and phospho-AMPK proteins and causes inhibition of mTOR, the main negative regulator of autophagy. In light of these observations, it is important to discover new therapeutic tools displaying a dual prosurvival mechanism. To this aim, we have analyzed the cardioprotective action of HGF/Met axis in hypoxic injury. To activate Met signaling we have used either the HGF ligand or two different monoclonal antibodies (mAbs) directed against the extracellular moiety of Met receptor. Owing a divalent structure, the two mAbs can dimerize and activate Met receptor, thus displaying agonist activity. Hypoxic injury was fully prevented by either HGF or Met agonist mAbs through both anti-apoptotic and anti-autophagic functions. By pharmacological inhibition we showed that activation of mTOR is the protective signaling downstream to Met, being involved in the anti-autophagic effect. In conclusion, HGF or Met agonist mAbs promote cell survival by negative dual regulation of apoptotic and autophagic cell death and represent promising new therapeutic tools to manage cardiac diseases
Human nicotinic acetylcholine receptor is a potential pharmacological target of oseltamivir
Get PDFOseltamivir (Tamiflu) effectively inhibits influenza virus-specific neuraminidase and therefore, is widely prescribed as an anti-influenza medication. Although a wide safety margin of oseltamivir has been reported, the possible neuronal adverse effects of this drug via unknown mechanisms are shown in some studies: dyskinesia, depressive episodes, hypothermia, and other CNS dysfunctions. We therefore, examined effects of oseltamivir on human nicotinic acetylcholine (ACh) receptors (nAChRs) with electrophysiological methods and found that oseltamivir reversely blocks nicotine- and ACh-evoked membrane currents in a concentration dependent manner in neuroblastoma cells derived from human peripheral neurons (IMR32) and in HEK cells expressing recombinant human ?3?4 nAChRs. In contrast, an active metabolite of oseltamivir, oseltamivir carboxylate (OC) had little effect on the nicotine-evoked currents. Moreover, single channel analysis revealed that oseltamivir reduces the channel open time of nAChR without affecting the channel conductance. Our results demonstrate that human ?3?4 nAChRs are a potential pharmacological target of oseltamivir, hence explaining a part of the adverse effects after ingestion of oseltamivir
Adrenomedullin and Glucocorticoids interaction at the glial/endothelial interface: two sides of the same regulatory coin?
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Adrenomedullin is a vasodilatatory peptide, important during the inflammation process and also able to regulate blood-brain barrier function. Adrenomedullin and its receptors have been shown to be glucocorticoid-dependent in many cell types, including primary T cells and the major cellular components of the blood-brain barrier. Considering that the immunosuppressant, glucocorticoids are also well-known to regulate inflammation and blood-brain barrier properties, in this research highlight we review the evidence for glucocorticoid modulation of adrenomedullin secretion and adrenomedullin receptor expression at the glial/endothelial interface during physiological and inflammatory conditions. This view would offer a platform for consideration of new therapeutic options aiming to restore or maintain the blood brain barrier
Beta-2-adrenergic receptor methylation influences asthma phenotype in the school inner city asthma study
Get PDFoai:ojs.pkp.sfu.ca:article/253Asthma is the most common chronic illness of childhood and inner city residents suffer a disproportionately high rate of asthma diagnosis and asthma morbidity. The School Inner City Asthma Study investigates the school classroom based environmental exposures that may lead to asthma morbidity in inner city school children with asthma. Within this cohort, we investigated the role of methylation at the promoter region of the beta-2-adrenergic receptor in relation to asthma morbidity. We found that high levels of methylation in the region studied was significantly associated with decreased report of dyspnea and trended towards significance for lower levels of asthma symptoms and airway obstruction. This Research Highlight discusses the findings of the recent study and the investigators’ active research endeavors