Effector Role Research Articles

The Verticillium dahliae SnodProt1-Like Protein VdCP1 Contributes to Virulence and Triggers the Plant Immune System.

During pathogenic infection, hundreds of proteins that play vital roles in the Verticillium dahliae-host interaction are secreted. In this study, an integrated proteomic analysis of secreted V. dahliae proteins was performed, and a conserved secretory protein, designated VdCP1, was identified as a member of the SnodProt1 phytotoxin family. An expression analysis of the vdcp1 gene revealed that the transcript is present in every condition studied and displays elevated expression throughout the infection process. To investigate the natural role of VdCP1 in V. dahliae, two vdcp1 knockout mutants and their complementation strains were generated. Bioassays of these mutants revealed no obvious phenotypic differences from the wild-type (WT) in terms of mycelial growth, conidial production or mycelial/spore morphology. However, compared with the WT, the vdcp1 knockout mutants displayed attenuated pathogenicity in cotton plants. Furthermore, treating plants with purified recombinant VdCP1 protein expressed in Pichia pastoris induced the accumulation of reactive oxygen species (ROS), expression of several defense-related genes, leakage of ion electrolytes, enhancement of defense-related enzyme activity and production of salicylic acid. Moreover, VdCP1 conferred resistance to Botrytis cinerea and Pseudomonas syringae pv. tabaci in tobacco and to V. dahliae in cotton. Further research revealed that VdCP1 possesses chitin-binding properties and that the growth of vdcp1 knockout mutants was more affected by treatments with chitinase, indicating that VdCP1 could protect V. dahliae cell wall from enzymatic degradation, which suggests an effector role of VdCP1 in infecting hosts.

Cdc42 Signaling Pathway Inhibition as a Therapeutic Target in Ras- Related Cancers.

The frequency of pro-oncogenic mutations and development of drug resistance are major challenges for successful Ras-related cancer treatment. Novel targets in the Ras-signaling pathway may address these challenges. Cell division cycle protein 42 (Cdc42) is a classical member of the Rho family of small GTPases in the Ras oncogene superfamily. Enhanced Cdc42-signaling facilitates Ras-mediated cellular transformation, tumorigenesis, and metastasis. Cdc42, Ras, and EGFR are involved in an activation loop that prolongs their signaling. This review evaluates the benefits of targeting Cdc42 signaling as an anti-Ras cancer target. We review the link between Ras and Cdc42 and summarize the roles of Cdc42 and select effectors in cancers. We discuss the discovery/development of Cdc42-signaling modulators and highlight studies that report the inhibition of the Cdc42-signaling pathway in several Ras-related cancer cell lines. Compared to EGFR and Ras, mutations that lead to the prolonged activation of Cdc42 are less common. Activation of upstream signals, changes in regulator expression, and alterations of Cdc42 protein expression play an important role in regulating Cdc42 activity. Eight selected effectors/adaptors of Cdc42 play a role in oncogenic Ras signaling. Of the fourteen natural and synthetic Cdc42 inhibitors discussed, eight small molecule inhibitors of Cdc42 have been used effectively in Ras-related cancer lines derived from breast, colon, lung, and pancreatic cancer. Cdc42 is a putative therapeutic target in Ras-related cancers since Cdc42 functions downstream of EGFR and Ras, Cdc42 promotes/activates EGFR and Ras signaling, and Cdc42 inhibition in Ras-related cancers elicits anticancer effects.

Maternal effector T cells within decidua: The adaptive immune response to pregnancy?

In human pregnancy the maternal immune system plays a critical role in the regulation of many aspects of human reproduction including implantation, placentation and defence against infection. Interest has been focussed on the role of uterine natural killer cells (uNK) in the maternal decidua whereas effector CD4+ and CD8+ T cells have received much less attention despite the observation that they represent a major proportion of decidual leucocytes in the latter phase of pregnancy. A range of recent studies have demonstrated that human decidual T cells are highly differentiated, express a range of cytokines and cytotoxic markers, and demonstrate a unique transcriptional profile characterized by high level expression of genes involved in interferon-signalling. Moreover, subpopulations of effector T cells demonstrate specificity for fetal tissue and are regulated through expression of inhibitory checkpoint proteins and T regulatory cells. Nevertheless, many questions remain to be answered, such as the potential role of maternal effector T cells in either supporting successful pregnancy or potentially clearing fetal cells that have entered the maternal circulation. In addition, there is an increasing interest in the role of maternal effector T cells in the pathogenesis of disorders such as chronic villitis miscarriage, stillbirth, fetal growth restriction and pre-eclampsia. Current debates in relation to these questions will be discussed within this review.

OR4 Development of an in vitro model of human antibody mediated rejection

Aim Antibody-mediated rejection (AbMR) remains a leading barrier to long term transplant survival. The immune mechanisms of AbMR are incompletely understood but recent evidence suggests that monocytes and NK cells are potential effectors against HLA ab-coated endothelium. We developed an in vitro model of human AbMR that incorporates the immune components currently known. Methods Human umbilical vein endothelial cells (HUVECs) served as endothelial targets and were pretreated with IFN-g for 48 h to maximize HLA expression. HLA abs were derived from sera pooled from highly sensitized patients on our waitlists. Primary NK cells and monocytes were isolated by immunomagnetic depletion from healthy controls and added to HLA ab-coated HUVECs. RNA was extracted for global gene expression analyses after 8 h. Analyses focused on 3 representative sets of transcripts: IFN-g response, chemokines, and endothelial activation (Table 1). Results NK cell/ HLA ab-mediated attack leads to increased chemokines that promote additional NK cell and monocyte recuitment (Fig. 1), many reflecting endothelial IFN-g effects. Adhesion molecules key to recruitment and leukocyte engagement were also increased, some of these being required for optimal NK cell activation (ICAM1). The presence of monocytes in the system (despite being separated from NK-HUVECs) increased all 3 responses observed with NK cells, particularly endothelial activation. Conclusions Our results suggest that we have a working model of human AbMR that incorporates 2 effector cell types, HLA abs, and HUVEC targets. This model argues for a key effector role by NK cells in AbMR, whose function is greatly enhanced by soluble mediators from monocytes in close proximity.

APKC Cycles between Functionally Distinct PAR Protein Assemblies to Drive Cell Polarity

SummaryThe conserved polarity effector proteins PAR-3, PAR-6, CDC-42, and atypical protein kinase C (aPKC) form a core unit of the PAR protein network, which plays a central role in polarizing a broad range of animal cell types. To functionally polarize cells, these proteins must activate aPKC within a spatially defined membrane domain on one side of the cell in response to symmetry-breaking cues. Using the Caenorhabditis elegans zygote as a model, we find that the localization and activation of aPKC involve distinct, specialized aPKC-containing assemblies: a PAR-3-dependent assembly that responds to polarity cues and promotes efficient segregation of aPKC toward the anterior but holds aPKC in an inactive state, and a CDC-42-dependent assembly in which aPKC is active but poorly segregated. Cycling of aPKC between these distinct functional assemblies, which appears to depend on aPKC activity, effectively links cue-sensing and effector roles within the PAR network to ensure robust establishment of polarity.

Place du macrophage au sein de la synovite rhumatoïde

Macrophages belong to the myelo-monocytic lineage. These cells are characterized by their plasticity, feature depending on their environment and illustrated by various phenotypic profiles or “polarizations”. Polarizations are associated with specific biological functions, such as pro-inflammation or immunoregulation or wound healing. Rheumatoid inflammation is generated and self-maintained by immune cells. Among them, macrophages play a central effector role, especially in synovitis. Two distinct populations of macrophages have been identified in rheumatoid synovitis: resident macrophages present in homeostatic condition and infiltrating macrophages recruited during inflammation. The later are differentiated from blood monocytes, and participate to local pathogenesis with the production of inflammatory mediators, the neo-angiogenesis, the chondrolysis and the bone erosion. However, macrophage contribution in rheumatoid arthritis is not restricted to inflammation. These cells also take part in homeostasis and inflammation resolution process, roles being potentially insured by resident synovial macrophages. All these aspects confirm macrophages as an interesting target for rheumatoid arthritis study and treatment.

Abstract 1355: Linking AP/MS-derived protein-protein interaction networks and pairwise sgRNA screens defines new KRAS effectors in non-small cell lung cancer

Abstract The KRAS oncogene is mutated in over one fourth of human cancers. Despite decades of work studying known effector pathways, no drugs in clinical use specifically target KRAS-mutant tumors. Uncharacterized feedback mechanisms and parallel pathways have stymied the treatment of KRAS-mutant tumors in patients, and the KRas protein does not easily accommodate the binding of inhibitory small molecules. These challenges demand better characterization of the physical and genetic relationships between Ras regulators and effectors. To that end, we used tandem affinity purification of Kras, Hras and Nras and twelve proteins with known regulatory or effector roles to generate a high-confidence protein-protein interaction (PPI). Interactions were cross-referenced with public PPI, genetic susceptibility, and patient data to assemble a physical PPI map annotated with important functional determinants. The final map contains 287 genes and 990 physical interactions among them. This map was used to construct a library of >1000 sgRNAs covering >100 genes of probable relevance to the Ras pathway. This library was screened for pairwise genetic effects in a dual sgRNA vector system to identify quantitative changes in the growth of the A549 NSCLC line. We will present the quantitative results of this screen and additional validation studies on several previously undescribed regulators and effectors of the Ras proteins. In particular, we highlight unknown interactions between KRAS and the cell adhesion regulator RADIL, and the specificity of Ras-family protein interaction with the Raf and Ral GEF family proteins. These data underscore the limitations of our current understanding of Kras-driven cancers and reveal their genetic vulnerabilities. Citation Format: Marcus R. Kelly. Linking AP/MS-derived protein-protein interaction networks and pairwise sgRNA screens defines new KRAS effectors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1355. doi:10.1158/1538-7445.AM2017-1355

GTSE1: a novel TEAD4-E2F1 target gene involved in cell protrusions formation in triple-negative breast cancer cell models.

GTSE1 over-expression has been reported as a potential marker for metastasis in various types of malignancies, including breast cancer. Despite this, the transcriptional regulation of this protein and the causes of its misregulation in tumors remain largely unknown. The aims of this work were to elucidate how GTSE1 is regulated at the transcriptional level and to clarify the mechanism underlying GTSE1-dependent cell functions in triple-negative breast cancer (TNBC).Here, we identified GTSE1 as a novel target gene of the TEAD4 transcription factor, highlighting a role for the YAP and TAZ coactivators in the transcriptional regulation of GTSE1.Moreover, we found that TEAD4 controls the formation of cell protrusions required for cell migration through GTSE1, unveiling a relevant effector role for this protein in the TEAD-dependent cellular functions and confirming TEAD4 role in promoting invasion and metastasis in breast cancer.Finally, we highlighted a role for the pRb-E2F1 pathway in the control of GTSE1 transcription and observed that treatment with drugs targeting the pRb-E2F1 or YAP/TAZ-TEAD pathways dramatically downregulated the expression levels of GTSE1 and of other genes involved in the formation of metastasis, suggesting their potential use in the treatment of TNBC.

Increased Levels of Pro-Inflammatory and Anti-Inflammatory Cellular Responses in Parkinson's Disease Patients: Search for a Disease Indicator.

BackgroundParkinson’s disease (PD) is the second most prevalent neurodegenerative disorder and it arises when most of the dopaminergic neurons of substantia nigra region die. Several mechanisms have been postulated as the causative event in PD pathology, and neuroinflammation is most crucial among them.Material/MethodsWe analyzed T-helper 17 (Th17) cells and myeloid-derived suppressor cells (MDSCs) from 80 PD patients to assess inflammatory processes and to find a cost-effective means to evaluate PD prognosis.ResultsWe found significantly increased numbers of Th17 cells and MDSCs count in peripheral circulation in PD patients compared with controls (p<0.001). A positive correlation was found between Th17 cells and MDSCs in PD patients (r=0.421, p<0.05).ConclusionsOur results show the effector role of Th17 cells and MDSCs in PD pathology and shows their utility as effective biomarkers for PD diagnosis.

Dipeptidyl Peptidase-4 and Adolescent Idiopathic Scoliosis: Expression in Osteoblasts

It has been proposed that girls with adolescent idiopathic scoliosis (AIS) tend to have a taller stature and a lower body mass index. Energy homeostasis, that is known to affect bone growth, could contribute to these characteristics. In circulation, dipeptidyl peptidase-4 (DPP-4) inactivates glucagon-like peptide-1 (GLP-1), an incretin that promotes insulin secretion and sensitivity. Our objectives were to investigate DPP-4 status in plasma and in osteoblasts of AIS subjects and controls and to evaluate the regulatory role of metabolic effectors on DPP-4 expression. DPP-4 activity was assessed in plasma of 113 girls and 62 age-matched controls. Osteoblasts were isolated from bone specimens of AIS patients and controls. Human cells were incubated with glucose, insulin, GLP-1 and butyrate. Gene and protein expressions were evaluated by RT-qPCR and Western blot. Our results showed 14% inferior plasma DPP-4 activity in AIS patients when compared to healthy controls (P = 0.0357). Similarly, osteoblasts derived from AIS subjects had lower DPP-4 gene and protein expression than controls by 90.5% and 57.1% respectively (P < 0.009). DPP-4 expression was regulated in a different manner in osteoblasts isolated from AIS participants compared to controls. Our results suggest a role for incretins in AIS development and severity.

Peptide Nucleic Acid Knockdown and Intra-host Cell Complementation of Ehrlichia Type IV Secretion System Effector.

Survival of Ehrlichia chaffeensis depends on obligatory intracellular infection. One of the barriers to E. chaffeensis research progress has been the inability, using conventional techniques, to generate knock-out mutants for genes essential for intracellular infection. This study examined the use of Peptide Nucleic Acids (PNAs) technology to interrupt type IV secretion system (T4SS) effector protein expression in E. chaffeensis followed by intracellular complementation of the effector to determine its requirement for infection. Successful E. chaffeensis infection depends on the E. chaffeensis-specific T4SS protein effector, ehrlichial translocated factor-1 (Etf-1), which induces Rab5-regulated autophagy to provide host cytosolic nutrients required for E. chaffeensis proliferation. Etf-1 is also imported by host cell mitochondria where it inhibits host cell apoptosis to prolong its infection. We designed a PNA specific to Etf-1 and showed that the PNA bound to the target region of single-stranded Etf-1 RNA using a competitive binding assay. Electroporation of E. chaffeensis with this PNA significantly reduced Etf-1 mRNA and protein, and the bacteria's ability to induce host cell autophagy and infect host cells. Etf-1 PNA-mediated inhibition of ehrlichial Etf-1 expression and E. chaffeensis infection could be intracellularly trans-complemented by ectopic expression of Etf-1-GFP in host cells. These data affirmed the critical role of bacterial T4SS effector in host cell autophagy and E. chaffeensis infection, and demonstrated the use of PNA to analyze the gene functions of obligate intracellular bacteria.

Kallikrein-kinin system and Type I Interferons in Neurolupus

Abstract Neuropsychiatric lupus is one of the most common manifestations of human systemic lupus erythematosus (SLE), causing depression in many. SLE is an autoimmune disease characterized by multi-organ damage including the brain and Interferon-α (IFN-α) is a central mediator in disease pathogenesis. Excessive production/response to Type I IFNs in SLE (called the “IFN signature”) is a hallmark of the disease. The mechanism of how IFN causes depression remain poorly understood; however, it is known that administration of IFN-α in certain chronic viral infections and some cancers causes the development of depressive symptoms in a high percentage of patients. The Kallikrein-Kinin System (KKS) that is comprised of kallikreins (klks), bradykinins (bk), angiotensin converting enzyme (ACE), and many other molecules, has classically known to be involved in a variety of physiological processes, including coagulation, angiogenesis and control of blood pressure. The KKS has been explored recently for their regulation of brain functions. We hypothesize that IFN-α may cause some of the symptoms in neurolupus patients and the KKS can ameliorate these effects. In this study, we used the MRL/lpr lupus-prone mouse model and showed that exposing MRL mice to IFN-α (a) increased depressive-like behavior, (b) decreased klk expression, and (c) enhanced ACE expression in the brain. Administering captopril (a commonly prescribed ACE inhibitor) decreased IFN-induced gene expression in the brain. It is also known that ACE activity decreases BK levels. The role of key KKS effectors and their interactions with the IFN pathway may provide a rationale for therapeutic use of KKS molecules for treatment of neurolupus.

Effector and regulatory B cells in Multiple Sclerosis

The role of B cells in the pathogenesis of Multiple Sclerosis (MS), an autoimmune neurodegenerative disease, is becoming eminent in recent years, but the specific contribution of the distinct B cell subsets remains to be elucidated. Several B cell subsets have shown regulatory, anti-inflammatory capacities in response to stimuli in vitro, as well as in the animal model of MS: Experimental Autoimmune Encephalomyelitis (EAE). However, the functional role of the B regulatory cells (Bregs) in vivo and specifically in the human disease is yet to be clarified. In the present review, we have summarized the updated information on the roles of effector and regulatory B cells in MS and the immune-modulatory effects of MS therapeutic agents on their phenotype and function.

Structural Implications for the Formation and Function of the Complement Effector Protein iC3b.

Complement-mediated opsonization, phagocytosis, and immune stimulation are critical processes in host defense and homeostasis, with the complement activation fragment iC3b playing a key effector role. To date, however, there is no high-resolution structure of iC3b, and some aspects of its structure-activity profile remain controversial. Here, we employed hydrogen-deuterium exchange mass spectrometry to describe the structure and dynamics of iC3b at a peptide resolution level in direct comparison with its parent protein C3b. In our hydrogen-deuterium exchange mass spectrometry study, 264 peptides were analyzed for their deuterium content, providing almost complete sequence coverage for this 173-kDa protein. Several peptides in iC3b showed significantly higher deuterium uptake when compared with C3b, revealing more dynamic, solvent-exposed regions. Most of them resided in the CUB domain, which contains the heptadecapeptide C3f that is liberated during the conversion of C3b to iC3b. Our data suggest a highly disordered CUB, which has acquired a state similar to that of intrinsically disordered proteins, resulting in a predominant form of iC3b that features high structural flexibility. The structure was further validated using an anti-iC3b mAb that was shown to target an epitope in the CUB region. The information obtained in this work allows us to elucidate determinants of iC3b specificity and activity and provide functional insights into the protein's recognition pattern with respect to regulators and receptors of the complement system.

Natural genomic amplification of cholinesterase genes in animals.

Tight control of the concentration of acetylcholine at cholinergic synapses requires precise regulation of the number and state of the acetylcholine receptors, and of the synthesis and degradation of the neurotransmitter. In particular, the cholinesterase activity has to be controlled exquisitely. In the genome of the first experimental models used (man, mouse, zebrafish and drosophila), there are only one or two genes coding for cholinesterases, whereas there are more genes for their closest relatives the carboxylesterases. Natural amplification of cholinesterase genes was first found to occur in some cancer cells and in insect species subjected to evolutionary pressure by insecticides. Analysis of the complete genome sequences of numerous representatives of the various metazoan phyla show that moderate amplification of cholinesterase genes is not uncommon in molluscs, echinoderms, hemichordates, prochordates or lepidosauria. Amplification of acetylcholinesterase genes is also a feature of parasitic nematodes or ticks. In these parasites, over-production of cholinesterase-like proteins in secreted products and the saliva are presumed to have effector roles related to host infection. These amplification events raise questions about the role of the amplified gene products, and the adaptation processes necessary to preserve efficient cholinergic transmission. This is an article for thespecial issue XVth International Symposium on Cholinergic Mechanisms.

Cross-talk of the biotrophic pathogen Claviceps purpurea and its host Secale cereale

BackgroundThe economically important Ergot fungus Claviceps purpurea is an interesting biotrophic model system because of its strict organ specificity (grass ovaries) and the lack of any detectable plant defense reactions. Though several virulence factors were identified, the exact infection mechanisms are unknown, e.g. how the fungus masks its attack and if the host detects the infection at all.ResultsWe present a first dual transcriptome analysis using an RNA-Seq approach. We studied both, fungal and plant gene expression in young ovaries infected by the wild-type and two virulence-attenuated mutants. We can show that the plant recognizes the fungus, since defense related genes are upregulated, especially several phytohormone genes. We present a survey of in planta expressed fungal genes, among them several confirmed virulence genes. Interestingly, the set of most highly expressed genes includes a high proportion of genes encoding putative effectors, small secreted proteins which might be involved in masking the fungal attack or interfering with host defense reactions. As known from several other phytopathogens, the C. purpurea genome contains more than 400 of such genes, many of them clustered and probably highly redundant. Since the lack of effective defense reactions in spite of recognition of the fungus could very well be achieved by effectors, we started a functional analysis of some of the most highly expressed candidates. However, the redundancy of the system made the identification of a drastic effect of a single gene most unlikely. We can show that at least one candidate accumulates in the plant apoplast. Deletion of some candidates led to a reduced virulence of C. purpurea on rye, indicating a role of the respective proteins during the infection process.ConclusionsWe show for the first time that- despite the absence of effective plant defense reactions- the biotrophic pathogen C. purpurea is detected by its host. This points to a role of effectors in modulation of the effective plant response. Indeed, several putative effector genes are among the highest expressed genes in planta.

CD103+ CD8 T Cells in the Toxoplasma-Infected Brain Exhibit a Tissue-Resident Memory Transcriptional Profile.

During chronic infection, memory T cells acquire a unique phenotype and become dependent on different survival signals than those needed for memory T cells generated during an acute infection. The distinction between the role of effector and memory T cells in an environment of persistent antigen remains unclear. Here, in the context of chronic Toxoplasma gondii infection, we demonstrate that a population of CD8 T cells exhibiting a tissue-resident memory (TRM) phenotype accumulates within the brain. We show that this population is distributed throughout the brain in both parenchymal and extraparenchymal spaces. Furthermore, this population is transcriptionally distinct and exhibits a transcriptional signature consistent with the TRM observed in acute viral infections. Finally, we establish that the CD103+ TRM population has an intrinsic capacity to produce both IFN-γ and TNF-α, cytokines critical for parasite control within the central nervous system (CNS). The contribution of this population to pro-inflammatory cytokine production suggests an important role for TRM in protective and ongoing immune responses in the infected CNS.Accession number: GSE95105

Dysregulation of BET proteins in levodopa-induced dyskinesia

Levodopa (L-DOPA) remains the most effective pharmacological treatment for Parkinson Disease (PD) but its use is limited by the development of debilitating drug-related side effects, particularly L-DOPA induced dyskinesia (LID). LID is a consequence of long-term L-DOPA use, and in model systems is characterized by a “priming effect”, whereby initial administrations of L-DOPA trigger a sensitized biochemical and transcriptional response upon subsequent dopaminergic stimulation. Preliminary studies into the mechanisms underlying this cellular memory have indicated an important role for epigenetic change but many of the downstream mechanisms remain unknown. The family of bromodomain and extraterminal (BET) proteins, which bind acetylated histones, play a critical effector role in the regulation of transcription. BET proteins have been implicated in several forms of neural plasticity, but their potential relevance to LID remains unexplored. Using the 6-OHDA rodent model of LID, we show that dyskinesia development induces alterations in BET protein expression along with enhanced occupation of sites at the promoter and enhancer regions of genes dysregulated during dyskinesia development. When BET function was blocked using the pharmacologic inhibitor JQ1, LID was prevented. In addition, we found that JQ1 treatment blocked the transcriptional upregulation of several immediate-early genes known to participate in the pathogenesis of dyskinesia. Together, these results demonstrate an essential role for BET protein activity as an epigenetic “reader” of the altered histone acetylation required for LID development and suggest that modulation of BET protein function is a potential therapeutic avenue for the prevention or reversal of LID in PD.

Elucidating the Role of the Desmosome Protein p53 Apoptosis Effector Related to PMP-22 in Growth Hormone Tumors.

Densely granulated and sparsely granulated (SG) growth hormone (GH) pituitary adenomas differ in biological behavior, which may be correlated with their known differences in cytoplasmic keratin distribution and E-cadherin expression. We wanted to explore candidate genes that might further explain this behavior. Exon expression microarray was performed on 21 GH tumors (10 SG and 11 densely granulated) and 20 normal control pituitaries from autopsy. Bioinformatic analyses confirmed a differential molecular signature between normal pituitary and GH tumors as well as between the GH tumor subtypes. There was a consistent downregulation of transcripts involved in the structure and function of the desmosome, including desmoplakin (eightfold), desmoglein 2 (sixfold), plakophilin 2 (sevenfold), and p53 apoptosis effector related to PMP-22 (PERP; sixfold) in SG tumors compared with normal pituitary. PERP is lost in more aggressive SG human GH pituitary tumors. PERP re-expression in GH3 rat GH tumor cells resulted in decreased colony formation compared with vector transfectants, confirming the role of PERP as a tumor suppressor with no effects on proliferation. Increased PERP expression was associated with loss of a survival advantage in a hypoxic environment, as assessed by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (P < 0.05) and cleaved caspase-3 (P < 0.05). Downregulation of desmosomal formation transcripts including PERP may contribute to the aggressive phenotype seen in SG GH pituitary tumors and their behavior in response to surgery and medical therapy.

Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions.

Dopamine-glutamate interplay dysfunctions have been suggested as pathophysiological key determinants of major psychotic disorders, above all schizophrenia and mood disorders. For the most part, synaptic interactions between dopamine and glutamate signaling pathways take part in the postsynaptic density, a specialized ultrastructure localized under the membrane of glutamatergic excitatory synapses. Multiple proteins, with the role of adaptors, regulators, effectors, and scaffolds compose the postsynaptic density network. They form structural and functional crossroads where multiple signals, starting at membrane receptors, are received, elaborated, integrated, and routed to appropriate nuclear targets. Moreover, transductional pathways belonging to different receptors may be functionally interconnected through postsynaptic density molecules. Several studies have demonstrated that psychopharmacologic drugs may differentially affect the expression and function of postsynaptic genes and proteins, depending upon the peculiar receptor profile of each compound. Thus, through postsynaptic network modulation, these drugs may induce dopamine-glutamate synaptic remodeling, which is at the basis of their long-term physiologic effects. In this review, we will discuss the role of postsynaptic proteins in dopamine-glutamate signals integration, as well as the peculiar impact of different psychotropic drugs used in clinical practice on postsynaptic remodeling, thereby trying to point out the possible future molecular targets of “synapse-based” psychiatric therapeutic strategies.