Receptorphin: A conserved peptide derived from the sequence of the opioid receptor, with opioid displacement activity and potent antiproliferative actions in tumor cells

BACKGROUND: In addition to endogenous opioids, a number of peptide sequences, derived from endogenous (hemorphins, alphaS1-casomorphin), and exogenous proteins (casomorphins, exorphins) have been reported, possessing opioid activity. In the present work, we report the identification of a new peptide, receptorphin (Tyr-Ile-Phe-Asn-Leu), derived from the sequence of the second transmembrane loop of the opioid receptor. This sequence is unique for the opioid receptor, and conserved in all species and receptor-types. RESULTS AND DISCUSSION: Receptorphin competes for opioid binding, presenting a kappa-receptor interaction, while it binds equally to delta- and mu- opioid and somatostatin-binding sites, and inhibits the cell proliferation of a number of human cancer cell lines, in a dose-dependent and reversible manner, at the picomolar or the nanomolar range. Receptorphin shows a preferential action on prostate cancer cells. CONCLUSION: Our work identifies, for the first time a peptide, in a receptor sequence, possessing ligand-agonistic activities. A hypothesis, based on receptorphin liberation after cell death, is presented, which could tentatively explain the time-lag observed during opioid antiproliferative action

Natural antisense RNA inhibits the expression of BCMA, a tumour necrosis factor receptor homologue.

BACKGROUND: BCMA (B-cell maturation) belongs to the tumour necrosis factor receptor gene family, and is specifically expressed in mature B lymphocytes. Antisense BCMA RNA is produced by transcription from the same locus and has typical mRNA features, e.g, polyadenylation, splicing, Kozak consensus sequence and an ORF (p12). To investigate the function of antisense BCMA RNA, we expressed BCMA in cell lines, in the presence of antisense p12 or a mutant lacking the initiation ATG codon (p12-ATG). RESULTS: Overexpression of both p12 and p12-ATG antisense BCMA resulted in a large decrease in the amount of BCMA protein produced, with no change in BCMA RNA levels, indicating that BCMA expression is regulated by antisense BCMA RNA at the translational level. We have also observed slight adenosine modifications, suggestive of the activity of a double-stranded RNA-specific adenosine deaminase. CONCLUSION: These data suggest that antisense BCMA may operate under physiological conditions using similar antisense-mediated control mechanisms, to inhibit the expression of the BCMA gene

TWEAK Affects Keratinocyte G2/M Growth Arrest and Induces Apoptosis through the Translocation of the AIF Protein to the Nucleus

The soluble TNF-like weak inducer of apoptosis (TWEAK, TNFSF12) binds to the fibroblast growth factor-inducible 14 receptor (FN14, TNFRSF12A) on the cell membrane and induces multiple biological responses, such as proliferation, migration, differentiation, angiogenesis and apoptosis. Previous reports show that TWEAK, which does not contain a death domain in its cytoplasmic tail, induces the apoptosis of tumor cell lines through the induction of TNFα secretion. TWEAK induces apoptosis in human keratinocytes. Our experiments clearly demonstrate that TWEAK does not induce the secretion of TNFα or TRAIL proteins. The use of specific inhibitors and the absence of procaspase-3 cleavage suggest that the apoptosis of keratinocytes follows a caspase- and cathepsin B-independent pathway. Further investigation showed that TWEAK induces a decrease in the mitochondrial membrane potential of keratinocytes. Confocal microscopy showed that TWEAK induces the cleavage and the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus, thus initiating caspase-independent apoptosis. Moreover, TWEAK induces FOXO3 and GADD45 expression, cdc2 phosphorylation and cdc2 and cyclinB1 degradation, resulting in the arrest of cell growth at the G2/M phase. Finally, we report that TWEAK and FN14 are normally expressed in the basal layer of the physiological epidermis and are greatly enhanced in benign (psoriasis) and malignant (squamous cell carcinoma) skin pathologies that are characterized by an inflammatory component. TWEAK might play an essential role in skin homeostasis and pathology

Expression of TNF-superfamily members BAFF and APRIL in breast cancer: Immunohistochemical study in 52 invasive ductal breast carcinomas

<p>Abstract</p> <p>Background</p> <p>Recent studies suggest an association between chronic inflammation, modulating the tissue microenvironment, and tumor biology. Tumor environment consists of tumor, stromal and endothelial cells and infiltrating macrophages, T lymphocytes, and dendritic cells, producing an array of cytokines, chemokines and growth factors, accounting for a complex cell interaction and regulation of differentiation, activation, function and survival of tumor and surrounding cells, responsible for tumor progression and spreading or induction of antitumor immune responses and rejection. Tumor Necrosis Factor (TNF) family members (19 ligands and 29 receptors) represent a pleiotropic family of agents, related to a plethora of cellular events from proliferation and differentiation to apoptosis and tumor reduction. Among these members, BAFF and APRIL (CD257 and CD256 respectively) gained an increased interest, in view of their role in cell protection, differentiation and growth, in a number of lymphocyte, epithelial and mesenchymal structures.</p> <p>Methods</p> <p>We have assayed by immunohistochemistry 52 human breast cancer biopsies for the expression of BAFF and APRIL and correlated our findings with clinicopathological data and the evolution of the disease.</p> <p>Results</p> <p>BAFF was ubiquitely expressed in breast carcinoma cells, DCIS, normal-appearing glands and ducts and peritumoral adipocytes. In contrast, APRIL immunoreactive expression was higher in non-malignant as compared to malignant breast structures. APRIL but not BAFF immunoreactivity was higher in N+ tumors, and was inversely related with the grade of the tumors. Neither parameter was related to DFS or the OS of patients.</p> <p>Conclusion</p> <p>Our data show, for the first time, an autocrine secretion of BAFF and APRIL from breast cancer cells, offering new perspectives for their role in neoplastic and normal breast cell biology and offering new perspectives for possible selective intervention in breast cancer.</p

LA PROTEINE BCMA (B CELL MATURATION) EST UN NOUVEAU MEMBRE DE LA FAMILLE DES RECEPTEURS AU TNF IMPLIQUE DANS L'HOMEOSTASIE DE LA POPULATION LYMPHOCYTAIRE B

LE GENE BCMA (B CELL MATURATION), ISOLE APRES ANALYSE MOLECULAIRE D'UNE TRANSLOCATION T(4 ; 16) SPECIFIQUE D'UN LYMPHOME T INTESTINAL, EST EXPRIME DE FACON PREFERENTIELLE DANS LES LYMPHOCYTES B MATURES. IL CODE UNE PROTEINE DE 184 ACIDES AMINES LOCALISEE DANS UNE STRUCTURE PERINUCLEAIRE. NOUS AVONS REALISE LE CLONAGE D'UN ADNC BCMA MURIN AFIN D'OBTENIR DES INFORMATIONS SUR LE ROLE BIOLOGIQUE DE LA PROTEINE. LA COMPARAISON DES SEQUENCES PROTEIQUES BCMA HUMAINE ET MURINE REVELE LA CONSERVATION DE SIX CYSTEINES DANS LE DOMAINE TERMINAL. LA TECHNIQUE HCA (HIGH CLUSTER ANALYSIS) INDIQUE QUE CES RESIDUS FORMENT UN DOMAINE CRD, CARACTERISTIQUE DE LA REGION EXTRACELLULAIRE DES RECEPTEURS AU TNF. LA PROTEINE BCMA CONSTITUE DONC A UN NOUVEAU MEMBRE DE CETTE FAMILLE (TNFRSF17). CE RECEPTEUR DONT L'EXPRESSION A LA SURFACE DES CELLULES B MATURES EST HAUTEMENT REGULEE, ACTIVE DES VOIES DE SIGNALISATION COMMUNES AUX AUTRES TNFR : KINASES JNK, P38, FACTEURS DE TRANSCRIPTION NF-KB, AP1 ET ELK-I ; VIA LE RECRUTEMENT DE PROTEINES ADAPTATRICES DE LA FAMILLE TRAF (TRAF 1, 2 ET 3). DE PLUS, IL FIXE UN LIGAND ORPHELIN DE LA FAMILLE TNF : BAFF (B CELL ACTIVATING FACTOR BELONGING TO THE TNF FAMILY). DES ETUDES REALISEES IN VIVO INDIQUENT QUE LE RECEPTEUR BCMA EST IMPLIQUE DANS LE MAINTIEN DE L'HOMEOSTASIE DE LA POPULATION LYMPHOCYTAIRE B, PROBABLEMENT VIA L'INDUCTION DE SIGNAUX DE SURVIE CELLULAIRE. PAR AILLEURS, LES FONCTIONS DE LA PROTEINE BCMA SONT REGULEES DE FACON NEGATIVE PAR UN ARNM ANTISENS NATUREL. CE DERNIER ALTERE LES FONCTIONS DU GENE SENS SOUS SA FORME POLYNUCLEOTIDIQUE, EN INHIBANT LA TRADUCTION DES MESSAGERS BCMA, CE PAR UN MECANISME IMPLIQUANT PARTIELLEMENT L'INTERVENTION D'UNE ENZYME DESAMINASE. DES ETUDES COMPLEMENTAIRES PERMETTRONT D'AFFINER NOS CONNAISSANCES SUR LES MECANISMES DE REGULATION DU GENE. NOS DONNEES SUGGERENT QUE LA PROTEINE BCMA POURRAIT CONSTITUER UN OUTILS INTERESSANT DANS LA THERAPIE DES PATHOLOGIES AUTO-IMMUNES LIEES A UNE SURPRODUCTION DE LYMPHOCYTES B.PARIS7-Bibliothèque centrale (751132105) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF