11-cis-retinal and Neoplasms

Protease-activated receptors (PARs) are G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. Besides the important role of blood coagulation factors in preventing bleeding after vascular injury, these serine proteinases actively engage target cells thereby fulfilling critical functions in cell biology. Cellular responses triggered by coagulation factor-induced PAR activation suggest that PARs play an important role in proliferation, survival and/or malignant transformation of tumor cells. Indeed, PAR expression correlates with cancer malignancy and clinical studies show that anticoagulant treatment is beneficial in cancer patients. In this review, we provide an overview on the PAR family, their mode of activation and mechanisms by which PAR signaling is terminated. In addition, we discuss the relationship between blood coagulation and cancer biology focusing on the potential role of PAR-induced modulation of cell survival, apoptosis and tumor growth.

Topics: Amino Acid Sequence; Animals; Apoptosis; Blood Coagulation Factors; Caspases; Cell Division; Cell Transformation, Neoplastic; Conserved Sequence; Enzyme Activation; Heterotrimeric GTP-Binding Proteins; Humans; Mice; Mice, Knockout; Models, Molecular; Molecular Sequence Data; Neoplasm Proteins; Neoplasms; Protein Conformation; Protein Structure, Tertiary; Receptors, Proteinase-Activated; Rhodopsin; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction; Thrombophilia; Thromboplastin

G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptors (GPCRs) to effect receptor phosphorylation and to initiate profound impairment of receptor signalling, or desensitization. GPCRs form the largest family of cell surface receptors known and defects in GRK function have the potential consequence to affect GPCR-stimulated biological responses in many pathological situations. This review focuses on the physiological role of GRKs revealed by genetically modified animals but also develops the involvement of GRKs in human diseases as, Oguchi disease, heart failure, hypertension or rhumatoid arthritis. Furthermore, the regulation of GRK levels in opiate addiction, cancers, psychiatric diseases, cystic fibrosis and cardiac diseases is discussed. Both transgenic mice and human pathologies have demonstrated the importance of GRKs in the signalling pathways of rhodopsin, beta-adrenergic and dopamine-1 receptors. The modulation of GRK activity in animal models of cardiac diseases can be effective to restore cardiac function in heart failure and opens a novel therapeutic strategy in diseases with GPCR dysregulation.

Topics: Animals; Arthritis, Rheumatoid; Cell Membrane; Cyclic AMP-Dependent Protein Kinases; Heart Diseases; Humans; Hypertension; Mice; Mice, Transgenic; Models, Biological; Neoplasms; Phosphorylation; Protein Kinases; Receptors, Adrenergic, beta; Receptors, Dopamine; Receptors, G-Protein-Coupled; Rhodopsin; Signal Transduction

To describe the clinical, perimetric, and electroretinographic (ERG) results of 4 patients with cone dysfunction following irofulven treatment including the histopathologic and immunocytochemical features of one patient's retinas.. Observational case series.. The patients were examined clinically, including perimetric and ERG evaluations. Eyes from patient 1 and healthy postmortem eyes were processed for histopathologic and immunocytochemistry studies with antibodies specific for cones, rods, and reactive Müller cells.. Clinical signs and symptoms, perimetry, ERG, retinal histopathologic and immunocytochemistry study results.. All 4 patients had ERG changes consistent with abnormal cone responses and relatively normal rod responses. Compared with control eyes, the retina of patient 1 had approximately half the normal numbers of macular cones and fewer peripheral cones. The number of rods were normal but all rod and cone outer segments were shortened.. High-dose irofulven treatment causes cone-specific damage with relative sparing of rods.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Electroretinography; Female; Fluorescent Antibody Technique, Indirect; Glial Fibrillary Acidic Protein; Humans; Middle Aged; Neoplasms; Retinal Cone Photoreceptor Cells; Retinal Diseases; Rhodopsin; Sesquiterpenes; Visual Field Tests; Visual Fields

Chemokine receptor trio composed by CXCR3, CXCR4 and CXCR7 represents a hard and interesting challenge for cancer biology because these three receptors are found to be over-expressed in different cancers as well as to bind the same chemokines. In fact, CXCR4 interacts with CXCL12, CXCR7 not only with CXCL12 but also with CXCL11, that is a natural ligand for CXCR3. For these reasons, it seems necessary to define and to identify the structural determinants of CXCR3, CXCR4 and CXCR7 and their related physic-chemical properties that permit them to bind CXCL11 and CXCL12. Hence in this paper we show the modeling of CXCR7 and its complex with CXCL11 and CXCL12 compared to CXCR3/CXCL11 and CXCR4/CXCL12. Our results show that (i) CXCR3, CXCR4 and CXCR7 present similar trans-membrane helices and different conformations of N-terminal and C-terminal regions as well as of three extracellular loops, and (ii) the predominant interaction between the three receptors and the two chemokines are on hydrophobic and electrostatic basis. Moreover, our data confirm that CXCL12 binds to CXCR7 with higher affinity than to CXCR4. Methodologically, we can also conclude that our computational strategy is adequate to model correctly the interactions between these chemokines and their receptors; therefore, our models represent a good structural basis to design and develop peptides able to block contemporaneously CXCR3, CXCR4 and CXCR7 receptor trio.

Topics: Amino Acid Sequence; Animals; Cattle; Cell Line, Tumor; Chemokine CXCL11; Chemokine CXCL12; Humans; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Molecular Sequence Data; Neoplasms; Protein Binding; Receptors, CXCR; Receptors, CXCR3; Receptors, CXCR4; Rhodopsin; Sequence Alignment; Sequence Analysis, Protein; Static Electricity

Topics: Awards and Prizes; BRCA2 Protein; Chlorophyta; Germany; History, 20th Century; History, 21st Century; Neoplasms; Proto-Oncogene Proteins B-raf; Rhodopsin; United Kingdom