St. Jude Children's Research Hospital

About: St. Jude Children's Research Hospital is a healthcare organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Virus. The organization has 9344 authors who have published 19233 publications receiving 1233399 citations. The organization is also known as: St. Jude Children's Hospital & St. Jude Hospital.

Inactivating mutations of acetyltransferase genes in B-cell lymphoma

Abstract: B-cell non-Hodgkin’s lymphoma comprises biologically and clinically distinct diseases the pathogenesis of which is associated with genetic lesions affecting oncogenes and tumour-suppressor genes. We report here that the two most common types—follicular lymphoma and diffuse large B-cell lymphoma—harbour frequent structural alterations inactivating CREBBP and, more rarely, EP300, two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signalling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these two genes. These lesions usually affect one allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein and activation of the p53 tumour suppressor. These results identify CREBBP/EP300 mutations as a major pathogenetic mechanism shared by common forms of B-cell non-Hodgkin’s lymphoma, with direct implications for the use of drugs targeting acetylation/deacetylation mechanisms. In three different subtypes of B-cell lymphomas, two papers report frequent somatic mutations in the genes CREBBP and EP300, which are present in primary tumours or acquired at relapse. These genes encode related acetyltransferases that mainly function to regulate gene expression by acetylating histones and other transcriptional regulators. The mutations disrupt these activities and thus alter chromatin regulation of gene expression, as well as proliferation and potentially the response to anticancer drugs. These studies may provide a rationale for the use of histone deacetylase inhibitors in certain B-cell lymphomas. In three different subtypes of B-cell lymphomas, two papers now report frequent somatic mutations in CREBBP and EP300, present in primary tumours or acquired at relapse. These genes encode related acetyltransferases that mainly function to regulate gene expression by acetylating histones and other transcriptional regulators. The mutations found inactivate these activities and thus alter chromatin regulation of gene expression, as well as proliferation and potentially the response to therapeutic drugs.

Signalling pathways and molecular interactions of NOD1 and NOD2

Abstract: NOD1 and NOD2 are intracellular sensors of microbial components derived from bacterial peptidoglycan. This Review describes the signalling pathways of these NOD proteins and details their role in the maintenance of mucosal homeostasis and the induction of mucosal immunity. The NOD (nucleotide-binding oligomerization domain) proteins NOD1 and NOD2 have important roles in innate immunity as sensors of microbial components derived from bacterial peptidoglycan. The importance of these molecules is underscored by the fact that mutations in the gene that encodes NOD2 occur in a subpopulation of patients with Crohn's disease, and NOD1 has also been shown to participate in host defence against infection with Helicobacter pylori. Here, we focus on the molecular interactions between these NOD proteins and other intracellular molecules to elucidate the mechanisms by which NOD1 and NOD2 contribute to the maintenance of mucosal homeostasis and the induction of mucosal inflammation.

Disruption of the ARF–Mdm2–p53 tumor suppressor pathway in Myc-induced lymphomagenesis

Abstract: Transgenic mice expressing the c-Myc oncogene driven by the immunoglobulin heavy chain enhancer (Emu) develop B-cell lymphoma and exhibit a mean survival time of approximately 6 months. The protracted latent period before the onset of frank disease likely reflects the ability of c-Myc to induce a p53-dependent apoptotic program that initially protects animals against tumor formation but is disabled when overtly malignant cells emerge. In cultured primary mouse embryo fibroblasts, c-Myc activates the p19(ARF)-Mdm2-p53 tumor suppressor pathway, enhancing p53-dependent apoptosis but ultimately selecting for surviving immortalized cells that have sustained either p53 mutation or biallelic ARF deletion. Here we report that p53 and ARF also potentiate Myc-induced apoptosis in primary pre-B-cell cultures, and that spontaneous inactivation of the ARF-Mdm2-p53 pathway occurs frequently in tumors arising in Emu-myc transgenic mice. Many Emu-myc lymphomas sustained either p53 (28%) or ARF (24%) loss of function, whereas Mdm2 levels were elevated in others. Its overexpression in some tumors lacking p53 function raises the possibility that Mdm2 can contribute to lymphomagenesis by interacting with other targets. Emu-myc transgenic mice hemizygous for ARF displayed accelerated disease (11-week mean survival), and 80% of these tumors lost the wild-type ARF allele. All ARF-null Emu-myc mice died of lymphoma within a few weeks of birth. About half of the tumors arising in ARF hemizygous or ARF nullizygous Emu-myc transgenic mice also overexpressed Mdm2. Therefore, Myc activation strongly selects for spontaneous inactivation of the ARF-Mdm2-p53 pathway in vivo, cancelling its protective checkpoint function and accelerating progression to malignancy.

Human aminopeptidase N is a receptor for human coronavirus 229E

Abstract: Human coronaviruses (HCV) in two serogroups represented by HCV-229E and HCV-OC43 are an important cause of upper respiratory tract infections. Here we report that human aminopeptidase N, a cell-surface metalloprotease on intestinal, lung and kidney epithelial cells, is a receptor for human coronavirus strain HCV-229E, but not for HCV-OC43. A monoclonal antibody, RBS, blocked HCV-229E virus infection of human lung fibroblasts, immunoprecipitated aminopeptidase N and inhibited its enzymatic activity. HCV-229E-resistant murine fibroblasts became susceptible after transfection with complementary DNA encoding human aminopeptidase N. By contrast, infection of human cells with HCV-OC43 was not inhibited by antibody RBS and expression of aminopeptidase N did not enhance HCV-OC43 replication in mouse cells. A mutant aminopeptidase lacking the catalytic site of the enzyme did not bind HCV-229E or RBS and did not render murine cells susceptible to HCV-229E infection, suggesting that the virus-binding site may lie at or near the active site of the human aminopeptidase molecule.