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.

Physical and Functional Interactions of the Arf Tumor Suppressor Protein with Nucleophosmin/B23.

Abstract: The Arf tumor suppressor inhibits cell cycle progression through both p53-dependent and p53-independent mechanisms, including interference with rRNA processing Using tandem-affinity-tagged p19Arf, we purified Arf-associated proteins from mouse NIH 3T3 fibroblasts undergoing cell cycle arrest Tagged p19Arf associated with nucleolar and ribosomal proteins, including nucleophosmin/B23 (NPM), a protein thought to foster the maturation of preribosomal particles NPM is an abundant protein, only a minor fraction of which binds to p19Arf; however, a significant proportion of p19Arf associates with NPM The interaction between p19Arf and NPM requires amino acid sequences at the Arf amino terminus, which are also required for Mdm2 binding, as well as the central acidic domain of NPM and an adjacent segment that regulates NPM oligomerization The interaction between p19Arf and NPM occurs in primary mouse embryonic fibroblasts, including those lacking both Mdm2 and p53 In an NIH 3T3 derivative cell line (MT-Arf) engineered to conditionally express an Arf transgene, induced p19Arf associates with NPM and colocalizes with it in high-molecular-weight complexes (2 to 5 MDa) An NPM mutant lacking its carboxyl-terminal nucleic acid-binding domain oligomerizes with endogenous NPM, inhibits p19Arf from entering into 2- to 5-MDa particles, and overrides the ability of p19Arf to retard rRNA processing

MOMP, cell suicide as a BCL-2 family business.

Abstract: Apoptosis shapes development and differentiation, has a key role in tissue homeostasis, and is deregulated in cancer. In most cases, successful apoptosis is triggered by mitochondrial outer membrane permeabilization (MOMP), which defines the mitochondrial or intrinsic pathway and ultimately leads to caspase activation and protein substrate cleavage. The mitochondrial apoptotic pathway centered on MOMP is controlled by an intricate network of events that determine the balance of the cell fate choice between survival and death. Here we will review how MOMP proceeds and how the main effectors cytochrome c, a heme protein that has a crucial role in respiration, and second mitochondria-derived activator of caspase (SMAC), as well as other intermembrane space proteins, orchestrate caspase activation. Moreover, we discuss recent insights on the interplay of the upstream coordinators and initiators of MOMP, the BCL-2 family. This review highlights how our increasing knowledge on the regulation of critical checkpoints of apoptosis integrates with understanding of cancer development and has begun to translate into therapeutic clinical benefit.

Pharmacogenomics: the inherited basis for interindividual differences in drug response.

Abstract: It is well recognized that most medications exhibit wide interpatient variability in their efficacy and toxicity. For many medications, these interindividual differences are due in part to polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, and/or drug targets (e.g., receptors, enzymes). Pharmacogenomics is a burgeoning field aimed at elucidating the genetic basis for differences in drug efficacy and toxicity, and it uses genome-wide approaches to identify the network of genes that govern an individual's response to drug therapy. For some genetic polymorphisms (e.g., thiopurine S-methyltransferase), monogenic traits have a marked effect on pharmacokinetics (e.g., drug metabolism), such that individuals who inherit an enzyme deficiency must be treated with markedly different doses of the affected medications (e.g., 5%-10% of the standard thiopurine dose). Likewise, polymorphisms in drug targets (e.g., beta adrenergic receptor) can alter the sensitivity of patients to treatment (e.g., beta-agonists), changing the pharmacodynamics of drug response. Recognizing that most drug effects are determined by the interplay of several gene products that govern the pharmacokinetics and pharmacodynamics of medications, pharmacogenomics research aims to elucidate these polygenic determinants of drug effects. The ultimate goal is to provide new strategies for optimizing drug therapy based on each patient's genetic determinants of drug efficacy and toxicity. This chapter provides an overview of the current pharmacogenomics literature and offers insights for the potential impact of this field on the safe and effective use of medications.

Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza a virus

Abstract: The SD0 mutant of influenza virus A/WSN/33 (WSN), characterized by a 24-amino-acid deletion in the neuraminidase (NA) stalk, does not grow in embryonated chicken eggs because of defective NA function. Continuous passage of SD0 in eggs yielded 10 independent clones that replicated efficiently. Characterization of these egg-adapted viruses showed that five of the viruses contained insertions in the NA gene from the PB1, PB2, or NP gene, in the region linking the transmembrane and catalytic head domains, demonstrating that recombination of influenza viral RNA segments occurs relatively frequently. The other five viruses did not contain insertions in this region but displayed decreased binding affinity toward sialylglycoconjugates, compared with the binding properties of the parental virus. Sequence analysis of one of the latter viruses revealed mutations in the hemagglutinin (HA) gene, at sites in close proximity to the sialic acid receptor-binding pocket. These mutations appear to compensate for reduced NA function due to stalk deletions. Thus, balanced HA-NA functions are necessary for efficient influenza virus replication.