HOIL-1L Interacting Protein (HOIP) as an NF-κB Regulating Component of the CD40 Signaling Complex

The tumor necrosis factor receptor (TNFR) superfamily mediates signals critical for regulation of the immune system. One family member, CD40, is important for the efficient activation of antibody-producing B cells and other antigen-presenting cells. The molecules and mechanisms that mediate CD40 signaling are only partially characterized. Proteins known to interact with the cytoplasmic domain of CD40 include members of the TNF receptor-associated factor (TRAF) family, which regulate signaling and serve as links to other signaling molecules. To identify additional proteins important for CD40 signaling, we used a combined stimulation/immunoprecipitation procedure to isolate CD40 signaling complexes from B cells and characterized the associated proteins by mass spectrometry. In addition to known CD40-interacting proteins, we detected SMAC/DIABLO, HTRA2/Omi, and HOIP/RNF31/PAUL/ZIBRA. We found that these previously unknown CD40-interacting partners were recruited in a TRAF2-dependent manner. HOIP is a ubiquitin ligase capable of mediating NF-κB activation through the ubiquitin-dependent activation of IKKγ. We found that a mutant HOIP molecule engineered to lack ubiquitin ligase activity inhibited the CD40-mediated activation of NF-κB. Together, our results demonstrate a powerful approach for the identification of signaling molecules associated with cell surface receptors and indicate an important role for the ubiquitin ligase activity of HOIP in proximal CD40 signaling.     

xGDB: open-source computational infrastructure for the integrated evaluation and analysis of genome features

The eXtensible Genome Data Broker (xGDB) provides a software infrastructure consisting of integrated tools for the storage, display, and analysis of genome features in their genomic context. Common features include gene structure annotations, spliced alignments, mapping of repetitive sequence, and microarray probes, but the software supports inclusion of any property that can be associated with a genomic location. The xGDB distribution and user support utilities are available online at the xGDB project website, http://xgdb.sourceforge.net/.     

Sunitinib Does Not Accelerate Tumor Growth in Patients with Metastatic Renal Cell Carcinoma

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Highlights? Drugs targeting the tumor vasculature are under investigation for cancer treatment ? However, changes in tumor vasculature may promote tumor growth and/or tumor spread ? Our analysis shows that sunitinib does not accelerate tumor growth in humans ? Sunitinib administration has positive effects and no negative effects when stopped     

Effects of N-nitrosopiperidine substitutions on mutagenicity in Drosophila melanogaster.

N-Nitrosopiperidine (NP) and various derivatives were fed to Drosophila melanogaster males over a wide concentration range in order to assess their mutagenic potency in the induction of X-linked recessive lethals and chromosome loss. NP was effective in inducing lethals, as were its halogen and methyl-substituted derivatives, with the exception of 2,6-dimethyl NP. (Methyl substitutions at the alpha carbon atoms reduce or eliminate mutagenic activity.) Substitution of halogen groups on the piperidine ring enhanced the mutagenic activity, with the 3-chloro compound being the most mutagenic. In contrast, substitutions with a hydroxyl, carboxyl, or keto group resulted in a loss of mutagenicity. None of the compounds tested increased the frequency of chromosome loss or breakage in mature sperm.     

Acquired amegakaryocytic thrombocytopenia purpura in a Rhesus macaque (Macaca mulatta)

A 10-y-old multiparous rhesus macaque presented for an annual routine physical examination. Clinically, the animal had pale mucous membranes, petechial and ecchymotic hemorrhages in multiple sites, and a laceration at the tail base. Severe pancytopenia was noted on hematologic evaluation. The monkey was seronegative for SIV, simian T-lymphotropic virus, simian retrovirus type D, and Macacine herpesvirus 1. Bone marrow evaluation revealed a paucity of megakaryocytic precursors in a hypercellular marrow with marked erythroid hyperplasia. In light of these findings, the diagnosis was acquired amegakaryocytic thrombocytopenia purpura. Due to the poor prognosis of the syndrome and clinical deterioration of the monkey, euthanasia was elected. A definitive cause of the thrombocytopenia was not identified; however, the syndrome may have developed secondary to a recent spontaneous abortion. To our knowledge, this case represents the first reported observation of acquired amegakaryocytic thrombocytopenia purpura in a rhesus monkey.