Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, beta-catenin, and Axin in sporadic medulloblastomas (MBs) have shown the importance of WNT signaling in the pathogenesis of MB. A subset of children with MB have germline mutations of SUFU, a known inhibitor of Hedgehog signal transduction. A recent report suggested that murine Sufu can bind beta-catenin, export it from the nucleus, and thereby repress beta-catenin/T-cell factor (Tcf)-mediated transcription. We show that an MB-derived mutant of SUFU has lost the ability to decrease nuclear levels of beta-catenin, and cannot inhibit beta-catenin/Tcf-mediated transcription as compared to wild type SUFU. Our results suggest that loss of function of SUFU results in overactivity of both the Sonic Hedgehog, and the WNT signaling pathways, leading to excessive proliferation and failure to differentiate resulting in MB.

Not being what you claim to be: impostors as sources of group threat

We examine the notion of impostors within groups, defined in this paper as people who make public claims to an identity while disguising their failure to fulfil key criteria for group membership. In Experiment 1, vegetarians showed heightened levels of negative affect toward vegetarians who ate meat occasionally compared to an authentic vegetarian. In contrast, non-vegetarians saw the impostor to be marginally more likeable than the authentic vegetarian. In Experiments 2 and 3, participants evaluated only a vegetarian who ate meat. Evaluations of the target were influenced by group attachment, such that participants who identified strongly as vegetarians downgraded the target more strongly and experienced more negative affect than did moderate identifiers and non-vegetarians. Participants were also sensitive to the size of the gulf between the target's claims for identity and their behaviour. Thus, targets who made public claims to being a vegetarian but ate meat were evaluated more negatively than were people who kept their claims for identity private (Experiment 2). Similarly, targets who tried to keep their deviant behaviour secret were evaluated more negatively than were people who openly admitted their deviant behaviour (Experiment 3). The reasons why impostors might threaten the integrity of group identities are discussed. Copyright (C) 2003 John Wiley Sons, Ltd.

Overcoming original antigenic sin to generate new CD8 T cell IFN-gamma responses in an antigen-experienced host

The failure to mount effective immunity to virus variants in a previously virus-infected host is known as original antigenic sin. We have previously shown that prior immunity to a virus capsid protein inhibits induction by immunization of an IFN-gamma CD8(+) T cell response to an epitope linked to the capsid protein. We now demonstrate that capsid protein-primed CD4(+) T cells secrete IL-10 in response to capsid protein presented by dendritic cells, and deviate CD8+ T cells responding to a linked MHC class I-restricted epitope to reduce IFN-gamma production. Neutralizing IL-10 while delivering further linked epitope, either in vitro or in vivo, restores induction by immunization of an Ag-specific IFN-gamma response to the epitope. This finding demonstrates a strategy for overcoming inhibition of MHC class I epitopes upon immunization of a host already primed to Ag, which may facilitate immunotherapy for chronic viral infection or cancer.