Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.     

Treatment of spontaneous murine lymphomas with syngeneic lymphoid cells

Syngeneic thymus grafts and spleen cells were administered to thymectomized and intact (C57BL/1XA)F1 mice with spontaneous lymphomas. Their life span was prolonged significantly compared to untreated tumor-bearing controls. Dramatic clinical and histologic evidence of tumor regression was observed.     

Increased incidence of lymphomas in survivors of the host-versus-graft syndrome

Summary When (SB)F₁ spleen cells were injected into perinatal parental B strain mice a lethal runting syndrome was induced. The survivors showed a significantly increased incidence of lymphomas in old age. the tumors occurred much later and less frequently than in the reverse reaction, B(SB)F₁ GVHD.Supported by U.S.P.H.S. grant No. 15,500.     

First insights into the biodiversity and biogeography of the Southern Ocean deep sea

Shallow marine benthic communities around Antarctica show high levels of endemism, gigantism, slow growth, longevity and late maturity, as well as adaptive radiations that have generated considerable biodiversity in some taxa. The deeper parts of the Southern Ocean exhibit some unique environmental features, including a very deep continental shelf and a weakly stratified water column, and are the source for much of the deep water in the world ocean. These features suggest that deep-sea faunas around the Antarctic may be related both to adjacent shelf communities and to those in other oceans. Unlike shallow-water Antarctic benthic communities, however, little is known about life in this vast deep-sea region. Here, we report new data from recent sampling expeditions in the deep Weddell Sea and adjacent areas (748-6,348 m water depth) that reveal high levels of new biodiversity; for example, 674 isopods species, of which 585 were new to science. Bathymetric and biogeographic trends varied between taxa. In groups such as the isopods and polychaetes, slope assemblages included species that have invaded from the shelf. In other taxa, the shelf and slope assemblages were more distinct. Abyssal faunas tended to have stronger links to other oceans, particularly the Atlantic, but mainly in taxa with good dispersal capabilities, such as the Foraminifera. The isopods, ostracods and nematodes, which are poor dispersers, include many species currently known only from the Southern Ocean. Our findings challenge suggestions that deep-sea diversity is depressed in the Southern Ocean and provide a basis for exploring the evolutionary significance of the varied biogeographic patterns observed in this remote environment.     

Bottom-up effects of plant diversity on multitrophic interactions in a biodiversity experiment

Biodiversity is rapidly declining, and this may negatively affect ecosystem processes, including economically important ecosystem services. Previous studies have shown that biodiversity has positive effects on organisms and processes across trophic levels. However, only a few studies have so far incorporated an explicit food-web perspective. In an eight-year biodiversity experiment, we studied an unprecedented range of above- and below-ground organisms and multitrophic interactions. A multitrophic data set originating from a single long-term experiment allows mechanistic insights that would not be gained from meta-analysis of different experiments. Here we show that plant diversity effects dampen with increasing trophic level and degree of omnivory. This was true both for abundance and species richness of organisms. Furthermore, we present comprehensive above-ground/below-ground biodiversity food webs. Both above ground and below ground, herbivores responded more strongly to changes in plant diversity than did carnivores or omnivores. Density and richness of carnivorous taxa was independent of vegetation structure. Below-ground responses to plant diversity were consistently weaker than above-ground responses. Responses to increasing plant diversity were generally positive, but were negative for biological invasion, pathogen infestation and hyperparasitism. Our results suggest that plant diversity has strong bottom-up effects on multitrophic interaction networks, with particularly strong effects on lower trophic levels. Effects on higher trophic levels are indirectly mediated through bottom-up trophic cascades.     

Increased incidence of lymphomas in thymectomized Mice - evidence for an immunological theory of aging

Zusammenfassung Bei einem Mäusestamm mit hoher Rate spontaner Retikulosarkome wird gezeigt, dass die Tumoren bei neonatal thymektomierten Tieren signifikant rascher und häufiger auftreten.

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Supported by U.S.P.H.S. grants No. CA06519 and No. AM12151     

A tumour suppressor network relying on the polyamine-hypusine axis

Tumour suppressor genes encode a broad class of molecules whose mutational attenuation contributes to malignant progression. In the canonical situation, the tumour suppressor is completely inactivated through a two-hit process involving a point mutation in one allele and chromosomal deletion of the other. Here, to identify tumour suppressor genes in lymphoma, we screen a short hairpin RNA library targeting genes deleted in human lymphomas. We functionally identify those genes whose suppression promotes tumorigenesis in a mouse lymphoma model. Of the nine tumour suppressors we identified, eight correspond to genes occurring in three physically linked 'clusters', suggesting that the common occurrence of large chromosomal deletions in human tumours reflects selective pressure to attenuate multiple genes. Among the new tumour suppressors are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, we establish the polyamine-hypusine axis as a new tumour suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas and co-suppression of both genes promotes lymphomagenesis in mice. Thus, some tumour suppressor functions can be disabled through a two-step process targeting different genes acting in the same pathway.