The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network

Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) tumour suppressor has been associated with cancer progression. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear-cytoplasmic partitioning. Here we show that functional promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia, in which PML function is disrupted by the PML-RARalpha fusion oncoprotein. Remarkably, treatment with drugs that trigger PML-RARalpha degradation, such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus, our results delineate a previously unknown PML-DAXX-HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization.     

Astronomical pacing of late Palaeocene to early Eocene global warming events

At the boundary between the Palaeocene and Eocene epochs, about 55 million years ago, the Earth experienced a strong global warming event, the Palaeocene-Eocene thermal maximum. The leading hypothesis to explain the extreme greenhouse conditions prevalent during this period is the dissociation of 1,400 to 2,800 gigatonnes of methane from ocean clathrates, resulting in a large negative carbon isotope excursion and severe carbonate dissolution in marine sediments. Possible triggering mechanisms for this event include crossing a threshold temperature as the Earth warmed gradually, comet impact, explosive volcanism or ocean current reorganization and erosion at continental slopes, whereas orbital forcing has been excluded. Here we report a distinct carbonate-poor red clay layer in deep-sea cores from Walvis ridge, which we term the Elmo horizon. Using orbital tuning, we estimate deposition of the Elmo horizon at about 2 million years after the Palaeocene-Eocene thermal maximum. The Elmo horizon has similar geochemical and biotic characteristics as the Palaeocene-Eocene thermal maximum, but of smaller magnitude. It is coincident with carbon isotope depletion events in other ocean basins, suggesting that it represents a second global thermal maximum. We show that both events correspond to maxima in the approximately 405-kyr and approximately 100-kyr eccentricity cycles that post-date prolonged minima in the 2.25-Myr eccentricity cycle, implying that they are indeed astronomically paced.     

A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size

Autosomal recessive primary microcephaly is a potential model in which to research genes involved in human brain growth. We show that two forms of the disorder result from homozygous mutations in the genes CDK5RAP2 and CENPJ. We found neuroepithelial expression of the genes during prenatal neurogenesis and protein localization to the spindle poles of mitotic cells, suggesting that a centrosomal mechanism controls neuron number in the developing mammalian brain.     

Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse

Vacuolar-vesicular protein sorting (Vps) factors are involved in vesicular trafficking in eukaryotic cells. We identified the missense mutation L967Q in Vps54 in the wobbler mouse, an animal model of amyotrophic lateral sclerosis, and also characterized a lethal allele, Vps54(beta-geo). Motoneuron survival and spermiogenesis are severely compromised in the wobbler mouse, indicating that Vps54 has an essential role in these processes.     

Bone marrow-derived mesenchymal cells and MMP13 contribute to experimental choroidal neovascularization

In this study, we evaluate the potential involvement of collagenase-3 (MMP13), a matrix metalloproteinase (MMP) family member, in the exudative form of age-related macular degeneration characterized by a neovascularisation into the choroid. RT-PCR analysis revealed that human neovascular membranes issued from patients with AMD expressed high levels of Mmp13. The contribution of MMP13 in choroidal neovascularization (CNV) formation was explored by using a murine model of laser-induced CNV and applying it to wild-type mice (WT) and Mmp13-deficient mice (Mmp13 ^?/? mice). Angiogenic and inflammatory reactions were explored by immunohistochemistry. The implication of bone marrow (BM)-derived cells was determined by BM engraftment into irradiated mice and by injecting mesenchymal stem cells (MSC) isolated from WT BM. The deficiency of Mmp13 impaired CNV formation which was fully restored by WT BM engraftment and partially rescued by several injections of WT MSC. The present study sheds light on a novel function of MMP13 during BM-dependent choroidal vascularization and provides evidence for a role for MSC in the pathogenesis of CNV.     

Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma

Hepatitis B virus (HBV) may be one of the agents involved in the aetiology of human primary liver cancer. This hypothesis is supported by (1) the similarity between the geographical distribution of chronic carriers of the viral surface antigen (HBsAg) and that of hepatocellular carcinoma (HCC); (2) the increase in the prevalence of HBV markers in serum of patients with primary liver cancer when compared with the general population; (3) the observation that HBV infection precedes the development of the tumour. Moreover, these epidemiological indications of an association between HBV infecton and hepatocellular carcinoma are supported by the detection of HBV markers such as HBsAg or viral DNA sequences, although in a non-integrated form in tumour tissue. To study the relationship between HBV and primary liver cancer further, we looked for the presence of free or integrated viral DNA in tumour tissue of human hepatocellular carcinomas and in a HBsAg-producing human hepatoma cell line. Using the blot-transfer hybridization technique and cloned HBV DNA as a probe, we have now demonstrated that the viral DNA is integrated in the cellular genome both in tumour tissue and in a hepatoma cell line.     

从碳到氢能源:昨天、今天、明天

简述了近期能源的发展动向,特别以氢能源为重点,就产氢、储氢及利用氢三个方面进行阐述。氢气作为高能量密度的燃料载体在提供能量的过程中可实现或接近实现无碳排放。作者及团队发现,将分散式电解水产氢技术应用在燃料电池模型汽车上,模型车的运行速度及里程可提高30%以上。     

Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring

The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic. Having either parent obese is an independent risk factor for childhood obesity. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established, the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs β-cell 'dysfunction' in rat F(1) female offspring. Chronic HFD consumption in Sprague-Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P?相似文献