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51.
Caspase-2 has been implicated in various cellular functions, including cell death by apoptosis, oxidative stress response, maintenance of genomic stability and tumor suppression. The loss of the caspase-2 gene (Casp2) enhances oncogene-mediated tumorigenesis induced by E1A/Ras in athymic nude mice, and also in the -Myc lymphoma and MMTV/c-neu mammary tumor mouse models. To further investigate the function of caspase-2 in oncogene-mediated tumorigenesis, we extended our studies in the TH-MYCN transgenic mouse model of neuroblastoma. Surprisingly, we found that loss of caspase-2 delayed tumorigenesis in the TH-MYCN neuroblastoma model. In addition, tumors from TH-MYCN/Casp2−/− mice were predominantly thoracic paraspinal tumors and were less vascularized compared with tumors from their TH-MYCN/Casp2+/+ counterparts. We did not detect any differences in the expression of neuroblastoma-associated genes in TH-MYCN/Casp2−/− tumors, or in the activation of Ras/MAPK signaling pathway that is involved in neuroblastoma progression. Analysis of expression array data from human neuroblastoma samples showed a correlation between low caspase-2 levels and increased survival. However, caspase-2 levels correlated with clinical outcome only in the subset of MYCN-non-amplified human neuroblastoma. These observations indicate that caspase-2 is not a suppressor in MYCN-induced neuroblastoma and suggest a tissue and context-specific role for caspase-2 in tumorigenesis.The caspase family of cysteine proteases are highly conserved regulators of cell death by apoptosis.1 In addition to their pro-apoptotic function, many caspases also have non-apoptotic roles in other physiological processes, such as inflammation, necrosis and tumor suppression.2, 3, 4 The most highly conserved caspase, caspase-2, has recently been demonstrated to function in the cellular stress response, protection against ageing, maintenance of genome stability and in tumor suppression.2, 5, 6, 7, 8The tumor suppressor function of caspase-2 was first demonstrated using E1A/Ras-transformed caspase-2-deficient mouse embryonic fibroblasts (MEFs), which showed an increased tumorigenic potential in athymic nude mice.7 Further supporting evidence came from experiments demonstrating that caspase-2 deficiency enhances B-cell lymphoma development in Eμ-Myc transgenic mice7 and mammary carcinomas in MMTV/c-neu mice,9 suggesting that caspase-2 prevents oncogene-induced lymphomas and epithelial tumors. Importantly, tumor suppression by caspase-2 is also evident in the non-oncogene-driven Atm−/− thymoma mouse model.10Given its role in apoptosis, the tumor suppression function of caspase-2 was thought to be associated with this role, via the elimination of mutagenic or potentially tumorigenic cells. Recent studies have now indicated that the role of caspase-2 may extend beyond apoptosis and that its tumor suppression function may, in part, be mediated by maintaining genomic stability and/or the oxidative stress response. Caspase-2-deficient MEFs and tumor cells from Eμ-Myc/Casp2−/−, MMTV/c-neu/Casp2−/− and Atm−/−;Casp2−/− mice all display aberrant proliferation, and increased genomic instability6, 9, 10 and indicate that caspase-2 is important for the maintenance of genome stability. Importantly, the role of caspase-2 in maintaining genomic stability in primary cells appears to be required for its tumor suppressor function.10Genomic instability is a hallmark of cancer11 and the overexpression of Myc family oncoproteins is commonly associated with genomic instability and a wide spectrum of human cancers.12, 13, 14 Interestingly, a common feature of the oncogene-induced tumor models used in the study of caspase-2 tumor suppressor function is the overexpression of c-Myc15 or aberrant c-Myc signaling.16, 17, 18 Given the role of Myc proteins as key mediators of genomic instability as well as cell proliferation, cell growth and DNA damage, we were interested in further assessing whether caspase-2 can promote tumor suppression in other MYC-dependent mouse tumor models. We used the MYCN mouse model of neuroblastoma (TH-MYCN mouse), in which MYCN is constitutively expressed under the control of the rat tyrosine hydroxylase (TH) promoter leading to neural crest cell-specific expression and early-onset neuroblastoma.19 Amplification of MYCN occurs in ∼20% of human neuroblastomas and high MYCN protein levels are strongly associated with tumor progression and poor clinical outcome.20, 21 Thus, the TH-MYCN transgenic mouse model recapitulates many clinical features of aggressive neuroblastomas in humans and provides a powerful model of preclinical neuroblastoma.19, 22MYCN-mediated neuroblastoma onset and progression is commonly associated with additional genetic events, including the expression of the key genes including Odc1, Mrp1, SirT1 and Ras.23, 24, 25 A recent study has found that caspase-8 is in fact a potent suppressor of neuroblastoma, with the loss of caspase-8 expression occurring in ∼70% of neuroblastoma patients.26, 27 Interestingly, the loss of caspase-8 also promotes bone marrow metastasis in the TH-MYCN neuroblastoma mouse model.26, 27 The role of other caspases in neuroblastoma has not previously been examined, and given the function of caspase-2 in tumor suppression, provided additional relevance in assessing its role in this model.This study shows that caspase-2 is not able to suppress neuroblastoma development in TH-MYCN mice. In contrast to a role for caspase-2 as a tumor suppressor, our findings demonstrate that loss of caspase-2 somewhat delays neuroblastoma onset in mice. Interestingly, expression array data from human neuroblastoma show a strong correlation between low caspase-2 levels and improved outcome. Our data demonstrate that the tumor suppressor function of caspase-2 is not specific to Myc-mediated oncogenesis and that its role is likely to be tissue- and/or context-specific.  相似文献   
52.
The first QSAR study on the activation of the human secretory isoform of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA VI, with a series of amines and amino acids is reported. A large set of topological indices have been used to obtain several tri-/tetra-parametric models. We compared the CA VI activating QSAR models with those calculated for activation of the cytosolic human isozymes hCA I and hCA II. In addition, the effect of D- and L-amino acids as activators of hCA I, hCA II and of hCA VI as compared to those of structurally related biogenic amines was investigated for obtaining statistically significant and predictive QSAR equations. The obtained models are discussed using a variety of statistical parameters. The best models were obtained for hCA II activation, followed by hCA I, whereas the QSAR models for the activation of hCA VI were statistically weaker.  相似文献   
53.
Proteolytic cleavage and subsequent activation of protein kinase C (PKC) delta is required for apoptosis induced by a variety of genotoxic agent, including UV radiation. In addition, overexpression of the constitutively active PKCdelta catalytic fragment (PKCdelta-cat) is sufficient to trigger Bax activation, cytochrome c release, and apoptosis. While PKCdelta is a key apoptotic effector, the downstream target(s) responsible for the mitochondrial apoptotic cascade are not known. We found that expression of the active PKCdelta-cat in HaCaT cells triggers a reduction in the anti-apoptotic protein Mcl-1, similar to UV radiation. The down-regulation of Mcl-1 induced by PKCdelta-cat was not at the mRNA level but was due to decreased protein half-life. Overexpression of Mcl-1 protected HaCaT cells from both UV and PKCdelta-cat-induced apoptosis and blocked the release of cytochrome c from the mitochondria, indicating that Mcl-1 down-regulation was required for apoptosis signaling. Indeed, down-regulation of Mcl-1 with siRNA slightly increased the basal apoptotic rate of HaCaT cells and dramatically sensitized them to UV or PKCdelta-cat-induced apoptosis. HaCaT cells with down-regulated Mcl-1 had higher activated Bax protein, as measured by Bax cross-linking, indicating that Mcl-1 down-regulation is sufficient for Bax activation. Finally, recombinant PKCdelta could phosphorylate Mcl-1 in vitro, identifying Mcl-1 as a direct target for PKCdelta. Overall our results identify Mcl-1 as an important target for PKCdelta-cat that can mediate its pro-apoptotic effects on mitochondria to amplify the apoptotic signaling induced by a wide range of apoptotic stimuli.  相似文献   
54.
The molecular mechanisms regulating the assembly of connexins (Cxs) into gap junctions are poorly understood. Using human pancreatic tumor cell lines BxPC3 and Capan-1, which express Cx26 and Cx43, we show that, upon arrival at the cell surface, the assembly of Cx43 is impaired. Connexin43 fails to assemble, because it is internalized by clathrin-mediated endocytosis. Assembly is restored upon expressing a sorting-motif mutant of Cx43, which does not interact with the AP2 complex, and by expressing mutants that cannot be phosphorylated on Ser-279 and Ser-282. The mutants restore assembly by preventing clathrin-mediated endocytosis of Cx43. Our results also document that the sorting-motif mutant is assembled into gap junctions in cells in which the expression of endogenous Cx43 has been knocked down. Remarkably, Cx43 mutants that cannot be phosphorylated on Ser-279 or Ser-282 are assembled into gap junctions only when connexons are composed of Cx43 forms that can be phosphorylated on these serines and forms in which phosphorylation on these serines is abolished. Based on the subcellular fate of Cx43 in single and contacting cells, our results document that the endocytic itinerary of Cx43 is altered upon cell–cell contact, which causes Cx43 to traffic by EEA1-negative endosomes en route to lysosomes. Our results further show that gap-junctional plaques formed of a sorting motif–deficient mutant of Cx43, which is unable to be internalized by the clathrin-mediated pathway, are predominantly endocytosed in the form of annular junctions. Thus the differential phosphorylation of Cx43 on Ser-279 and Ser-282 is fine-tuned to control Cx43’s endocytosis and assembly into gap junctions.  相似文献   
55.
This study aimed to determine whether, following two years of specialized support for first‐episode psychosis, the addition of a new digital intervention (Horyzons) to treatment as usual (TAU) for 18 months was more effective than 18 months of TAU alone. We conducted a single‐blind randomized controlled trial. Participants were people with first‐episode psychosis (N=170), aged 16‐27 years, in clinical remission and nearing discharge from a specialized service. They were randomly assigned (1:1) to receive Horyzons plus TAU (N=86) or TAU alone (N=84) between October 2013 and January 2017. Horyzons is a novel, comprehensive digital platform merging: peer‐to‐peer social networking; theory‐driven and evidence‐informed therapeutic interventions targeting social functioning, vocational recovery and relapse prevention; expert clinician and vocational support; and peer support and moderation. TAU involved transfer to primary or tertiary community mental health services. The primary outcome was social functioning at 18 months as measured by the Personal and Social Performance Scale (PSP). Forty‐seven participants (55.5%) in the Horyzons plus TAU group logged on for at least 6 months, and 40 (47.0%) for at least 9 months. Social functioning remained high and stable in both groups from baseline to 18‐month follow‐up, with no evidence of significant between‐group differences (PSP mean difference: –0.29, 95% CI: –4.20 to 3.63, p=0.77). Participants in the Horyzons group had a 5.5 times greater increase in their odds to find employment or enroll in education compared with those in TAU (odds ratio, OR=5.55, 95% CI: 1.09‐28.23, p=0.04), with evidence of a dose‐response effect. Moreover, participants in TAU were twice as likely to visit emergency services compared to those in the Horyzons group (39% vs. 19%; OR=0.31, 95% CI: 0.11‐0.86, p=0.03, number needed to treat, NNT=5). There was a non‐significant trend for lower hospitalizations due to psychosis in the Horyzons group vs. TAU (13% vs. 27%; OR=0.36, 95% CI: 0.11‐1.08, p=0.07, NNT=7). So, although we did not find a significant effect of Horyzons on social functioning compared with TAU, the intervention was effective in improving vocational or educational attainment, a core component of social recovery, and in reducing usage of hospital emergency services, a key aim of specialized first‐episode psychosis services. Horyzons holds significant promise as an engaging and sustainable intervention to provide effective vocational and relapse prevention support for young people with first‐episode psychosis beyond specialist services.  相似文献   
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Histone deacetylases (HDACs) have emerged as effective therapeutic targets in the treatment of various diseases including cancers as these enzymes directly involved in the epigenetic regulation of genes. However the development of isoform-selective HDAC inhibitors has been a challenge till date since all HDAC enzymes possess conserved tunnel-like active site. In this study, using molecular dynamics simulation we have analyzed the behavior of tunnels present in HDAC8, 10, and 11 enzymes of class I, II, and IV, respectively. We have identified the equivalent tunnel forming amino acids in these three isoforms and found that they are very much conserved with subtle differences to be utilized in selective inhibitor development. One amino acid, methionine of HDAC8, among six tunnel forming residues is different in isoforms of other classes (glutamic acid (E) in HDAC10 and leucine (L) in HDAC 11) based on which mutations were introduced in HDAC11, the less studied HDAC isoform, to observe the effects of this change. The HDAC8-like (L268M) mutation in the tunnel forming residues has almost maintained the deep and narrow tunnel as present in HDAC8 whereas HDAC10-like (L268E) mutation has changed the tunnel wider and shallow as observed in HDAC10. These results explained the importance of the single change in the tunnel formation in different isoforms. The observations from this study can be utilized in the development of isoform-selective HDAC inhibitors.  相似文献   
58.
Susceptibility for giant cell arteritis increases with chronological age, in parallel with age-related restructuring of the immune system and age-induced remodeling of the vascular wall. Immunosenescence results in shrinkage of the naïve T-cell pool, contraction of T-cell diversity, and impairment of innate immunity. Aging of immunocompetent cells forces the host to take alternative routes for protective immunity and confers risk for pathogenic immunity that causes chronic inflammatory tissue damage. Dwindling immunocompetence is particularly relevant as the aging host is forced to cope with an ever growing infectious load. Immunosenescence coincides with vascular aging during which the arterial wall undergoes dramatic structural changes and medium and large arteries lose their pliability and elasticity. On the molecular level, elastic fibers deteriorate and matrix proteins accumulate biochemical modifications. Thus, the aging process impacts the two major biologic systems that liaise to promote giant cell arteritis; the immune system and the vessel wall niche.  相似文献   
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