| |||
|
|
|||
|
      |
|
 |
|
| |||||||||||
| |||||||||||
| |||||||||||
| | | | ||||||||
|
In brief: May 2008Gene expression Nuclear receptor-enhanced transcription requires motor- and LSD1-dependent gene networking in interchromatin granules It is unclear how transcriptional responses are integrated in the nucleus. Nunez et al. now show that 17 Ageing Nuclear envelope defects cause stem cell dysfunction in premature-aging mice Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing. Two studies show strikingly diverse effects of premature ageing models on stem-cell function. Espada et al. observed that Zmpste24-/- progeroid mice, which show nuclear lamina defects, have increased numbers of hair follicle stem cells with decreased proliferative capacity and altered nuclear architecture. ZMPSTE24 deficiency is also associated with reduced Wnt signalling, which is important for stem-cell maintenance. Scaffidi and Misteli produced cell lines that expressed progerin, which is a mutant form of lamin A. Progerin induced Notch signalling — an important regulator of stem-cell maintenance and fate. Induction of progerin in mesenchymal stem cells (the main tissues affected in progeria are of mesenchymal origin) affected their molecular identity and their differentiation potential. These studies suggest that accelerated ageing may be the result of adult stem-cell dysfunction and resulting tissue deterioration. MHC molecules MHC class II-peptide complexes internalize using a clathrin- and dynamin-independent endocytosis pathway Recycling of peptide–MHC class II complexes from the cell surface is thought to increase the repertoire of peptides available for presentation, but the molecular mechanisms behind this recycling is not known. Newly synthesized invariant chain (Ii)-associated MHC class II molecules are known to travel from the trans-Golgi network to the cell surface where they enter the endocytic pathway by clathrin- and dynamin-mediated endocytosis for delivery to the antigen-processing compartments. Now, Walseng et al. show that, by contrast, the internalization of complexes involves a clathrin- and dynamin-independent pathway. Internalized peptide–MHC class II complexes entered elongated tubules that contained GTPases associated with protein recycling, suggesting that these complexes rapidly recycle back to the cell surface through these tubules. B-cell signalling Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion Much is known about the proximal pre-B-cell receptor (BCR) signalling events that regulate B-cell development but how these signals are transduced to the nucleus is less clear. SYK- and SRC-family members are known to be activated by the pre-BCR, so serine and threonine kinases downstream of these proteins could be possible intermediate signal transducers. Two such kinases are extracellular-signal-regulated kinase 1 (ERK1) and ERK2. Yasuda et al. generated inducible-ERK double-deficient mice and found that the transition of pro-B cells to pre-B cells was defective in these mice. Further analysis showed that ERK1 and ERK2 were activated by pre-BCR signals downstream of SYK and ZAP70 and were required for pre-BCR-mediated cell expansion through the activation of the transcription factors ELK1 and CREB. Antiviral immunity ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response Interferons trigger a number of essential host defence pathways following virus infection. A new study has now identified a pathway that involves the interferon-inducible ubiquitin-like protein ISG15 that is important for limiting the spread of pathogens such as Ebola and rabies viruses. To promote their own spread, viruses commonly exploit host-cell intracellular pathways, including the ubiquitin pathway. Ubiquitylation of viral proteins by the host NEDD4 (neural precursor-cell expressed, developmentally downregulated gene 4) family of ubiquitin E3 ligases is an important step in the release of viruses from host cells. In this study, it was found that NEDD4 is a substrate of ISG15 activity, and that interaction between these two proteins led to a reduction in the ubiquitin E3 ligase activity of NEDD4. ISG15-mediated inhibition of NEDD4 proteins limited ubiquitylation of Ebola virus matrix protein VP40 and thereby the release of Ebola virus-like particles from host cells. Further investigation revealed that ISG15 also inhibits other NEDD4-like ubiquitin E3 ligases, illustrating the role of NEDD4 family proteins in regulating virus budding and highlighting the crucial role of ISG15 in suppressing this process. RNA world Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Two papers report roles for endogenous small interfering RNAs (endo-siRNAs) in the mouse; regulation by RNAs of this type had previously been shown only in species that have RNA-dependent RNA polymerases, which are not present in mammals. Both groups carried out deep sequencing of small-RNA libraries that were derived from mouse oocytes, and they demonstrated the production of siRNAs from various sources. These sources include pseudogenes, suggesting that these genomic elements might function to regulate the genes from which they are derived through RNAi, and retrotransposons, suggesting a role in genome defence. In the case of pseudogenes, double-stranded siRNAs could be generated either from hybridization of pseudogene transcripts to mRNAs that are expressed from the protein-coding genes that they are derived from, or from inverted-repeat pseudogenes. In support of regulatory roles for these endo-siRNAs, their levels are decreased and complementary transcripts are upregulated in the absence of Dicer or Ago2, which are required for siRNA generation and effector functions, respectively. Reward Food reward in the absence of taste receptor signaling The TRPM5 ion channel is thought to be a receptor for sweet taste. This article shows that mice lacking TRPM5 can nevertheless develop a preference for a sucrose-containing solution over water, but not for a solution containing the non-caloric sweetener sucralose. Moreover, in Trpm5-/- mice, ingestion of sucrose but not sucralose resulted in dopamine release in the nucleus accumbens. These findings indicate that the preference for high-calorie foods might be based on the rewarding properties of a food's metabolic value as well as of its palatability. Addiction Brain chromatin remodeling: a novel mechanism of alcoholism In rats, the anxiolytic effects of acute ethanol exposure were accompanied by increased levels of CREB-binding protein (CBP, which has histone acetylase activity) and neuropeptide Y, increased acetylation of histones H3 and H4, and decreased histone deacetylase (HDAC) activity in the amygdala. Withdrawal from chronic ethanol exposure induced the opposite changes, which — with the exception of the decrease in CBP levels — were prevented by treatment with an HDAC inhibitor. These data indicate that chromatin remodelling in the amygdala might be involved in the anxiolytic and anxiogenic effects of alcohol use and withdrawal, respectively. Cannabinoids Endocannabinoids mediate neuron-astrocyte communication The authors demonstrated that cannabinoid type 1 receptors (CB1Rs) are present on hippocampal astrocytes. Endocannabinoids released from pyramidal neurons activated these CB1Rs, which induced phospholipase-C-dependent Ca2+ mobilization in the astrocytes. This resulted in glutamate release from the astrocytes, which in turn activated NMDA receptors on the pyramidal neurons. Thus, endocannabinoids have a role in bidirectional communication between neurons and astrocytes. The presence of CB1Rs on astrocytes suggests that these cells might be involved in cannabis addiction and endocannabinoid-mediated processes. Traditional Chinese medicine Dissection of mechanisms of Chinese medicinal formula Realgar–Indigo naturalis as an effective treatment for promyelocytic leukemia To investigate the mechanisms of a traditional Chinese medicine, Wang and colleagues analysed the active ingredients of the Realgar–Indigo naturalis formula. At a cellular level, the combination of active ingredients were synergistic and intensified ubiquitylation/degradation of promyelocytic leukaemia (PML)-retinoic acid receptor- Cancer The inhibition of tumor cell intravasation and subsequent metastasis via regulation of in vivo tumor cell motility by the tetraspanin CD151 Tumour cell metastasis involves cell migration through integrin-dependent pathways. Zijlstra and colleagues used an integrin-associated tetraspanin CD151-specific monoclonal antibody to promote cell immobility. The loss of migration was the result of enhanced tumour cell–matrix interactions, promoted by CD151, which prevented dissociation by individual cells and leads to a subsequent inhibition of invasion and intravasation at the site of the primary tumour. This provides in vivo proof of principle that regulation of adhesion can function as an antimetastatic target. Gene regulation Gene Activation Using FLP Recombinase in C. elegans For Caenorhabditis elegans, researchers primarily rely on endogenous enhancers to regulate transgene expression, but this approach restricts them to the spatiotemporal activity of those enhancers during development. Davis et al. created a system to turn on transgene activity when a site-specific recombinase removes an intervening marker gene. Different regulatory regions for the transgene and recombinase create a combinatorial code that can better target transgene expression. Malaria A malaria parasite formin regulates actin polymerization and localizes to the parasite–erythrocyte moving junction during invasion The malaria parasite and other apicomplexans move using a form of motility that is known as gliding motility and is actomyosin-based. Actin polymerization and actin-filament turnover are known to be essential for this motility, but how these processes are controlled in apicomplexans is unknown. In eukaryotes, formins have been shown to be actin nucleators, and previous microarray analysis had indicated that Plasmodium falciparum produces two formin proteins. Baum et al. confirmed that both these proteins are expressed during the erythrocytic stages of the parasite's life cycle. Immunofluorescence analysis showed that PfFormin1 localizes at the apical pole of free merozoites. Further immunofluorescence combined with phase-contrast microscopy revealed that, during invasion, PfFormin1 co-migrates with the moving tight junction that is formed between the merozoite and the host erythrocyte and is thought to be the location of the actinomyosin motor. This effect was also observed with the Toxoplasma gondii homologue of PfFormin1. Finally, in vitro analysis demonstrated that PfFormin1 is a potent nucleator of filamentous actin. The authors conclude from these results that formins are key regulators of apicomplexan cell motility. | |
| ||||||||
| |||||||||||
 | |||||||||||
| |||||||||||
| |||||||||||
| |||||||||||
HOME | SIGNALING UPDATE | MOLECULE PAGES | DATA CENTER | ABOUT US | |||||||||||
| |||||||||||
-estradiol ligand induces interchromosomal interactions among oestrogen receptor-
-bound transcriptional units. These interchromosomal interactions depend on a subset of coactivators and chromatin remodelling complexes, as well as on the nuclear actin and myosin motor machineries. The histone lysine demethylase LSD1 is required for directing the specific interchromosomal interaction loci to distinct interchromatin granules, also known as nuclear speckles, that are thought to store factors for transcriptional elongation and pre-mRNA splicing. These ligand-induced intranuclear interactions provide evidence for a dynamic nuclear architecture that may be required for the integration of regulated gene transcription and RNA-processing events.