| |||
|
|
|||
|
      |
|
 |
|
| |||||||||||
| |||||||||||
| |||||||||||
| | | | ||||||||
|
In brief: January 2003Cell fate
A critical role for Cyclin E in cell fate determination in the central nervous system of Drosophila melanogaster
Structural and functional diversity in the central nervous system of Drosophila melanogaster is generated by different cell lineages that arise from some of the serially homologous neuroblasts within the thoracic and abdominal segments. Berger et al. showed that the cell-cycle protein cyclin E is required to specify cell fate in the thoracic neuroblast NB6-4 lineage. It is expressed asymmetrically after the first division of NB6-4t cells and functions upstream of prospero and glial cell missing to generate neuronal cells. Chromatin
Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions
These authors showed that the Drosophila melanogaster Tip60 complex uses both its chromatin-remodelling and acetylation activities to catalyse the exchange of the histone variant H2Av (the fly homologue of human H2AX). By mimicking the phosphorylation of H2Av in a manner analogous to the DNA-damage-induced phosphorylation of mammalian H2AX, Kusch et al. found that histone exchange is enhanced by Tip60-mediated acetylation of phosphorylated H2Av. This could explain how phosphorylated H2AX is removed from the damage site. Ageing
The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans
Limiting energy availability is thought to extend lifespan in some organisms. Apfeld and colleagues have now found that the cellular ratio of AMP:ATP, which is a measure of energy levels, increases with age in Caenorhabditis elegans. They also identified an enzyme, AMP-activated protein kinase Lymphocyte migration
CLEVER-1 mediates lymphocyte transmigration through vascular and lymphatic endothelium
Lymphocyte trafficking from the blood to the tissues has been extensively studied and is described by the multistep adhesion cascade. By contrast, the mechanism used by lymphocytes to cross lymphatic-vessel walls is much less well understood. Salmi and colleagues show that the glycoprotein CLEVER1 (common lymphatic endothelial and vascular endothelial receptor 1) is constitutively expressed on lymphatic endothelial vessels, and its expression is upregulated by inflamed vascular endothelial cells. CLEVER1 can mediate the adhesion and migration of lymphocytes (and the adhesion of tumour cells) through lymphatic-vessel walls, as well as through blood-vessel walls, under physiologically relevant shear forces. CLEVER1 is therefore a potential target for the development of new therapies for inflammation and cancer. HIV
Secretory leukocyte protease inhibitor binds to annexin II, a cofactor for macrophage HIV-1 infection
One of the earliest identified functions of the serine-protease inhibitor SLPI (secretory leukocyte protease inhibitor) was as an inhibitor of HIV-1 infection of macrophages. However, the identity of the cell-surface receptor for SLPI is unknown. This study shows that the phospholipid-binding protein annexin II is a receptor for SLPI. Inhibitors of annexin II mimicked the kinetics of action of HIV-1 suppression by SLPI, indicating a connection. The authors identified annexin II as a fusogenic cofactor for HIV-1 infection and a possible target for new therapeutics: HIV-1 can bind annexin II through phosphatidylserine molecules in the HIV-1 envelope, which are acquired from the host during viral exit from infected cells. Macrophages
IFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR- and Nod2-independent mechanism
Type I interferons (IFNs) produced by macrophages in response to infection with Listeria monocytogenes sensitize macrophages to L. monocytogenes-induced cell death. In this study, Stockinger et al. sought to determine the molecular mechanisms of the L. monocytogenes-mediated induction of genes that encode type I IFNs. IFN- Genetics
Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene
Fbwx7 encodes a ubiquitin ligase associated with maintenance of chromosome stability. Mao et al. show that this gene is regulated by p53, and that its downregulation in mice leads to radiation-induced tumorigenesis. The authors propose that loss of FBWX7 activity leads to genetic instability through activation of the spindle-checkpoint protein Aurora A. Colon cancer
15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF- Upregulation of cyclooxygenase 2 (COX2) is an early event in human colon tumorigenesis. Yan et al. report that colon cancer further targets the prostaglandin biogenesis pathway by downregulating expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that antagonizes COX2. Re-expression of 15-PGDH in colon cancer cells inhibits their ability to form tumours in mice, and the authors show its expression in colon cells is induced by activation of the transforming growth factor- Tumour suppressors
Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumours
In some cancers where p53 is wild type, its function is effectively inhibited due to degradation through the proteasome, often a result of the aberrant increased expression of its regulator, the ubiquitin ligase HDM2. Issaeva et al. have identified a small molecule, RITA, which prevents the interaction between HDM2 and p53, and induces massive apoptosis due to the stabilization of p53. RITA has shown significant antitumour effect in vivo and shows promise as a drug to target tumours with wild-type p53. Cell adhesion
Specific deletion of focal adhesion kinase suppresses tumour formation and blocks malignant progression
Loss of cellular focal adhesions is crucial to the development and progression of invasive cancer. One component of focal adhesions — focal-adhesion kinase (FAK) — has been associated with tumour progression but has never definitively been shown to be a regulatory factor. Using a regulable FAK allele, McLean et al. show that FAK prevents apoptosis and its loss suppresses skin tumour formation and progression in vivo. RNA silencing
A link between mRNA turnover and RNA interference in Arabidopsis
MicroRNA binding sites in Arabidopsis class III HD-ZIP mRNAs are required for methylation of the template chromosome
These papers provide new insights into RNA-mediated silencing. RNA-dependent RNA polymerase (RdRP) promotes RNA interference in several species, but its substrate is unknown. Gazzani et al. showed that mutation of the Arabidopsis thaliana XRN4 exonuclease gene promotes RdRP-dependent silencing of a transgene. Plants that lack both RdRP and XRN4 accumulate decapped transgene mRNA, implicating uncapped transcripts as RdRP substrates. Bao et al. investigated the regulation of the A. thaliana PHB and PHV leaf-patterning genes. Both genes are heavily methylated in wild-type plants, but this is reduced by mutation of microRNA binding sites that are present in PHB and PHV mRNAs, but not in the corresponding genomic sequences. MicroRNAs therefore seem to regulate expression of these genes by interacting with their transcripts to produce epigenetic changes at the genomic level. Cell biology of the neuron
Truncated TrkB receptor-induced outgrowth of dendritic filopodia involves the p75 neurotrophin receptor
Truncated splice variants of the TrkB neurotrophin receptor are abundant in the adult rodent CNS, but little is known about their physiological functions. Hartmann et al. present evidence that the TrkB.T1 isoform interacts with the p75NTR receptor, thereby initiating a signalling cascade that induces outgrowth of dendritic filopodia. This could be one of the mechanisms that contribute to the formation of new synapses in the postnatal CNS. Stem cells
Chromatin remodeling and histone modification in the conversion of oligodendrocyte precursors to neural stem cells
Purified oligodendrocyte precursor cells (OPCs) can be converted to multipotent neural stem-like cells (NSLCs) that generate both neurons and glia, so they could provide a source of neurons for CNS repair. To investigate how this potential might be harnessed, Kondo and Raff analysed the molecular mechanisms that underlie the conversion of OPCs to NSLCs. They show that this process depends on the reactivation of Sox2 gene expression, which in turn depends on chromatin remodelling at the Sox2 promoter. Cardiovascular disease
Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis.
The c-Jun N-terminal kinases (JNKs) have been implicated in pro-atherogenic processes. To clarify their role in these processes, Ricci et al. used mice that lacked apolipoprotein E (ApoE), which are prone to atherosclerosis, and which also lacked either JNK1 or JNK2. ApoE-deficient mice that lacked JNK2 developed significantly less atherosclerosis than either ApoE-deficient mice or ApoE-deficient mice that also lacked JNK1. Specific inhibition of JNK2 could therefore be a potential therapeutic approach to ameliorate atherosclerosis. Anticancer drugs
Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors.
Inhibiting the interaction between the tumour suppressor p53 and HDM2, which leads to degradation of p53, is thought to have potential as a widely applicable and efficient anticancer strategy. However, discovering molecules that disrupt protein–protein interactions is challenging. Rather than searching for HDM2-binding molecules, Issaeva et al. screened for compounds that suppressed the growth of tumour cells in a p53-dependent manner, and identified a small molecule that inhibited the p53–HDM2 interaction — RITA — which had antitumour effects in mice. | |
| ||||||||
| |||||||||||
 | |||||||||||
| |||||||||||
| |||||||||||
| |||||||||||
HOME | SIGNALING UPDATE | MOLECULE PAGES | DATA CENTER | ABOUT US | |||||||||||
| |||||||||||
-subunit (AAK-2), that acts as a sensor of high levels of AMP and functions to extend lifespan.
production, and IFN-