Biochemical Society Symposia最新文献

The regulation of the synthesis of PtdIns(4,5)P2 is emerging as being as complex as we might expect from the multi-functional nature of this lipid. In the present chapter we focus on one aspect of inositide metabolism, which is the functions of the Type II PIPkins (Type II PtdInsP kinases). These are primarily PtdIns5P 4-kinases, although in vitro they will also phosphorylate PtdIns3P to PtdIns(3,4)P2. Thus they have three, not necessarily exclusive, functions: to make PtdIns(4,5)P2 by a quantitatively minor route, to remove PtdIns5P and to make PtdIns(3,4)P2 by a route that does not involve a Class I PtdIns 3-kinase. None of these three possible functions has yet been unambiguously proven or ruled out. Of the three isoforms, alpha and beta are widely expressed, the IIalpha being predominantly cytosolic and the IIbeta primarily nuclear. PIPkin IIgamma has a much more restricted tissue expression pattern, and appears to be localized primarily to intracellular vesicles. Here we introduce in turn each of the three Type II PIPkins, and discuss what we know about their localization, their regulation and their function.

Among the many derivatives of the inositol-based signalling family are a subgroup that possess diphosphates. In this review, some recent research into the actions of these specialized polyphosphates is analysed, and key goals for future studies are identified, which, it is hoped, will result in the wider cell-signalling community giving considerably greater attention to this intriguing but relatively neglected class of inositol polyphosphates.

Defects in the DNA damage response pathways can lead to tumour development. The tumour suppressor p53 is a key player in the DNA damage response, and the precise regulation of p53 is critical for the suppression of tumorigenesis. DNA damage induces the activity of p53, via damage sensors such as ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia-related), which leads to the transcriptional regulation of a variety of genes involved in cell cycle control and apoptosis. p53 is therefore tightly controlled, and its activity is regulated at a multiplicity of levels. An increasing array of cofactors are now known to influence p53 activity. Here we will discuss several of the cofactors that impact on p53 activity, specifically those involved in the function of the two novel p53 cofactors JMY (junction-mediating and regulatory protein) and Strap (serine/threonine-kinase-receptor-associated protein).

In the 30 years since the discovery of the nucleosome, our picture of it has come into sharp focus. The recent high-resolution structures have provided a wealth of insight into the function of the nucleosome, but they are inherently static. Our current knowledge of how nucleosomes can be reconfigured dynamically is at a much earlier stage. Here, recent advances in the understanding of chromatin structure and dynamics are highlighted. The ways in which different modes of nucleosome reconfiguration are likely to influence each other are discussed, and some of the factors likely to regulate the dynamic properties of nucleosomes are considered.

MOZ (monocytic leukaemia zinc finger protein; also known as ZNF220 or MYST3) is a member of the MYST family of protein acetyltransferases. Chromosomal translocations involving the MOZ gene are associated with AML (acute myeloid leukaemia), suggesting that it has a role in haematopoiesis. Recurrent reciprocal translocations fuse the MOZ gene [or the gene encoding MORF (MOZ-related factor); also known as MYST4] to genes encoding the nuclear receptor co-activators CBP [CREB (cAMP response element-binding protein)-binding protein], p300 or the p160 protein TIF2 (transcription intermediary factor 2). The resulting fusion proteins can transform haematopoietic progenitors in vitro, and induce myeloproliferative disease in mice. Recent insights into the molecular mechanisms underlying these effects indicate that MOZ fusion proteins interfere with the activities of transcription factors such as nuclear receptors, p53 and Runx proteins. Our studies suggest that subverting the function of cellular CBP and p300 proteins may play a key role in this process. Here we review the recent progress in understanding the role of MOZ fusion proteins in the aetiology of AML.

The proto-oncogene product c-Myc can induce cell growth and proliferation. It regulates a large number of RNA polymerase II-transcribed genes, many of which encode ribosomal proteins, translation factors and other components of the biosynthetic apparatus. We have found that c-Myc can also activate transcription by RNA polymerases I and III, thereby stimulating production of rRNA and tRNA. As such, c-Myc may possess the unprecedented capacity to induce expression of all ribosomal components. This may explain its potent ability to drive cell growth, which depends on the accumulation of ribosomes. The activation of RNA polymerase II transcription by c-Myc is often inefficient, but its induction of rRNA and tRNA genes can be very strong in comparison. We will describe what is known about the mechanisms used by c-Myc to activate transcription by RNA polymerases I and II.

It has generally been assumed that transcriptionally active genes are in an 'open' chromatin structure and that silent genes have a 'closed' chromatin structure. Here we re-assess this axiom in the light of genome-wide studies of chromatin fibre structure. Using a combination of sucrose gradient sedimentation and genomic microarrays of the human genome, we argue that open chromatin fibres originate from regions of high gene density, whether or not those genes are transcriptionally active.

We have previously suggested a model for the eukaryotic genome based on the structure of the bacterial nucleoid where active RNA polymerases cluster to loop the intervening DNA. This organization of polymerases into clusters--which we call transcription 'factories'--has important consequences. For example, in the nucleus of a HeLa cell the concentration of soluble RNA polymerase II is approximately 1 mM, but the local concentration in a factory is 1000-fold higher. Because a promoter can diffuse approximately 100 nm in 15 s, one lying near a factory is likely to initiate; moreover, when released at termination, it will still lie near a factory, and the movement and modifications (e.g. acetylation) accompanying elongation will leave it in an 'open' conformation. Another promoter out in a long loop is less likely to initiate, because the promoter concentration falls off with the cube of the distance from the factory. Moreover, a long tether will buffer it from transcription-induced movement, making it prone to deacetylation, deposition of HP1 (heterochromatin protein 1), and incorporation into heterochromatin. The context around a promoter will then be self-sustaining: productive collisions of an active promoter with the factory will attract factors increasing the frequency of initiation, and the longer an inactive promoter remains inactive, the more it becomes embedded in heterochromatin. We review here the evidence that different factories may specialize in the transcription of different groups of genes.

The ETS-domain transcription factor Elk-1 is regulated by phosphorylation in response to activation of the MAPK (mitogen-activated protein kinase) pathways. This phosphorylation triggers a series of molecular events that convert Elk-1 from a transcriptionally silent state into a highly active state and then back to a basal level. At the same time, activation of the ERK (extracellular-signal-regulated kinase) MAPK pathway leads to loss of modification of Elk-1 by SUMO (small ubiquitin-related modifier). As SUMO imparts repressive properties on Elk-1, ERK-mediated SUMO loss leads to de-repression at the same time as the ERK pathway promotes activation of Elk-1. Thus a two-step mechanism is employed to convert Elk-1 into its fully activated state. Here, the molecular events underlying these changes in Elk-1 status, and the role of PIASxalpha [protein inhibitor of activated STAT (signal transducer and activator of transcription) xalpha] as a co-activator that facilitates this process, are discussed.