1,721,056 research outputs found
Long-term starvation and ageing induce AGE-1/PI 3-kinase-dependent translocation of DAF-16/FOXO to the cytoplasm
Full text linkBackground
The provision of stress resistance diverts resources from development and reproduction and must therefore be tightly regulated. In Caenorhabditis elegans, the switch to increased stress resistance to promote survival through periods of starvation is regulated by the DAF-16/FOXO transcription factor. Reduction-of-function mutations in AGE-1, the C. elegans Class IA phosphoinositide 3-kinase (PI3K), increase lifespan and stress resistance in a daf-16 dependent manner. Class IA PI3Ks downregulate FOXOs by inducing their translocation to the cytoplasm. However, the circumstances under which AGE-1 is normally activated are unclear. To address this question we used C. elegans first stage larvae (L1s), which when starved enter a developmentally-arrested diapause stage until food is encountered.
Results
We find that in L1s both starvation and daf-16 are necessary to confer resistance to oxidative stress in the form of hydrogen peroxide. Accordingly, DAF-16 is localised to cell nuclei after short-term starvation. However, after long-term starvation, DAF-16 unexpectedly translocates to the cytoplasm. This translocation requires functional age-1. H2O2 treatment can replicate the translocation and induce generation of the AGE-1 product PIP3. Because feeding reduces to zero in ageing adult C. elegans, these animals may also undergo long-term starvation. Consistent with our observation in L1s, DAF-16 also translocates to the cytoplasm in old adult worms in an age-1-dependent manner.
Conclusion
DAF-16 is activated in the starved L1 diapause. The translocation of DAF-16 to the cytoplasm after long-term starvation may be a feedback mechanism that prevents excessive expenditure on stress resistance. H2O2 is a candidate second messenger in this feedback mechanism. The lack of this response in age-1(hx546) mutants suggests a novel mechanism by which this mutation increases longevity
Phosphoinositides in the nucleus and myogenic differentiation: how a nuclear turtle with a PHD builds muscle
No full textPhosphoinositides are a family of phospholipid messenger molecules that control various aspects of cell biology in part by interacting with and regulating downstream protein partners. Importantly, phosphoinositides are present in the nucleus. They form part of the nuclear envelope and are present within the nucleus in nuclear speckles, intra nuclear chromatin domains, the nuclear matrix and in chromatin. What their exact role is within these compartments is not completely clear, but the identification of nuclear specific proteins that contain phosphoinositide interaction domains suggest that they are important regulators of DNA topology, chromatin conformation and RNA maturation and export. The plant homeo domain (PHD) finger is a phosphoinositide binding motif that is largely present in nuclear proteins that regulate chromatin conformation. In the present study I outline how changes in the levels of the nuclear phosphoinositide PtdIns5P impact on muscle cell differentiation through the PHD finger of TAF3 (TAF, TATA box binding protein (TBP)-associated factor), which is a core component of a number of different basal transcription complexes
Lipid Kinases: Charging PtdIns(4,5)P2 Synthesis
No full textPhosphatidylinositol (4,5) bisphosphate is a lipid second messenger that controls diverse cellular processes. Phosphatidylinositolphosphate-5-kinases synthesise this lipid at the plasma membrane, although it is not clear how the localisation of these kinases is controlled. A recent study suggests that the intrinsic surface charge of the plasma membrane may be an important factor. © 2010 Elsevier Ltd. All rights reserved
Marked for nuclear export?
No full textPublished in the News and Views section of Nature 394 in August 1998. No abstract available
Cloning and characterisation of two new cDNAs encoding murine triple LIM domains
No full textWe have cloned and sequenced two new cDNAs that code for proteins carrying the related triple LIM domains (acronym of Lin-11, Isl-1, Mec-3) proteins. These LIM domains show good agreement to the LIM domain consensus sequence, but also exhibit some novel variations. The 1.36-and 2.8-kb cDNAs are probably splice variants of one gene and code for 42- and 50-kDa proteins, respectively. The larger transcript has a 900-nucleotide (nt) 3' untranslated region (UTR). High levels of the 2.8-kb transcript can be detected in many tissues, and all tissues show some level of expression of both transcripts, the larger transcript being more abundant. In adult testis there are very high levels of the 1.36-kb transcript and moderate levels of the 2.8-kb transcript. The wide tissue distribution and high levels of expression suggest an important role for these proteins in cellular function
Methods to assess changes in the pattern of nuclear phosphoinositides.
No full textPhosphatidylinositol (PtdIns) and its phosphorylated derivatives represent less than 5% of total membrane phospholipids in cells. Despite their low abundance, they form a dynamic signalling system that is regulated in response to a variety of extra and intra-cellular cues (Curr Opin Genet Dev 14:196-202, 2004). Phosphoinositides and the enzymes that synthesize them are found in many different sub-cellular compartments including the nuclear matrix, heterochromatin, and sites of active RNA splicing, suggesting that phosphoinositides may regulate specific functions within the nuclear compartment (Nat Rev Mol Cell Biol 4:349-360, 2003; Curr Top Microbiol Immunol 282:177-206, 2004; Cell Mol Life Sci 61:1143-1156, 2004). The existence of distinct sub-cellular pools has led to the challenging task of understanding how the different pools are regulated and how changes in the mass of lipids within the nucleus can modulate nuclear specific pathways. Here we describe methods to determine how enzymatic activities that modulate nuclear phosphoinositides are changed in response to extracellular stimuli
Linking lipids to chromatin
No full textDynamic regulation of chromatin structure is thought to be a prerequisite for nuclear functions that require accessibility to DNA such as replication, transcription and DNA repair. The phosphoinositide (PI) pathway is a second messenger signalling system regulated in response to a variety of extracellular (growth factors, differentiation signals) and intracellular (cell cycle progression, DNA damage) stimuli. The presence of a PI pathway in the nucleus together with the recent findings that specific nuclear proteins can interact with and are regulated by phosphoinositides suggest that changes in the nuclear phosphoinositide profile may have a direct role in modulating chromatin structure
Phospholipids in the nucleus--metabolism and possible functions
No full textMost of the phospholipids in the nuclear envelope are contained in the double nuclear membrane, and this has an active lipid metabolism consistent with its origins as a component of the endoplasmic reticular system. However, even after removal of the nuclear membrane with detergents, some phospholipids, mostly of unknown location and function, remain. Amongst these are all of the components of what appears to be a nuclear polyphosphoinositide signalling system, distinct from the well-established inositide pathway found in the plasma membrane. The consequences for nuclear function of the activation of these two inositide pathways are discussed, with a detailed consideration of proposed intranuclear functions for protein kinase C, and the maintenance of nuclear Ca2+ homoeostasis
Inositides and the nucleus and inositides in the nucleus
No full textAlthough there are many forms of evidence linking phosphoinositides to nuclear function, the substance of the links remains largely undefined. One link between inositide metabolism and the nucleus is suggested by the implication of inositol trisphosphate (IP3) in the process of nuclear envelope reassembly (Sullivan et al., 1993). That paper will be discussed below in its context, but this review will principally focus on another nuclear-inositide connection - a potential inositide cycle in the nucleus. It comes as something of a shock to see data that point to a phosphoinositide cycle entirely separate from the familiar one in the plasma membrane. Again contrary to expectation, the data suggest that the cycle is not in the nuclear membrane but appears to be within the nucleus. This aspect of inositide function has profound implications for the role of inositides in cell division and growth. For example, it makes us rethink the tumor-promoting actions of phorbol esters and the teratogenic effects of Li÷ that have been associated with inositide homeostasis. In this article the evidence of a nuclear inositide cycle and what is known about its control are reviewed, and the role it may play in eukaryotic cell function is discussed. For a discussion of proposed nuclear functions for protein kinase C and what little is known about nuclear Ca2÷, the reader is referred to a more comprehensive recent review (Irvine and Divecha, 1992)
The nuclear phosphoinositide cycle - does it play a role in nuclear Ca2+ homoeostasis?
No full textThe probable answer to this question is no. Much of the current evidence summarised elsewhere in this issue points to nuclear Ca2+ changes changing in response to cytosolic Ca2+, with little evidence for an independently controlled nuclear Ca2+ homeostasis. There are InsP3 receptors in the nuclear membrane, and it is possible that during nuclear membrane assembly the InsP3 acting on these (Sullivan and Wilson, this issue) is formed by an inositide cycle located on the assembling nuclear skeleton. But our current experimental data suggest that when the nucleus is intact, InsP3 generated by this cycle would have to exit through the nuclear pores to act on any known InsP3 receptors. Thus the nuclear inositide cycle appears more likely to serve to generate diacylglycerol to activate protein kinase C, and/or to generate inositol phosphates such as InsP2, which may have distinct intranuclear functions
- …
