Nuclear inositides: inconsistent consistencies

Divecha, Nullin; Clarke, Jonathan H.; Roefs, Mieke; Halstead, Jonathan R.; D’Santos, Clive S.

doi:10.1007/pl00000700

Cited by 39 publications

(31 citation statements)

References 166 publications

(208 reference statements)

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“…The presence of inositide-modifying enzymes and independent lipid pools within the nucleus also supports the hypothesis that inositide pathways function within the nucleus (37,38). Pik1, an essential phosphatidylinositol 4-kinase, and Mss4, an essential phosphatidylinositol-4-phosphate (PI(4)P) 5-kinase, are both required for PI(4,5)P 2 production in budding yeast (39,40).…”

supporting

confidence: 64%

Cytoplasmic Inositol Hexakisphosphate Production Is Sufficient for Mediating the Gle1-mRNA Export Pathway

Miller

Suntharalingam

Johnson

et al. 2004

Journal of Biological Chemistry

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Production of inositol hexakisphosphate (IP 6 ) by Ipk1, the inositol-1,3,4,5,6-pentakisphosphate 2-kinase, is required for Gle1-mediated mRNA export in Saccharomyces cerevisiae cells. To examine the network of interactions that require IP 6 production, an analysis of fitness defects was conducted in mutants harboring both an ipk1 null allele and a mutant allele in genes encoding nucleoporins or transport factors. Enhanced lethality was observed with a specific subset of mutants, including nup42, nup116, nup159, dbp5, and gle2, all of which had been previously connected to Gle1 function. Complementation of the nup116⌬ipk1⌬ and nup42⌬ipk1⌬ double mutants did not require the Phe-Gly repeat domains in the respective nucleoporins, suggesting that IP 6 was acting subsequent to heterogeneous nuclear ribonucleoprotein targeting to the nuclear pore complex. With Nup42 and Nup159 localized exclusively to the nuclear pore complex cytoplasmic side, we speculated that IP 6 may regulate a cytoplasmic step in mRNA export. To test this prediction, the spatial requirements for the production of IP 6 were investigated. Restriction of Ipk1 to the cytoplasm did not block IP 6 production. Moreover, coincident sequestering of both Ipk1 and Mss4 (an enzyme required for phosphatidylinositol 4,5-bisphosphate production) to the cytoplasm also did not block IP 6 production. Given that the kinase required for inositol 1,3,4,5,6-pentakisphosphate production (Ipk2) is localized in the nucleus, these results indicated that soluble inositides were diffusing between the nucleus and the cytoplasm. Additionally, the cytoplasmic production of IP 6 by plasma membrane-anchored Ipk1 rescued a gle1-2 ipk1-4 synthetic lethal mutant. Thus, cytoplasmic IP 6 production is sufficient for mediating the Gle1-mRNA export pathway.The nucleus is the defining structure of a eukaryotic cell and houses the genetic information that characterizes the organism. The nuclear compartment is separated from the cytoplasm by the nuclear envelope (NE), 1 two lipid bilayer membranes that join to form pores containing nuclear pore complexes (NPCs). The 60-MDa NPC structure is assembled from multiple copies of ϳ30 distinct proteins designated nucleoporins (Nups) (1, 2). The central region of the NPC consists of inner and outer rings connected by a series of spokes. Fibrils extend from either face of the NPC, and the filaments on the nuclear side are joined at the distal end to form a basket structure (3). The NPCs create aqueous semipermeable portals across the NE that allow the passive diffusion of small molecules. However, translocation of macromolecules through the NPC requires facilitated transport mediated by Nups, other NPC-associated proteins, and shuttling transport factors (4 -6). One class of macromolecules that must traverse the NPC is mRNAs. The movement of mRNA through the NPC is a regulated process in the progression from DNA transcription in the nucleus to the production of a translated protein in the cytoplasm (7,8). To ensure proper gene expression, there are...

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supporting

confidence: 64%

Cytoplasmic Inositol Hexakisphosphate Production Is Sufficient for Mediating the Gle1-mRNA Export Pathway

Miller

Suntharalingam

Johnson

et al. 2004

Journal of Biological Chemistry

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“…4C). Given the many studies documenting the occurrence and directionality of the IP 3 and ryanodine receptors on the inner nuclear membrane (8,48) as well as the existence of a nuclear phosphoinositol cycle (13,12), mGlu5 receptors oriented in the latter fashion would be ideally situated to activate nuclear PLC/IP 3 /Ca 2ϩ cascades. The question arises then as to what ligand activates these receptors and how does it do so.…”

Section: Discussionmentioning

confidence: 99%

“…Many components of G protein signaling pathways are also found in the nucleus or associated with nuclear membranes. These include phospholipase C isozymes (11,12), nuclear inositol phosphates (12,13), DAG (13), PKC isozymes (14), adenylate cyclase (15), regulators of G protein signaling (RGS proteins; Refs. 16 and 17) as well as heterotrimeric G proteins themselves (18).…”

Section: Changes In Nuclear Camentioning

confidence: 99%

Activation of Metabotropic Glutamate Receptor mGlu5 on Nuclear Membranes Mediates Intranuclear Ca2+ Changes in Heterologous Cell Types and Neurons

O’Malley

Jong

Gonchar

et al. 2003

Journal of Biological Chemistry

122

116

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Nuclear Ca2؉ plays a critical role in many cellular functions although its mode (s) of regulation is unclear. This study shows that the metabotropic glutamate receptor, mGlu5, mobilizes nuclear Ca 2؉ independent of cytosolic Ca 2؉ regulation. Immunocytochemical, ultrastructural, and subcellular fractionation techniques revealed that the metabotropic glutamate receptor, mGlu5, can be localized to nuclear membranes in heterologous cells as well as midbrain and cortical neurons. Changes in nuclear Ca2ϩ play an integral role in cellular functions such as protein import, apoptosis, and gene transcription (1, 2). Nuclear Ca 2ϩ may be generated from a number of sources including diffusion of cytosolic Ca 2ϩ waves through nuclear pore complexes (2). Because the outer nuclear envelope is continuous with the endoplasmic reticulum, which serves as an internal store of Ca 2ϩ , rises in nuclear Ca 2ϩ may also be attributable to a luminal source (3). Recent studies using high speed imaging of intracellular Ca 2ϩ have shown that waves of Ca 2ϩ can invade the nucleus by emptying intracellular stores (4). Calcium release from internal stores is controlled by various channels including the inositol 1,4,5-trisphosphate (IP 3 ) 1 receptor and ryanodine receptor families (5, 6) both of which are present on nuclear membranes (7,8). Calcium itself is an activator of these channels (1) although nuclear IP 3 can stimulate IP 3 receptors located on the inner nuclear membrane and cADP ribose has been shown to activate nuclear ryanodine receptors (7,8). Luminal Ca 2ϩ is refilled at least in part by the nuclear Ca 2ϩ -ATPase (9, 10) located on the outer nuclear membrane. Thus, although signals originating at the plasma membrane may be transmitted to the nucleus (4), the presence of specific Ca 2ϩ transporters on the nuclear envelope argues for a nuclear Ca 2ϩ regulatory system that may be independent of cytosolic Ca 2ϩ regulation. Many components of G protein signaling pathways are also found in the nucleus or associated with nuclear membranes. These include phospholipase C isozymes (11, 12), nuclear inositol phosphates (12, 13), DAG (13), PKC isozymes (14), adenylate cyclase (15), regulators of G protein signaling (RGS proteins; Refs. 16 and 17) as well as heterotrimeric G proteins themselves (18). These observations raise the possibility that plasma membrane-based signaling components may also serve a similar function at nuclear membranes. Indeed, several recent reports are consistent with the notion that nuclear G protein-coupled receptors directly modulate nuclear signal transduction pathways. For example, angiotensin II receptors were found on hepatocyte nuclear membranes (19), opioid binding sites were described on ventricular myocardial nuclei (20) and endothelin-1 receptors were reported on vascular smooth muscle nuclear membranes (21). Direct evidence of nuclear receptor G protein signaling has also been demonstrated for prostaglandin receptors which, when stimulated, cause rapid Ca 2ϩ influx into the nucleus (22,23). Taken togeth...

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“…The presence in the nucleus of both polyphoshoinositides and the enzymes responsible for their metabolism has suggested that they may constitute a signaling system [Divecha et al, 2000;Irvine, 2003]. It is noteworthy that nuclear inositol lipid metabolism is independently regulated from its plasma membrane counterpart and is modulated in response to short-term growth factor signaling, cell cycle progression and during differentiation [Martelli et al, 2004].…”

mentioning

confidence: 99%

Nuclear inositol lipid metabolism: More than just second messenger generation?

Martelli

Follo

Evangelisti

et al. 2005

J of Cellular Biochemistry

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A distinct polyphosphoinositide cycle is present in the nucleus, and growing evidence suggests its importance in DNA replication, gene transcription, and apoptosis. Even though it was initially thought that nuclear inositol lipids would function as a source for second messengers, recent findings strongly indicate that lipids present in the nucleus also fulfil other roles. The scope of this review is to highlight the most intriguing advances made in the field over the last few years, such as the possibility that nuclear phosphatidylinositol (4,5) bisphosphate is involved in maintaining chromatin in a transcriptionally active conformation, the new emerging roles for intranuclear phosphatidylinositol (3,4,5) trisphosphate and phosphoinositide 3-kinase, and the evidence which suggests a tight relationship between a decreased level of nuclear phosphoinositide specific phospholipase C-b1 and the evolution of myelodisplastic syndrome into acute myeloid leukemia.

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Nuclear inositides: inconsistent consistencies

Cited by 39 publications

References 166 publications

Cytoplasmic Inositol Hexakisphosphate Production Is Sufficient for Mediating the Gle1-mRNA Export Pathway

Cytoplasmic Inositol Hexakisphosphate Production Is Sufficient for Mediating the Gle1-mRNA Export Pathway

Activation of Metabotropic Glutamate Receptor mGlu5 on Nuclear Membranes Mediates Intranuclear Ca2+ Changes in Heterologous Cell Types and Neurons

Nuclear inositol lipid metabolism: More than just second messenger generation?

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