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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of colorectal cancer (CRC) cells to ionizing radiation results in a cell-cycle arrest in G1 and G2. The G1 arrest is due to p53-mediated induction of the cyclin-dependent kinase inhibitor p21WAF1/CIP1/SDI1, but the basis for the G2 arrest is unknown. Through a quantitative analysis of gene expression patterns in CRC cell lines, we have discovered that 14-3-3sigma is strongly induced by gamma irradiation and other DNA-damaging agents. The induction of 14-3-3sigma is mediated by a p53-responsive element located 1.8 kb upstream of its transcription start site. Exogenous introduction of 14-3-3sigma into cycling cells results in a G2 arrest. As the fission yeast 14-3-3 homologs rad24 and rad25 mediate similar checkpoint effects, these results document a molecular mechanism for G2/M control that is conserved throughout eukaryotic evolution and regulated in human cells by p53.
Mol Cell 1997 Dec
PMID:14-3-3sigma is a p53-regulated inhibitor of G2/M progression. 965 98

By binding to serine-phosphorylated proteins, 14-3-3 proteins function as effectors of serine phosphorylation. The exact mechanism of their action is, however, still largely unknown. Here we demonstrate a requirement for 14-3-3 for Raf-1 kinase activity and phosphorylation. Expression of dominant negative forms of 14-3-3 resulted in the loss of a critical Raf-1 phosphorylation, while overexpression of 14-3-3 resulted in enhanced phosphorylation of this site. 14-3-3 levels, therefore, regulate the stoichiometry of Raf-1 phosphorylation and its potential activity in the cell. Phosphorylation of Raf-1, however, was insufficient by itself for kinase activity. Removal of 14-3-3 from phosphorylated Raf abrogated kinase activity, whereas addition of 14-3-3 restored it. This supports a paradigm in which the effects of phosphorylation on serine as well as tyrosine residues are mediated by inducible protein-protein interactions.
Mol Cell Biol 1998 Sep
PMID:14-3-3 proteins are required for maintenance of Raf-1 phosphorylation and kinase activity. 971 Jun 7

Mitosis in early embryos is independent of exogenous mitogens, although mitogen stimulations and subsequent activation of a mitogen-activated protein (MAP) kinase cascade are essential for the proliferation of somatic cells. The activation state of the MAP kinase cascade during early cleavage has never been reported. In the present study, factors involved in the MAP kinase cascade--Ras, Raf-1, 14-3-3, MEK, and ERKs--and their activation states were detected by immunoblotting during early cleavage of mouse embryos. We found the constant presence of these molecules in mouse early embryos and the activation of Raf-1 exclusively at the M-phase. An immunoprecipitation study revealed that active Raf-1 in the M-phase was dissociated from 14-3-3, as in somatic cells, whereas inactive Raf-1 was associated with 14-3-3. Surprisingly, the ERKs (MAP kinases) were not activated throughout early cleavage, although M-phase-specific activation of the MAP kinase kinase, MEK was observed. Myelin basic protein kinase activity was, however, significantly higher in the M-phase than in the interphase. These results indicate that the MAP kinase cascade is activated at the M-phase and that some MAP kinases other than ERKs are activated during early cleavage of mouse embryos.
Mol Reprod Dev 1998 Oct
PMID:MAP kinase cascade, but not ERKs, activated during early cleavage of mouse embryos. 974 Mar 22

Genetic and biochemical studies have identified kinase suppressor of Ras (KSR) to be a conserved component of Ras-dependent signaling pathways. To better understand the role of KSR in signal transduction, we have initiated studies investigating the effect of phosphorylation and protein interactions on KSR function. Here, we report the identification of five in vivo phosphorylation sites of KSR. In serum-starved cells, KSR contains two constitutive sites of phosphorylation (Ser297 and Ser392), which mediate the binding of KSR to the 14-3-3 family of proteins. In the presence of activated Ras, KSR contains three additional sites of phosphorylation (Thr260, Thr274, and Ser443), all of which match the consensus motif (Px[S/T]P) for phosphorylation by mitogen-activated protein kinase (MAPK). Further, we find that treatment of cells with the MEK inhibitor PD98059 blocks phosphorylation of the Ras-inducible sites and that activated MAPK associates with KSR in a Ras-dependent manner. Together, these findings indicate that KSR is an in vivo substrate of MAPK. Mutation of the identified phosphorylation sites did not alter the ability of KSR to facilitate Ras signaling in Xenopus oocytes, suggesting that phosphorylation at these sites may serve other functional roles, such as regulating catalytic activity. Interestingly, during the course of this study, we found that the biological effect of KSR varied dramatically with the level of KSR protein expressed. In Xenopus oocytes, KSR functioned as a positive regulator of Ras signaling when expressed at low levels, whereas at high levels of expression, KSR blocked Ras-dependent signal transduction. Likewise, overexpression of Drosophila KSR blocked R7 photoreceptor formation in the Drosophila eye. Therefore, the biological function of KSR as a positive effector of Ras-dependent signaling appears to be dependent on maintaining KSR protein expression at low or near-physiological levels.
Mol Cell Biol 1999 Jan
PMID:Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression. 985 47

Soybean (Glycine max [L.] Merr.) cell suspension cultures (cv. Williams 82) inoculated with the pathogenic bacteria Pseudomonas syringae pv. glycinea respond with a hypersensitive reaction (HR) when the bacteria express the avirulence gene avrA. A mRNA differential display was established for this system to allow the identification of genes induced during the HR. Six PCR-fragments (DD1-DD6) from the differential display analysis were identified, which are induced during the HR. Database searches revealed that the fragment DD1 encodes chalcone isomerase and DD2 was identified as ubiquitin. The fragment DD3 shares significant homology to the signalling molecule 14-3-3. The partial DD4 product is homologous to the enhancer of rudimentary from Drosophila and an uncharacterized homologue of it from Arabidopsis. The fragment DD5 is similar to glucose-6-phosphate dehydrogenase which provides NADPH to the cell. The PCR-product DD6 seems to be a new leucine-rich-repeat disease resistance gene from soybean, which is significantly induced during the HR. All of the identified genes are clearly induced during a HR in infected plants of the same cultivar, indicating that results from the cell culture model system can be transferred to intact plants. These studies show that complex mRNA differential display is a powerful tool to identify new induced gene in plant-pathogen interactions.
Plant Mol Biol 1998 Dec
PMID:Cloning of genes by mRNA differential display induced during the hypersensitive reaction of soybean after inoculation with Pseudomonas syringae pv. glycinea. 986 27

cdc25C induces mitosis by activating the cdc2-cyclin B complex. The intracellular localization of cyclin B1 is regulated in a cell cycle-specific manner, and its entry into the nucleus may be required for the initiation of mitosis. To determine the cellular localization of cdc25C, monoclonal antibodies specific for cdc25C were developed and used to demonstrate that in human cells, cdc25C is retained in the cytoplasm during interphase. A deletion analysis identified a 58-amino-acid region (amino acids 201 to 258) in cdc25C that was required for the cytoplasmic localization of cdc25C. This region contained a specific binding site for 14-3-3 proteins, and mutations in cdc25C that disrupted 14-3-3 binding also disrupted the cytoplasmic localization of cdc25C during interphase. cdc25C proteins that do not contain a binding site for 14-3-3 proteins showed a pancellular localization and an increased ability to induce premature chromosome condensation. The cytoplasmic localization of cdc25C was not altered by gamma irradiation or treatment with the nuclear export inhibitor leptomycin B. These results suggest that 14-3-3 proteins may negatively regulate cdc25C function by sequestering cdc25C in the cytoplasm.
Mol Cell Biol 1999 Jun
PMID:Cytoplasmic localization of human cdc25C during interphase requires an intact 14-3-3 binding site. 1033 Jan 86

Genetic screens for modifiers of activated Ras phenotypes have identified a novel protein, kinase suppressor of Ras (KSR), which shares significant sequence homology with Raf family protein kinases. Studies using Drosophila melanogaster and Caenorhabditis elegans predict that KSR positively regulates Ras signaling; however, the function of mammalian KSR is not well understood. We show here that two predicted kinase-dead mutants of KSR retain the ability to complement ksr-1 loss-of-function alleles in C. elegans, suggesting that KSR may have physiological, kinase-independent functions. Furthermore, we observe that murine KSR forms a multimolecular signaling complex in human embryonic kidney 293T cells composed of HSP90, HSP70, HSP68, p50(CDC37), MEK1, MEK2, 14-3-3, and several other, unidentified proteins. Treatment of cells with geldanamycin, an inhibitor of HSP90, decreases the half-life of KSR, suggesting that HSPs may serve to stabilize KSR. Both nematode and mammalian KSRs are capable of binding to MEKs, and three-point mutants of KSR, corresponding to C. elegans loss-of-function alleles, are specifically compromised in MEK binding. KSR did not alter MEK activity or activation. However, KSR-MEK binding shifts the apparent molecular mass of MEK from 44 to >700 kDa, and this results in the appearance of MEK in membrane-associated fractions. Together, these results suggest that KSR may act as a scaffolding protein for the Ras-mitogen-activated protein kinase pathway.
Mol Cell Biol 1999 Aug
PMID:Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization. 1040 42

Verticillium wilt is a vascular disease of cotton (Gossypium spp.) caused by the fungal pathogen Verticillium dahliae. To begin to understand the molecular mechanisms of the disease response in cotton cultivars that display superior wilt tolerance, such as Gossypium hirsutum cv. Sicala V-1, a cDNA library was constructed with mRNA isolated from root tissue of Sicala V-1, 24 h after inoculation with V. dahliae. The library was screened by a differential screening technique which was successful in identifying differences in gene expression between uninfected and V. dahliae-infected G. hirsutum root tissue. Among the differentially expressed clones, 51% represented up-regulated genes which had the potential to be involved in the defence response of G. hirsutum. The temporal expression patterns of nine suspected defence response genes were examined by northern blot analysis at several time intervals after inoculation with V. dahliae. The rapid increase in mRNA transcripts corresponding to each of these clones upon infection suggests a role for these genes in the defence response of G. hirsutum. Genes not previously associated with the defence response of the cotton plant, such as those for a 14-3-3-like protein and pathogenesis-related (PR) proteins, have been identified together with presumably novel genes, for which a definite function could not be ascribed.
Plant Mol Biol 1999 May
PMID:Identification of disease response genes expressed in Gossypium hirsutum upon infection with the wilt pathogen Verticillium dahliae. 1041 7

This paper reports the identification of 14-3-3 in Plasmodium. 14-3-3 is an evolutionarily conserved protein that is most noted as a mediator in signal transduction events and cell cycle regulation. The complete cDNA (approximately 2.6 kb) and gDNA (approximately 3.4 kb) of a Plasmodium knowlesi 14-3-3 (Pk14-3-3) is reported. The gene has three introns; two near the beginning and one close to the end of the coding sequence. Also reported, is the gDNA of the Plasmodium falciparum homologue (Pf14-3-3). Unlike in many other organisms, where multiple gene copies and different functional isoforms exist, Plasmodium 14-3-3 is encoded as a single-copy gene. Northern blot analyses show that the Pk14-3-3 transcript in asexual blood stages begins to be expressed in the ring-stage, predominates in young trophozoites, and thereafter declines. An antiserum produced against recombinant Pk14-3-3 reacts via immunoblot and immunoprecipitation with the approximately 30 kDa and the approximately 32 kDa Pk14-3-3 and Pf14-3-3 proteins, respectively. Protein expression in P. knowlesi closely mimics the pattern of the transcript.
Mol Biochem Parasitol 1999 Jul 30
PMID:Stage-specific expression of 14-3-3 in asexual blood-stage Plasmodium. 1047 81

The enigmatically named 14-3-3 proteins have been the subject of considerable attention in recent years since they have been implicated in the regulation of diverse physiological processes, in eukaryotes ranging from slime moulds to higher plants. In plants they have roles in the regulation of the plasma membrane H+-ATPase and nitrate reductase, among others. Regulation of target proteins is achieved through binding of 14-3-3 to short, often phosphorylated motifs in the target, resulting either in its activation (e.g. H+-ATPase), inactivation (e.g. nitrate reductase) or translocation (although this function of 14-3-3 proteins has yet to be demonstrated in plants). The native 14-3-3 proteins are homo- or heterodimers and, as each monomer has a binding site, a dimer can potentially bind two targets, promoting their association. Alternatively, target proteins may have more than one 14-3-3-binding site. In this mini review, we present a synthesis of recent results from plant 14-3-3 research and, with reference to known 14-3-3-binding motifs, suggest further subjects for research.
Plant Mol Biol 1999 Jul
PMID:14-3-3 proteins: eukaryotic regulatory proteins with many functions. 1048 Mar 79


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