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

The Wnt/beta-catenin/Tcf and IkappaB/NF-kappaB cascades are independent pathways involved in cell cycle control, cellular differentiation, and inflammation. Constitutive Wnt/beta-catenin signaling occurs in certain cancers from mutation of components of the pathway and from activating growth factor receptors, including RON and MET. The resulting accumulation of cytoplasmic and nuclear beta-catenin interacts with the Tcf/LEF transcription factors to induce target genes. The IkappaB kinase complex (IKK) that phosphorylates IkappaB contains IKKalpha, IKKbeta, and IKKgamma. Here we show that the cyclin D1 gene functions as a point of convergence between the Wnt/beta-catenin and IkappaB pathways in mitogenic signaling. Mitogenic induction of G(1)-S phase progression and cyclin D1 expression was PI3K dependent, and cyclin D1(-/-) cells showed reduced PI3K-dependent S-phase entry. PI3K-dependent induction of cyclin D1 was blocked by inhibitors of PI3K/Akt/IkappaB/IKKalpha or beta-catenin signaling. A single Tcf site in the cyclin D1 promoter was required for induction by PI3K or IKKalpha. In IKKalpha(-/-) cells, mitogen-induced DNA synthesis, and expression of Tcf-responsive genes was reduced. Reintroduction of IKKalpha restored normal mitogen induction of cyclin D1 through a Tcf site. In IKKalpha(-/-) cells, beta-catenin phosphorylation was decreased and purified IKKalpha was sufficient for phosphorylation of beta-catenin through its N-terminus in vitro. Because IKKalpha but not IKKbeta induced cyclin D1 expression through Tcf activity, these studies indicate that the relative levels of IKKalpha and IKKbeta may alter their substrate and signaling specificities to regulate mitogen-induced DNA synthesis through distinct mechanisms.
Mol Biol Cell 2003 Feb
PMID:IKKalpha regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf. 1258 56

Positron emission tomography (PET) using methyl-[(11)C]- l-methionine ([(11)C]MET) is a useful tool in the diagnosis of brain tumours. The main mechanism of [(11)C]MET uptake is probably increased transport via the L-transporter system located in the endothelial cell membrane. We used [(11)C]MET-PET and microvessel count in glioma specimens to investigate whether the increased amino acid uptake is related to angiogenesis. Twenty-one patients with newly diagnosed and histologically confirmed glioma were investigated with [(11)C]MET-PET before open surgery. [(11)C]MET uptake was determined within an 8-mm region of interest in the area of the tumour showing the highest uptake, and the ratio to uptake in the corresponding contralateral region was calculated. To measure angiogenesis, immunostaining with factor VIII antibody was applied to sections from tumour tissue, and highlighted microvessels were counted in the area of highest vascularisation. In the entire patient group, a positive correlation was found between microvessel count and [(11)C]MET uptake (Spearman: r=0.89, P<0.001). This correlation was also significant in subgroups of patients [patients with grade II and III astrocytomas (Spearman: r=0.77, P<0.01) and patients with glioblastoma (Spearman: r=0.64, P<0.05)]. Angiogenesis, as assessed by microvessel count, and increased amino acid uptake, as assessed by [(11)C]MET-PET, are closely related events in gliomas. [(11)C]MET-PET offers a direct measure of amino acid transport and an indirect measure of microvessel density. [(11)C]MET-PET might be a useful tool to select potential responders to anti-angiogenic therapy and to monitor patients during such therapy.
Eur J Nucl Med Mol Imaging 2003 Jun
PMID:Methyl-[11C]- l-methionine uptake as measured by positron emission tomography correlates to microvessel density in patients with glioma. 1269 87

The receptor tyrosine kinases (RTKs) RET, MET, and RON all carry the Met(p+1loop)-->Thr point mutation (i.e., 2B mutation), leading to the formation of tumors with high metastatic potential. Utilizing a novel antibody array, we identified constitutive phosphorylation of STAT3 in cells expressing the 2B mutation but not wild-type RET. MET or RON with the 2B mutation also constitutively phosphorylated STAT3. Members of the EPH, the only group of wild-type RTK that carry Thr(p+1loop) residue, are often expressed unexpectedly in different types of cancers. Ectopic expression of wild-type but not Thr(p+1loop)-->Met substituted EPH family members constitutively phosphorylated STAT3. In both RTK(Metp+1loop) with 2B mutation and wild-type EPH members the Thr(p+1loop) residue is required for constitutive kinase autophosphorylation and STAT3 recruitment. In multiple endocrine neoplasia 2B (MEN-2B) patients expressing RET(M918T), nuclear enrichment of STAT3 and elevated expression of CXCR4 was detected in metastatic thyroid C-cell carcinoma in the liver. In breast adenocarcinoma cell lines expressing multiple EPH members, STAT3 constitutively bound to the promoters of MUC1, MUC4, and MUC5B genes. Inhibiting STAT3 expression resulted in reduced expression of these metastasis-related genes and inhibited mobility. These findings provide insight into Thr(p+1loop) residue in RTK autophosphorylation and constitutive activation of STAT3 in metastatic cancer cells.
Mol Cell Biol 2004 Nov
PMID:Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells. 1548 8

Previous analyses have identified related cytoplasmic Lsm1-7p and nuclear Lsm2-8p complexes. Here we report that mature heat shock and MET mRNAs that are trapped in the nucleus due to a block in mRNA export were strongly stabilized in strains lacking Lsm6p or the nucleus-specific Lsm8p protein but not by the absence of the cytoplasmic Lsm1p. These nucleus-restricted mRNAs remain polyadenylated until their degradation, indicating that nuclear mRNA degradation does not involve the incremental deadenylation that is a key feature of cytoplasmic turnover. Lsm8p can be UV cross-linked to nuclear poly(A)(+) RNA, indicating that an Lsm2-8p complex interacts directly with nucleus-restricted mRNA. Analysis of pre-mRNAs that contain intronic snoRNAs indicates that their 5' degradation is specifically inhibited in strains lacking any of the Lsm2-8p proteins but Lsm1p. Nucleus-restricted mRNAs and pre-mRNA degradation intermediates that accumulate in lsm mutants remain 5' capped. We conclude that the Lsm2-8p complex normally targets nuclear RNA substrates for decapping.
Mol Cell Biol 2004 Nov
PMID:Nuclear pre-mRNA decapping and 5' degradation in yeast require the Lsm2-8p complex. 1548 30

The MET tyrosine kinase, the receptor of hepatocyte growth factor-scatter factor (HGF/SF), is known to be essential for normal development and cell survival. We report that stress stimuli induce the caspase-mediated cleavage of MET in physiological cellular targets, such as epithelial cells, embryonic hepatocytes, and cortical neurons. Cleavage occurs at aspartic residue 1000 within the SVD site of the juxtamembrane region, independently of the crucial docking tyrosine residues Y1001 or Y1347 and Y1354. This cleavage generates an intracellular 40-kDa MET fragment containing the kinase domain. The p40 MET fragment itself causes apoptosis of MDCK epithelial cells and embryonic cortical neurons, whereas its kinase-dead version is impaired in proapoptotic activity. Finally, HGF/SF treatment does not favor MET cleavage and apoptosis, confirming the known survival role of ligand-activated MET. Our results show that stress stimuli convert the MET survival receptor into a proapoptotic factor.
Mol Cell Biol 2004 Dec
PMID:Proapoptotic function of the MET tyrosine kinase receptor through caspase cleavage. 1554 41

The island of Madagascar harbors a highly endemic vertebrate fauna including a high diversity of lizards of the subfamily "Scincinae," with about 57 species in eight genera. Since limb reduction seems to have been a common phenomenon during the evolution of Malagasy "scincines," diagnosing evolutionary relationships based on morphology has been difficult. Phylogenetic analyses of multiple mitochondrial DNA sequences including the entire ND1, tRNA(LEU), tRNA(ILE), tRNA(GLN) genes, and fragments of the 12S and 16S rRNA and tRNA(MET) genes were conducted to test the monophyly of the largest genus Amphiglossus, and to evaluate the various formal and informal species groupings previously proposed for this species-rich group. A further objective was to determine the phylogenetic placements of the several greatly limb-reduced and limbless Malagasy "scincines" and ascertain whether any of these are derived from within the morphologically plesiomorphic Amphiglossus. As limb reduction in skinks is mostly associated with body elongation via an increase in the number of presacral vertebrae, we evaluate the pattern of evolution of the numbers of presacral vertebrae in the context of our phylogeny. We demonstrate that Amphiglossus as currently diagnosed is non-monophyletic, and the species fall into two major groups. One of these groups is a clade that contains the included species of the subgenus Amphiglossus (Madascincus) among other species and is a member of a larger clade containing Paracontias and Pseudoacontias. In the second group, the nominate subgenus Amphiglossus (Amphiglossus) forms several subclades within a larger clade that also contains Androngo crenni and Pygomeles braconnieri, and is sister to Voeltzkowia. All analyses provide strong support for the monophyly of Paracontias and Voeltzkowia. Based on the preferred phylogenetic hypothesis and weighted squared-change parsimony we show that the ancestor of the Malagasy clade was already elongated and had a moderately high number of presacral vertebrae (46-48), which is hypothesized to be the ancestral condition for the whole Malagasy "scincine" clade. We further demonstrate that both multiple increases and reductions of presacral vertebrae evolved in many clades of Malagasy "scincines" and that the use of presacral vertebrae as a major character to diagnose supraspecific units is dubious. Based on our results and published morphological evidence we consider Scelotes waterloti Angel, 1930 to be a junior synonym of Amphiglossus reticulatus (Kaudern, 1922).
Mol Phylogenet Evol 2005 Jan
PMID:Opening the black box: phylogenetics and morphological evolution of the Malagasy fossorial lizards of the subfamily "Scincinae". 1557 86

The SCF family of ubiquitin-ligases consists of a common core machinery, namelySkp1p, Cdc53p, Hrt1p, and a variable component, the F-box protein that is responsible for substrate recognition. The F-box motif, which consists of approximately 40 amino acids, connects the F-box protein to the core ubiquitin-ligase machinery. Distinct SCF complexes, defined by distinct F-box proteins, target different substrate proteins for proteasome-dependent degradation. As part of the SCF(Met30p) complex, the F-box protein Met30p selects the substrate Met4p, a transcriptional activator for MET biosynthetic genes that mediate sulfur uptake and biosynthesis of sulfur containing compounds. When cells are grown in the absence of methionine, Met4p evades degradation by the SCF(Met30p) complex and activates the MET biosynthetic pathway. However, overproduction of Met30p represses MET gene expression and induces methionine auxotrophy in an otherwise methionine prototrophic strain. Here we demonstrate that overproduction of the C-terminal portion of Met30p, which is composed almost entirely of seven WD-40 repeat motifs, is necessary and sufficient to induce methionine auxotrophy and complement the temperature sensitive (ts) met30-6 mutation. Furthermore, we show that this region of Met30p is important for binding Met4p and that mutations that disrupt this interaction prevent both the induction of methionine auxotrophy and complementation of the met30-6 mutation. These assays have been exploited to identify residues that are important for the interaction of Met30p with its substrate. Since the C-terminal domain of Met30p lacks the F-box and cannot support the ubiquitination of Met4p, our results indicate that the recruitment of Met4p to the SCF(Met30p) complex itself results in inactivation of Met4p, independently of its ubiquitination.
Mol Genet Genomics 2005 Jun
PMID:Identification of residues in the WD-40 repeat motif of the F-box protein Met30p required for interaction with its substrate Met4p. 1588 25

The deregulation of tyrosine kinase receptors (RTKs) is frequent in human tumors and is often associated with the acquisition of an aggressive phenotype. The Met oncogene, encoding the RTK for hepatocyte growth factor (HGF), controls genetic programs leading to cell growth, invasion and protection from apoptosis. The deregulated activation of Met is crucial not only for the acquisition of tumorigenic properties but also to achieve an invasive phenotype. The involvement of MET in human tumors has been definitively established and can be achieved through several mechanisms, including MET interaction with unrelated membrane receptors, such as integrins, plexins, CD44, FAS and other RTKs. Interfering with Met activation is thus a new and challenging approach to hamper tumorigenic and metastatic processes.
Trends Mol Med 2005 Jun
PMID:Cancer therapy: can the challenge be MET? 1594 70

Morphine has been widely accepted as the opioid agonist that sustains signaling because it does not cause receptor desensitization or internalization. This notion has led to the hypothesis that long-term morphine treatment initiates downstream adaptations that underlie tolerance and dependence. This study uses whole-cell recordings from neurons in the locus ceruleus to measure the potassium current induced by morphine. The results show that morphine does cause short-term desensitization. The desensitization induced by morphine was slower and smaller then that induced by [MET](5)-enkephalin (ME). After a brief application of a saturating concentration of ME, the current induced by morphine was smaller, and desensitization was not observed. In tissue taken from morphine-treated animals, the peak current induced by morphine was the same as in untreated animals, but morphine-induced desensitization was facilitated. The results suggest that morphine, like other agonists, can initiate receptor desensitization to decrease signaling.
Mol Pharmacol 2005 Oct
PMID:Morphine-Induced mu-opioid receptor desensitization. 1602 Jul 43

Protein kinase CK2 has diverse links to gene control and cell cycle. Comparative genome-wide expression profiling of CK2 mutants of the budding yeast Saccharomyces cerevisiae at cell cycle entry has revealed that a significant proportion of cell-cycle genes are affected by CK2. Here, we examine how CK2 realizes this effect. We show that the CK2 action may be directed to gene promoters causing genes with promoter homologies to respond comparably to CK2 perturbation. Examples are metabolic pathway and nutrition supply genes such as the PHO and MET regulon genes, responsible for phosphate maintenance and methionine biosynthesis, respectively. CK2 perturbation affects both regulons permanently and both via repression of a central transcription factor, but with different mechanisms: In the PHO regulon, the gene encoding the central transcription factor Pho4 is repressed and, in addition, Pho4 and/or the cyclin-dependent kinase of the regulon's control complex may be affected by CK2 phosphorylation. In the MET regulon, the repression of the central transcription factor Met4 occurs not by expression inhibition, but rather by availability tuning via a CK2-mediated phosphorylation of a degradation complex. On the other hand, the CK2 action may be directed to the chromatin regulon, thus affecting globally the expression of genes, i.e., the CK2 perturbation results either in comparable responses of genes which have no promoter homologies or in deviating responses despite promoter homologies. The effect is rather transient and concerns aside various cell cycle control genes a notable number of genes encoding chromatin remodeling and modification proteins with functions in chromatin assembly and (anti-)silencing as well as in histone (de-)acetylation, and frequently are also substrates of CK2, suggesting additional tuning at protein level. In line with these findings, we observe in human cells sequence-independent but cell-cycle-dependent CK2 associations with promoters of cell-cycle-regulated genes at periods of extensive gene expression alterations, including cell cycle entry. Our observations are compatible with the idea that the gene control by CK2 is achieved via different mechanisms and at different levels of organization and includes a global role in transcription-related chromatin remodelling and modification.
Mol Cell Biochem 2005 Jun
PMID:Protein kinase CK2 in gene control at cell cycle entry. 1633 38


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