Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

cDNA arrays were used to characterize the gene expression profiles in 6 oral carcinoma cell lines (UT-SCC-10, UT-SCC-14, UT-SCC-37, UT-SCC-54A and UT-SCC-54B, UT-SCC-74) established from 5 patients with different etiological backgrounds, including young patients, classical risk factors and lichen-derived lesions. In addition, 2 human papillomavirus (HPV)-positive cell lines (hypophraryngeal cancer and HPV16 E6/E7-transformed oral keratinocytes) were similarly tested. Two distinct global gene expression profiles with down-regulated and up-regulated patterns were identified, which closely related to the etiologic backgrounds of the primary tumors. Typically in cluster analysis, interferon or interferon-related genes and T- and B-lymphocyte-related genes were up-regulated in lichen-derived carcinoma cell lines. Common to all carcinoma cell lines were 6 genes, which were up- or down-regulated (IgC mu heavy chain constant region, semaphorin, T-cell growth factor, cAMP-dependent protein kinase beta-catalytic subunit, desmocollin 1A/1B precursor and recA-like protein HsRad51). In HPV-positive cell lines, 13 genes were identified with similar down-regulation as shown in our previous studies on HPV-positive genital cell lines. Importantly, all of these genes were also down-regulated in 3 of the 6 oral cancer cell lines. These data suggest that oral carcinomas with different etiological backgrounds can be distinguished by their different global gene expression patterns.
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PMID:Two different global gene expression profiles in cancer cell lines established from etiologically different oral carcinomas. 1627 47

Chronic lymphocytic leukemia is one of the most common malignant lymphoid diseases in the western world and is frequently diagnosed by internists. There have been clinically significant changes in method of diagnosis, prognostic tools, supportive care, and treatment over the past 2 decades. Most patients with chronic lymphocytic leukemia now have Rai stage 0 or I disease at diagnosis. Patients with early-stage disease are a heterogeneous group: Approximately 30% to 50% will have accelerated disease progression, and the remainder may live for decades and possibly never require therapy. Recent insights into the biological characteristics of leukemic B cells have led to the discovery of new prognostic tools (immunoglobulin variable-region heavy chain gene mutation status, cytogenetic abnormalities assessed by fluorescent in situ hybridization, and Z-chain-associated protein kinase-70 protein expression) that can identify patients with early-stage disease who are at high risk for early disease progression. These tools allow physicians to individualize counseling, follow-up, and management on the basis of disease risk. In addition, new treatments developed over the past 2 decades (purine nucleoside analogues, monoclonal antibodies, and combination chemoimmunotherapy regimens) have dramatically improved response rates and appear to prolong survival. In this review, the authors discuss the current work-up of lymphocytosis and highlight how to use recently identified prognostic tools to stratify risk in patients with newly diagnosed, early-stage chronic lymphocytic leukemia. Recommendations for patient counseling, follow-up, supportive care, and initial treatment are presented for each risk category.
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PMID:Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia. 1698 31

Chronic lymphocytic leukemia (CLL) is unique among malignancies since it represents an accumulation of B-lymphocytes resistant to apoptosis. Several factors are thought to confer this unusual feature to a CLL B-cell. Misbalance between cytoplasmic pro-survival and pro-death molecules, such as Bcl-2, Mcl-1 and alike, appears to be one of the key factors defining B-cell longevity. Autocrine pathways, such as vascular endothelial growth factor-receptor pathway, also contribute to survival. The role of B-cell receptor (BCR) is less straightforward. In the last decade it became clear that CLL does not constitute a uniform disease, but, based on the prevalence of mutations in the BCR heavy chain (IgVH), can be classified into two distinct subgroups. Several molecular markers correlate with IgVH mutations. Some of them, like zeta-chain associated protein kinase, are also involved in BCR signaling and influence cell cycle. Yet the primary pathogenic event leading to increased proliferation and survival in CLL is difficult to ascertain. Molecules involved in BCR signaling pathways and cytoplasmic pro-survival players probably act in concert to confer resistance to apoptosis. In this respect, the role of the B-CLL environment, which includes nurse-like cells and T-cells, cannot be underestimated. Nurse-like cells provide stimuli necessary for perpetuation of life in CLL. On the other hand, abnormal T-cell function, whether it is excessive immunosuppression delivered by regulatory T-cells or insufficient anti-tumor immunity rendered by T-helpers, allows malignant CLL cells to go unnoticed by the cellular immune system.
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PMID:Molecular pathogenesis of chronic lymphocytic leukemia. 1702 36

Bovine fetuin-A is a member of a glycoprotein family with a wide spectrum of functions. Until now the bovine protein has been thought to be a single-chain protein. Recently we have shown that native bovine plasma fetuin-A partially exists as a disulfide-bridged two-chain protein with a heavy N-terminal and a lighter C-terminal chain similar to the structure of human fetuin-A homologue (alpha2HS glycoprotein), and also is partially phosphorylated at residues Ser120, Ser302, Ser305 and Ser306 (Wind et al., Anal. Biochem. 317 (2003) 26-33). Both fetuin-A modifications, the phosphorylation at the four sites as well as the proteolysis which causes longer or shorter light chains (termed lc-1 and lc-2, respectively), are probably brought about by targeted enzymatic activities which still need to be defined. In this study we show that authentic bovine fetuin-A disulfide-bridged two-chain forms, which include the original C-terminus, were liberated from the single-chain precursor by metalloproteinases MMP-3 (stromelysin-1) and MMP-7 (matrilysin), but not by elastase, cathepsin E and cathepsin G. Peptide sequencing suggested cleavage sites chiefly at the Pro277-Ser278 or Arg294-His295 peptide bonds. Fetuin-A radioactive phosphorylation in vitro by protein kinase CK2 caused (32)P incorporation into the fetuin-A light chain lc-1 but not lc-2 or the fetuin-A heavy chain, as revealed by MMP assisted proteolysis. Analysis by nanoESI-MS pinpointed phosphorylation at the native phospho-residues Ser302, Ser305 and Ser306 by increased relative abundance following in vitro phosphorylation. Moreover, CK2 phosphorylation of synthetic C-terminal fetuin-A peptides, used as effective controls to the native protein, strongly implies that CK2 is involved in the in vivo phosphorylation of fetuin-A. The phosphorylation of N-terminally truncated peptide homologs seemed highly dependent on the sequence context N-terminal of the phosphorylation sites, thus providing a likely explanation for the non-phosphorylation of the light chain lc-2 in native fetuin-A.
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PMID:Proteolytic processing by matrix metalloproteinases and phosphorylation by protein kinase CK2 of fetuin-A, the major globulin of fetal calf serum. 1711 14

TRPM7 is a member of the melastatin-related subfamily of TRP channels and represents a protein that contains both an ion channel and a kinase domain. The protein is ubiquitously expressed and represents the only ion channel known that is essential for cellular viability. TRPM7 is a divalent cation-selective ion channel that is permeable to Ca2+ and Mg2+, but also conducts essential metals such as Zn2+, Mn2+, and Co2+, as well as nonphysiologic or toxic metals such as Ni2+, Cd2+, Ba2+, and Sr2+. The channel is constitutively open but strongly downregulated by intracellular levels of Mg2+ and MgATP and other Mg-nucleotides. Reducing the cellular levels of these regulators leads to activation of TRPM7-mediated currents that exhibit a characteristic nonlinear current-voltage relationship with pronounced outward rectification due to divalent influx at physiologically negative voltages and monovalent outward fluxes at positive voltages. TRPM7 channel activity is also actively regulated following receptor-mediated changes in cyclic AMP (cAMP) and protein kinase A activity. This regulation as well as that by Mg-nucleotides requires a functional endogenous kinase domain. The function of the kinase domain is not completely understood, but may involve autophosphorylation of TRPM7 as well as phosphorylation of other target proteins such as annexin and myosin IIA heavy chain. Based on these properties, TRPM7 is currently believed to represent a ubiquitous homeostatic mechanism that regulates Ca2+ and Mg2+ fluxes based on the metabolic state of the cell. Physiologically, the channel may serve as a regulated transport mechanism for these ions that could affect cell adhesion, cell growth and proliferation, and even cell death under pathological stress such as anoxia.
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PMID:The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7. 1721 66

In mammalian nonmuscle cells, the mechanisms controlling the localized formation of myosin-II filaments are not well defined. To investigate the mechanisms mediating filament assembly and disassembly during generalized motility and chemotaxis, we examined the EGF-dependent phosphorylation of the myosin-IIA heavy chain in human breast cancer cells. EGF stimulation of MDA-MB-231 cells resulted in transient increases in both the assembly and phosphorylation of the myosin-IIA heavy chains. In EGF-stimulated cells, the myosin-IIA heavy chain is phosphorylated on the casein kinase 2 site (S1943). Cells expressing green fluorescent protein-myosin-IIA heavy-chain S1943E and S1943D mutants displayed increased migration into a wound and enhanced EGF-stimulated lamellipod extension compared with cells expressing wild-type myosin-IIA. In contrast, cells expressing the S1943A mutant exhibited reduced migration and lamellipod extension. These observations support a direct role for myosin-IIA heavy-chain phosphorylation in mediating motility and chemotaxis.
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PMID:Myosin-IIA heavy-chain phosphorylation regulates the motility of MDA-MB-231 carcinoma cells. 1756 56

Interaction of activation-induced cytidine deaminase (AID) with replication protein A (RPA) has been proposed to promote AID access to transcribed double-stranded (ds) DNA during immunoglobulin light chain and heavy chain class switch recombination (CSR). Mouse AID (mAID) interaction with RPA and transcription-dependent dsDNA deamination in vitro requires protein kinase A (PKA) phosphorylation at serine 38 (S38), and normal mAID CSR activity depends on S38. However, zebrafish AID (zAID) catalyzes robust CSR in mouse cells despite lacking an S38-equivalent PKA site. Here, we show that aspartate 44 (D44) in zAID provides similar in vitro and in vivo functionality as mAID S38 phosphorylation. Moreover, introduction of a PKA site into a zAID D44 mutant made it PKA dependent for in vitro activities and restored normal CSR activity. Based on these findings, we generated mAID mutants that similarly function independently of S38 phosphorylation. Comparison of bony fish versus amphibian and mammalian AIDs suggests evolutionary divergence from constitutive to PKA-regulated RPA/AID interaction.
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PMID:Evolution of phosphorylation-dependent regulation of activation-induced cytidine deaminase. 1895 Oct 95

The Ser493 residue in the E-segment of the rat neurofilament heavy chain (NF-H) is phosphorylated by glycogen synthase kinase 3beta (GSK3 beta) in vitro and in spinal cord. We examined Ser493 phosphorylation by analyzing developmental changes and cellular distribution of phospho-Ser493 using phosphorylation-site-specific antibodies. This residue was phosphorylated in NF-H prepared from human, rat, and mouse spinal cord, all species in which the amino acid sequence of NF-H is known. Phosphorylated Ser493 appeared on postnatal day 2 in rat brain, at the same time when NF-H is first detected. It gradually increased together with the increase in total NF-H during brain development. Phospho-Ser493 was detected on the phosphorylated form of NF-H at multiple Lys-Ser-Pro (KSP) repeats, which are distributed mainly in axons. In rat ventral horn, phosphorylated Ser493 was localized in axons but not in cell bodies or dendrites. However, the distributions of phosphorylated Ser493 and KSP phosphorylation in axons were not identical. Ser493 was continuously phosphorylated at nodes of Ranvier, whereas the KSP sites were dephosphorylated. Ser493 was also phosphorylated in unmyelinated regions of optic nerve axons. A biochemical difference in phosphorylation between Ser493 and KSP repeats was also found; the subtle phosphorylation at Ser493 was detected in NF-H unphosphorylated at the KSP repeats by immunoblotting cerebral cortex extracts. These results indicate that Ser493 in the NF-H E-segment is a novel site that is phosphorylated in both the myelinated and the unmyelinated regions of axons.
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PMID:Novel axonal distribution of neurofilament-H phosphorylated at the glycogen synthase kinase 3beta-phosphorylation site in its E-segment. 1953 Jan 63

The non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC) has been implicated in the activation of cascades responsible for trophic actions and neuroprotection by inhibition of apoptosis. Previous in vitro studies have described signalling pathways that underlie the administration of TTC to neurons. We investigated whether these properties were maintained in a mouse model of neurodegenerative disease. Naked DNA encoding for TTC was injected intramuscularly and neuromuscular function and clinical behaviour were monitored until endstage in the transgenic SOD1G93A mouse model that expresses a mutant variant of human superoxide dismutase 1 (SOD1). Our results indicate that TTC treatment ameliorated the decline of hindlimb muscle innervation, significantly delayed the onset of symptoms and functional deficits, improved spinal motor neuron survival, and prolonged lifespan. Furthermore, we found that caspase-1 and caspase-3 proapoptotic genes were down-regulated in the spinal cord of treated mice. Western blot analysis showed that the active form of caspase-3 was also down-regulated after TTC treatment and survival signals, such as the significant phosphorylation of serine/threonine protein kinase Akt, were also detected. These results suggest that fragment C of tetanus toxin, TTC, provides a potential therapy for neurodegenerative diseases.
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PMID:Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy. 1992 1

To identify immunoglobulin variable heavy chain (VH) gene usages in Korean ankylosing spondylitis (AS) patients, expression level of VH2 genes from peripheral blood mononuclear cells (PBMCs) of 8 AS patients and 9 healthy donors was analysed by quantitative real-time PCR (Q-PCR). Q-PCR results demonstrated VH2 genes were overexpressed in AS patients (Relative amount of mRNA of VH2 genes to a house-keeping gene, 7.13+/-7.77 vs, 0.68+/-0.55; P<0.0001). The sequence analysis revealed the majority of them contained CDC42 binding protein kinase Beta (CDC42 BPB) genes. The insertion of CDC42 BPB gene was confirmed by PCR with primers corresponding CDC42 BPB and CH genes. Our study revealed VH2 overexpression and unique rearrangement in Ig VH genes from peripheral blood of AS patients. This may imply aberrant immunoglobulin gene rearrangement in B cell occurs in Korean AS patients, which requires further investigation.
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PMID:Overexpression and unique rearrangement of VH2 transcripts in immunoglobulin variable heavy chain genes in ankylosing spondylitis patients. 2017 45


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