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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet-derived growth factor BB (PDGF-BB) has been assigned a critical role in vascular stability by promoting the recruitment of PDGF receptor-beta-expressing perivascular cells. Here we present data indicating that early hematopoietic/endothelial (hemangio) precursors express PDGFR-beta based on coexpression with CD31, vascular endothelial growth factor receptor-2, and CD41 in 2 models: mouse yolk sac (embryonic day 8 [E8]) and differentiating mouse embryonic stem cells (embryoid bodies). Expression of PDGFR-beta on hemangioprecursor cells in the embryoid bodies gradually disappeared, and, at E14, expression appeared on perivascular cells. Activation of the PDGFR-beta on the hemangioprecursors accelerated the differentiation of endothelial cells, whereas differentiation of the hematopoietic lineage was suppressed. In E9.5 yolk sacs derived from recombinant mice expressing kinase-active PDGFR-beta with an aspartic acid to asparagine (D894N) replacement in the kinase activating loop and from mice with ubiquitous expression of PDGF-BB driven by the Rosa26 locus, the number of CD41-expressing early hematopoietic cells decreased by 36% and 34%, respectively, compared with staged wild-type littermates. Moreover, enhanced vascular remodeling was evident in the Rosa26-PDGF-BB yolk sacs. We conclude that PDGFR-beta is expressed on early hemangioprecursor cells, regulating vascular/hematopoietic development.
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PMID:Platelet-derived growth factor receptor-beta promotes early endothelial cell differentiation. 1669 Sep 64

Long-term memory formation is regulated by many distinct molecular mechanisms that control gene expression. An emerging model for effecting a stable, coordinated pattern of gene transcription involves epigenetic tagging through modifications of histones or DNA. In this study, we investigated the regulation of histone phosphorylation in the hippocampus by the ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway. We found that activation of ERK/MAPK in vitro significantly increased histone H3 phosphorylation in hippocampal area CA1. Furthermore, we found that contextual fear conditioning in vivo leads to a rapid time-dependent increase in histone H3 phosphorylation in area CA1. This increase paralleled the time course of contextual fear-dependent activation of ERK, and was inhibited in vivo by a latent inhibition paradigm as well as by injection of an N-methyl-d-aspartic acid receptor (NMDA-R) antagonist. Finally, injection of an inhibitor of MEK (MAP kinase/ERK kinase), the unique dual-specificity kinase upstream of ERK, blocked the increase in histone H3 phosphorylation seen after contextual fear conditioning. These results demonstrate that changes in histone phosphorylation in the hippocampus are regulated by ERK/MAPK following a behavioral fear conditioning paradigm.
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PMID:ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. 1674 Dec 77

Progesterone receptor (PR) action is linked to epidermal growth factor (EGF) initiated signaling pathways at multiple levels; mitogen-activated protein kinases (MAPKs) are key mediators of this important cross-talk. Herein, we probed the effects of EGF on PR function and regulation of breast cancer cell growth. EGF stimulated rapid and transient phosphorylation of PR-B Ser294 relative to persistent phosphorylation of this site induced by the synthetic progestin, R5020. EGF induced nuclear translocation and DNA binding of unliganded wild-type, but not mutant PRs containing an Ala at position 294 (S294A). However, EGF alone induced little to no PR-B transcriptional activity; S294A PR-B was transcriptionally impaired. In contrast, pretreatment of cells with EGF (30min) significantly increased the potency and efficacy of wild-type, but not S294A PR transcriptional activity in response to progestin, and enhanced ligand-dependent downregulation of wild-type but not S294A PR. Replacement of Ser294 with aspartic acid (S294D) to mimic phosphorylation at this site decreased receptor stability and, as predicted, heightened progestin-induced transcription relative to wild-type PR-B. RT-PCR demonstrated the Ser294 phosphorylation-dependence of selected PR target genes (TGFalpha and HB-EGF). Surprisingly, PR-B expressing cells growing in soft agar were highly responsive to EGF or progestin, and this was further stimulated by the combination of both hormones. Cells expressing S294A PR exhibited reduced soft agar growth, and were also sensitive to R5020 alone, but failed to respond to EGF. These results suggest that PR Ser294 is an important "sensor" for growth factor inputs that affects PR function and breast cancer cell growth in the absence of progestin or in the presence of low or "sub-threshold" progestin concentrations. PR function likely contributes to breast cancer progression when EGFR family members or their ligands are overexpressed, a condition that predicts low abundance, but highly active and nuclear PR.
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PMID:Linkage of progestin and epidermal growth factor signaling: phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth. 1717 41

An arginine-glycine-aspartic acid (RGD) containing model peptide was conjugated to the surface of poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) micelles as a ligand that can recognize adhesion molecules overexpressed on the surface of metastatic cancer cells, that is, integrins, and that can enhance the micellar delivery of encapsulated hydrophobic drug into a tumor cell. Toward this goal, PEO-b-PCL copolymers bearing acetal groups on the PEO end were synthesized, characterized, and assembled to polymeric micelles. The acetal group on the surface of the PEO-b-PCL micelles was converted to reactive aldehyde under acidic condition at room temperature. An RGD-containing linear peptide, GRGDS, was conjugated on the surface of the aldehyde-decorated PEO-b-PCL micelles by incubation at room temperature. A hydrophobic fluorescent probe, that is, DiI, was physically loaded in prepared polymeric micelles to imitate hydrophobic drugs loaded in micellar carrier. The cellular uptake of DiI loaded GRGDS-modified micelles by melanoma B16-F10 cells was investigated at 4 and 37 degrees C by fluorescent spectroscopy and confocal microscopy techniques and was compared to the uptake of DiI loaded valine-PEO-b-PCL micelles (as the irrelevant ligand decorated micelles) and free DiI. GRGDS conjugation to polymeric micelles significantly facilitated the cellular uptake of encapsulated hydrophobic DiI most probably by intergrin-mediated cell attachment and endocytosis. The results indicate that acetal-terminated PEO-b-PCL micelles are amenable for introducing targeting moieties on the surface of polymeric micelles and that RGD-peptide conjugated PEO-b-PCL micelles are promising ligand-targeted carriers for enhanced drug delivery to metastatic tumor cells.
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PMID:Conjugation of arginine-glycine-aspartic acid peptides to poly(ethylene oxide)-b-poly(epsilon-caprolactone) micelles for enhanced intracellular drug delivery to metastatic tumor cells. 1731 46

Germline mutations in the RET proto-oncogene (RET gene) are well documented as the genetic causes of multiple endocrine neoplasia type 2A (MEN2A). We performed genetic analysis by direct RET gene mutation analysis in a Chinese MEN2A family and compared these results with biochemical screening tests and pathological examinations. Twenty-one exons and flanking introns of the RET gene were amplified using polymerase chain reaction (PCR). The PCR products were subjected to sequencing directly, or cloned into pGEM-T plasmids and sequenced. Restriction fragment length polymorphism (RFLP) was employed to confirm the mutation on the RET sequence. A novel heterozygous mutation of a 3-bp (GAC) deletion at codon 631 (D631del) of exon 11, resulting in the deletion of an aspartic acid at the locus, was identified in four MEN2A patients and one phenotypically normal family member. The average clinical onset-age of four MEN2A patients was 33.7 years, no cervical lymph node metastasis was found in MEN2A patients with medullary thyroid carcinoma in the family. The study indicated that the novel heterozygous deletion mutation at D631 of RET gene was co-segregated with MEN2A phenotype and promoted the development of MEN2A. This report is the first description of the D631del mutation in the family with MEN2A.
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PMID:A novel mutation (D631del) of the RET gene was associated with MEN2A in a Chinese pedigree. 1884 6

The MET tyrosine kinase is the hepatocyte growth factor/scatter factor (HGF/SF) receptor, which elicits multiple biological responses in epithelial cells, including cell survival. We previously demonstrated that in stress conditions, the MET receptor is cleaved by caspases within its juxtamembrane region, generating a pro-apoptotic intracellular fragment of 40 kDa. The caspase cleavage site at aspartic acid D1000 is adjacent to tyrosine Y1001, which when phosphorylated upon MET activation, is involved in CBL recruitment, allowing receptor ubiquitination and down regulation. Scanning mutagenesis of the MET juxtamembrane region led us to demonstrate that V999 and D1000 are essential for the caspase cleavage, while D1000 and Y1001 are essential for CBL recruitment. By examining whether overlapping of these sites leads to a functional interference, an inverse relationship was found between generation of p40 MET and phosphorylation of MET, with a direct involvement of phosphorylated Y1001 in protecting MET against its caspase cleavage. A molecular modeling analysis of caspase 3 interaction with the juxtamembrane region of MET confirmed that phosphorylation of this tyrosine is not compatible with its recognition by active caspase 3. These data demonstrate a direct protection mechanism of an activated phosphorylated MET receptor, against its caspase-dependent cleavage.
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PMID:Phosphorylation of the MET receptor on juxtamembrane tyrosine residue 1001 inhibits its caspase-dependent cleavage. 1945 Jun 81

Methoxy poly(ethylene glycol)-block-oligo(l-aspartic acid)-block-poly(epsilon-caprolactone) with four aspartic acid groups was synthesized with a molecular weight and M(w)/M(n) of 8930 and 1.22. Polymeric micelles were formed by dialysis and stabilized by electrostatic interactions between the carboxylic acid groups and calcium cations. The critical micelle concentration of mPEG-Asp-PCL was determined to be 0.078 mg/mL. At 0.02 mg/mL, the dissociation of micelles without ionic stabilization formed an opaque, phase-separated solution, while the stabilized micelles under the same conditions showed structural stability through ionic stabilization. The paclitaxel-loading and efficiency were 8.7% and 47.6%, respectively, and the drug loading increased the mean diameter from 73.0 nm to 87 nm, which was increased further to 96 nm after ionic fixation. Rapid releases of approximately 65% of the encapsulated paclitaxel from a non-stabilized micelle and 45% from a stabilized micelle were observed in the first 24h at pH 7.4 in a PBS solution containing 0.1 wt% Tween 80. The stabilized micelles then showed a sustained, slow release pattern over a couple of weeks, while the profile from the non-stabilized micelles reached a plateau at approximately 75% after 50h. The enhanced micelle stability independent of concentration through ionic stabilization opens a way for preparing long circulating delivery systems encapsulating water-insoluble drugs.
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PMID:Stabilized polymeric micelles by electrostatic interactions for drug delivery system. 1973 30

Rat major histocompatibility complex (MHC) class II molecules RT1.B(l) (DQ-like) and RT1.D(l) (DR-like) were cloned from the LEW strain using reverse transcription-polymerase chain reaction and expressed in mouse L929 cells. The transduced lines bound MHC class II-specific monoclonal antibodies in an MHC-isotype-specific manner and presented peptide antigens and superantigens to T-cell hybridomas. The T-cell-hybridomas responded well to all superantigens presented by human MHC class II, whereas the response varied considerably with rat MHC class II-transduced lines as presenters. The T-cell hybridomas responded to the pyrogenic superantigens Staphylococcus enterotoxin B (SEB), SEC1, SEC2 and SEC3 only at high concentrations with RT1.B(l)-transduced and RT1.D(l)-transduced cells as presenters. The same was true for streptococcal pyrogenic exotoxin A (SPEA), but this was presented only by RT1.B(l) and not by RT1.D(l). SPEC was recognized only if presented by human MHC class II. Presentation of Yersinia pseudotuberculosis superantigen (YPM) showed no MHC isotype preference, while Mycoplasma arthritidis superantigen (MAS or MAM) was presented by RT1.D(l) but not by RT1.B(l). Interestingly, and in contrast to RT1.B(l), the RT1.D(l) completely failed to present SEA and toxic shock syndrome toxin 1 even after transduction of invariant chain (CD74) or expression in other cell types such as the surface MHC class II-negative mouse B-cell lymphoma (M12.4.1.C3). We discuss the idea that a lack of SEA presentation may not be a general feature of RT1.D molecules but could be a consequence of RT1.D(l)beta-chain allele-specific substitutions (arginine 80 to lysine, asparagine 82 to aspartic acid) in the extremely conserved region flanking the Zn(2+)-binding histidine 81, which is crucial for high-affinity SEA-binding.
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PMID:Superantigen-presentation by rat major histocompatibility complex class II molecules RT1.Bl and RT1.Dl. 1974 Mar 18

We describe a case of systemic mastocytosis associated with myelodysplastic syndrome. The bone marrow showed multifocal clusters of mast cells and myeloid dysplasia. Sequencing of the KIT DNA revealed a point mutation at codon 816 including a substitution of valine for aspartic acid (D816V). The patient's tumor did not respond to imatinib; however, interferon-alpha reduced the bone marrow mast cells and serum total tryptase. The patient remains alive at one year after the diagnosis without disease progression.
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PMID:Successful treatment of KIT D816V-positive, imatinib-resistant systemic mastocytosis with interferon-alpha. 1991 99

Retinal transplantation experiments have advanced considerably during recent years, but remaining diseased photoreceptor cells in the host retina and inner retinal cells in the transplant physically obstruct the development of graft-host neuronal contacts which are required for vision. Recently, we developed methods for the isolation of donor photoreceptor layers in vitro, and the selective removal of host photoreceptors in vivo using biodegradable elastomeric membranes composed of poly(glycerol-co-sebacic acid) (PGS). Here, we report the surface modification of PGS membranes to promote the attachment of photoreceptor layers, allowing the resulting composite to be handled surgically as a single entity. PGS membranes were chemically modified with peptides containing an arginine-glycine-aspartic acid (RGD) extracellular matrix ligand sequence. PGS membranes were also coated with electrospun nanofiber meshes, containing laminin and poly(epsilon-caprolactone) (PCL). Following in vitro co-culture of biomaterial membranes with isolated embryonic retinal tissue, composites were tested for surgical handling and examined with hematoxylin and eosin staining and immunohistochemical markers. Electrospun nanofibers composed of laminin and PCL promoted sufficient cell adhesion for simultaneous transplantation of isolated photoreceptor layers and PGS membranes. Composites developed large populations of recoverin and rhodopsin labeled photoreceptors. Furthermore, ganglion cells, rod bipolar cells and AII amacrine cells were absent in co-cultured retinas as observed by neurofilament, PKC and parvalbumin labeling respectively. These results facilitate retinal transplantation experiments in which a composite graft composed of a biodegradable membrane adhered to an immature retina dominated by photoreceptor cells may be delivered in a single surgery, with the possibility of improving graft-host neuronal connections.
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PMID:The use of surface modified poly(glycerol-co-sebacic acid) in retinal transplantation. 1996 54


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