Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

STAT 1, a member of signal transducers and transcription activators of STAT family proteins, has been implicated as important mediator of IFN signaling. Functional activation of STAT 1 requires tyrosine and serine phosphorylation. Defects in its expression or activation in response to IFNs were observed in numerous pathological conditions including cancer. To further explore cancer-associated impaired STAT 1 response to IFNs, the inducibility of serine (S 727) and tyrosine (Y 701) phosphorylation by IFN-alpha/-gamma was assessed in 21 melanoma cell lines and in 35 primary cultures derived from melanoma patients. STAT 1 levels and inducibility of its activated phospho-forms were detected by Western analysis using specific polyclonal and monoclonal antibodies. All cell lines as well as patient melanoma samples expressed STAT 1 with variable signal intensity. Significant impaired IFN-induced STAT 1 S 727 phosphorylation was observed in both model systems with average of 77% of non-responders recorded in patient melanoma cells and 76% in melanoma cell lines. Failure of PY 701 induction occurred in patient samples (63% after IFN-alpha and 34% after IFN-gamma induction) and to a lesser degree in cell lines (i.e. response absence to IFN-alpha in 5 and to IFN-gamma in 2 melanoma lines). Our study demonstrates STAT 1 functional abnormalities in melanoma cells. On the basis of detailed analyses of patient melanoma cells with respect to the inducibility of STAT 1 phosphorylation by IFNs, four categories of patients could be distinguished: a) activation on both S 727 and Y 701, b) not inducible response, c) activation on Y 701 but not on S 727, d) heterogeneous response. Clinical study is now in progress to establish the significance of in vitro STAT 1 activation for predicting the response to IFN-based therapy and to explore biological consequences in cases responding in vitro to IFN-induced STAT 1 activation on only one of the critical amino acid residues.
Int J Mol Med 2003 Sep
PMID:Malignant melanoma associates with deficient IFN-induced STAT 1 phosphorylation. 1288 49

Chaperonins, such as the GroE complex of the bacteria Escherichia coli, assist the folding of proteins under non-permissive folding conditions by providing a cavity in which the newly translated or translocated protein can be encapsulated. Whether the chaperonin cage plays a passive role in protecting the protein from aggregation, or an active role in accelerating folding rates, remains a matter of debate. Here, we investigate the role of confinement in chaperonin mediated folding through molecular dynamics simulations. We designed a substrate protein with an alpha/beta sandwich fold, a common structural motif found in GroE substrate proteins and confined it to a spherical hydrophilic cage which mimicked the interior of the GroEL/ES cavity. The thermodynamics and kinetics of folding were studied over a wide range of temperature and cage radii. Confinement was seen to significantly raise the collapse temperature, T(c), as a result of the associated entropy loss of the unfolded state. The folding temperature, T(f), on the other hand, remained unaffected by encapsulation, a consequence of the folding mechanism of this protein that involves an initial collapse to a compact misfolded state prior to rearranging to the native state. Folding rates were observed to be either accelerated or retarded compared to bulk folding rates, depending on the temperature of the simulation. Rate enhancements due to confinement were observed only at temperatures above the temperature T(m), which corresponds to the temperature at which the protein folds fastest. For this protein, T(m) lies above the folding temperature, T(f), implying that encapsulation alone will not lead to a rate enhancement under conditions where the native state is stable (T<T(f)). For confinement to positively impact folding rates under physiological conditions, it is hence necessary for the protein to exhibit a folding transition above the temperature at which it exhibits its fastest folding rate (T(m)<T(f)). We designed a protein with this property by reducing the energetic frustration in the original alpha/beta sandwich substrate protein. The modified protein exhibited a twofold acceleration in folding rates upon encapsulation. This rate enhancement is due to a mechanistic change in folding involving the elimination, upon encapsulation, of accessible local energy minima corresponding to structures with large radii of gyration. For this protein, confinement hence plays more than the role of a passive cage, but rather adopts an active role, accelerating folding rates by decreasing the roughness of the energy landscape of the protein.
J Mol Biol 2003 Sep 19
PMID:Effects of confinement in chaperonin assisted protein folding: rate enhancement by decreasing the roughness of the folding energy landscape. 1296 77

Dimeric (hydrated and anhydrated) complexes of Cu(II) with N,N'-bis(3-carboxy-1-oxo-2-prop-2-enyl)ethylenediamine(BCOPENH(2), A) and N,N'-bis(2-carboxy-1-oxo-phenylenyl)ethylenediamine(BCOPHENH(2), B) have been prepared and characterised by elemental analysis, magnetic susceptibility measurements, EPR, thermal and spectral (IR, UV/Vis) studies. EPR parameters and magnetic behaviour indicates that the complexes are antiferromagnetic in nature and most likely adopt the typical carboxylate cage structure. Interesting amide bonding patterns have been observed and various EPR parameters have been evaluated on the basis of these studies, tentative probable structures of the complexes have been proposed.
Spectrochim Acta A Mol Biomol Spectrosc 2003 Oct
PMID:Spectral studies of dimeric copper(II) complexes of acid amide derivatives as models for type III copper enzymes. 1449 38

The clinical management of non-small cell lung cancer (NSCLC) would benefit greatly by a test that was able to detect small amounts of NSCLC in the peripheral blood. In this report, we used a novel strategy to enrich tumor cells from the peripheral blood of 24 stage I to IV NSCLC patients and determined expression levels for six cancer-associated genes (lunx, muc1, KS1/4, CEA, CK19, and PSE). Using thresholds established at three standard deviations above the mean observed in 15 normal controls, we observed that lunx (10 of 24, 42%), muc1 (5 of 24, 21%), and CK19 (5 of 24, 21%) were overexpressed in 14 of 24 (58%) peripheral blood samples obtained from NSCLC patients. Patients who overexpressed either KS1/4 (n = 2) or PSE (n = 1) also overexpressed either lunx or muc1. Of patients with presumed curable and resectable stage I to II disease (n = 7), at least one marker was overexpressed in three (43%) patients. In advanced stage III to IV patients (n = 17), at least one marker was overexpressed in 11 patients (65%). These results provide evidence that circulating tumor cells can be detected in NSCLC patients by a high throughput molecular technique. Further studies are needed to determine the clinical relevance of gene overexpression.
J Mol Diagn 2003 Nov
PMID:Lunx is a superior molecular marker for detection of non-small cell lung cancer in peripheral blood [corrected]. 1457 83

The phylogeographical patterns of a small marine fish, the common goby, Pomatoschistus microps, were assessed at 12 sites along the northeastern Atlantic coasts and the western Mediterranean Sea. A combination of two genetic markers was employed: cellulose acetate allozyme electrophoresis (CAGE) and sequence analysis of a 289 bp fragment of the mitochondrial locus cytochrome b. Both markers were congruent in revealing significant differences between samples (global FST = 0.247 for the allozymes and PhiST = 0.437 for the mitochondrial DNA data) and a pattern of isolation-by-distance. Phylogeographical analyses yielded a shallow branching structure with four groups. Three of those were confined to the Atlantic basin and showed a star-like pattern. The fourth group contained a central haplotype occurring at the edges of the species' distribution, accompanied by a few more rare variants, which were restricted to the Mediterranean Sea. A genetic break was observed around the British Isles, with distinct haplotypes dominating at either side of the English Channel. A significantly negative correlation between the degree of genetic diversity and latitude was recorded both for mitochondrial DNA (mtDNA) and allozymes in the Atlantic basin. Gene flow analysis suggested that recolonization of the North Sea and the coasts of western Scotland and Ireland may have taken place from a glacial refugium in the Southern Bight of the North Sea. These results are discussed in the perspective of possible postglacial migration routes of marine fish along the northeastern Atlantic coasts.
Mol Ecol 2004 Feb
PMID:Phylogeography of the common goby, Pomatoschistus microps, with particular emphasis on the colonization of the Mediterranean and the North Sea. 1471 95

Drosophila Crumbs (Crb), Stardust (Sdt), Discs large (Dlg), Scribble (Scrib) and Lethal giant larvae (Lgl) are involved in the establishment and the maintenance of apicobasal polarity in epithelial tissues. Because epithelial polarity is disrupted in tumors, human homologs of Drosophila crb, sdt, dlg, scrib, and lgl are potential cancer-associated genes. MPP1/EMP55, MPP2, MPP3, MPP4, MPP5/PALS1 and MPP6/PALS2 genes are human homologs of Drosoplila sdt. Here, we identified and characterized a novel member of MPP gene family, MPP7, by using bioinformatics. Uncharacterized FLJ32798 cDNAs (BC038105 and AK057360) were derived from human MPP7 gene. BC038105 was a representative MPP7 cDNA, while AK057360 was an aberrant MPP7 cDNA with a frame shift. Human MPP7 mRNA was expressed in placenta, brain, testis as well as in uterus tumor, bladder tumor, and lymphoma. Microsatellite marker D10S588, linked to IDDM and hereditary thrombocytopenia, was located within the MPP7 gene at human chromosome 10p12.1. Nucleotide sequence of mouse Mpp7 cDNA was determined in silico by assembling 3'-truncated cDNA AK078849, genome clone RP24-255J24, and EST AV260217. Human MPP7 showed 92.9% total-amino-acid identity with mouse Mpp7, and 75.7% total-amino-acid identity with zebrafish humpback. MPP7 orthologs were MAGUK proteins with two L27 domains, PDZ domain, SH3 domain, and GuKc domain. MPP7 was most related to MPP3 among MPP family members, functioning as adopter molecules assembling Crb homologs (CRB1, CRB3), Dlt homologs (INADL/PATJ, MPDZ/MUPP1), and Lin-7 homologs (LIN7A, LIN7B, LIN7C). This is the first report on identification and characterization of human MPP7 and mouse Mpp7 genes.
Int J Mol Med 2004 Feb
PMID:Identification and characterization of human MPP7 gene and mouse Mpp7 gene in silico. 1471 43

Missense mutations in the DNA-binding core domain of the tumour suppressor protein p53 are frequent in cancer. Many of them result in loss of native structure. The mutation R249S is one of the six most common cancer-associated p53 mutations ("hot-spots"). As it is highly frequent in hepatocellular carcinoma, its rescue is an important therapeutic target. We have used NMR techniques to study the structural effects of the R249S mutation. The overall fold of the core domain is retained in R249S, and it does not take up a denatured "mutant conformation". However, the beta-sandwich had increased flexibility and, according to changes in chemical shift, there was local distortion throughout the DNA-binding interface. It is likely that the R249S mutation resulted in an ensemble of native and native-like conformations in a dynamic equilibrium. The peptide FL-CDB3 that was designed to rescue mutants of p53 by binding specifically to its native structure was found to revert the chemical shifts of R249S back towards the wild-type values and so reverse the structural effects of mutation. We discuss the implications for a rescue strategy and also for the analysis of antibody-binding data.
J Mol Biol 2004 Feb 06
PMID:Structural distortion of p53 by the mutation R249S and its rescue by a designed peptide: implications for "mutant conformation". 1474 Dec 14

The Dna J homologue, auxilin, acts as a co-chaperone for Hsc70 in the uncoating of clathrin-coated vesicles during endocytosis. Biochemical studies have aided understanding of the uncoating mechanism but until now there was no structural information on how auxilin interacts with the clathrin cage. Here we have determined the three-dimensional structure of a complex of auxilin with clathrin cages by cryo-electron microscopy and single particle analysis. We show that auxilin forms a discrete shell of density on the inside of the clathrin cage. Peptide competition assays confirm that a candidate clathrin box motif in auxilin, LLGLE, can bind to a clathrin construct containing the beta-propeller domain and also displace the well-characterised LLNLD clathrin box motif derived from the beta-adaptin hinge region. The means by which auxilin could both aid clathrin coat assembly and displace clathrin from AP2 during uncoating is discussed.
J Mol Biol 2004 Feb 13
PMID:Location of auxilin within a clathrin cage. 1475 58

The micronucleus test (MN) is used as an indicator of genotoxic exposition, since it is associated with chromosome aberrations. An increased mutation rate in oral squamous cells, indicated by an increased MN frequency, is also related to the development of oral carcinomas. We evaluated the frequencies of MN and other metanucleated anomalies in the buccal squamous cells of 30 alcoholics with oral or oropharyngeal carcinomas, and compared them to a control group of abstinent health individuals. Microscopic examination was made of 2000 cells per individual from each of three distinct areas of the mouth: around the lesion (A), opposite to the lesion (B) and in the upper gingival-labial gutter (C); C was used as a control region because of low tumor frequency. There was a seven-fold increase in MN frequency in region B, a three-fold increase in region A and a two-fold, though nonsignificant, increase in C; indicating a gradient of frequencies towards carcinogenesis: C --> A --> B. Comparisons of frequencies of various types of metanucleated cells: binucleated, karyorrhexis (KR), karyolysis (KL) and broken egg (BE) in patients and controls showed, with few exceptions, highly significant differences. This gave us a better understanding of the dynamics of this squamous epithelium, supporting a more efficient biomonitor based on these various metanucleated anomalies: the repair index RI=(KL+KR)/(MN+BE). Also, the apparently contradictory results from regression analysis revealed that the MN frequency decreased with age and alcohol consumption, probably because of slow cell proliferation, and consequently led to a loss of homeostasis due to aging. In addition, in the analysis of nonparametric variables only one CAGE question was significant, confirming the effect of alcohol. In conclusion, the MN test and the repair index could be used for monitoring clinical evolution, by means of intra- and inter-individual cellular comparisons, in subjects with healed or surgically removed tumors or leukoplastic lesions, after chemo- or radiotherapeutic treatments.
Genet Mol Res 2002 Sep 30
PMID:Micronucleus investigation of alcoholic patients with oral carcinomas. 1496 32

LMO4 belongs to a family of transcriptional regulators that comprises two zinc-binding LIM domains. LIM-only (LMO) proteins appear to function as docking sites for other factors, leading to the assembly of multiprotein complexes. The transcription factor Deaf-1/NUDR has been identified as one partner protein of LMO4. We have disrupted the Lmo4 and Deaf-1 genes in mice to define their biological function in vivo. All Lmo4 mutants died shortly after birth and showed defects within the presphenoid bone, with 50% of mice also exhibiting exencephaly. Homeotic transformations were observed in Lmo4-null embryos and newborn mice, but with incomplete penetrance. These included skeletal defects in cervical vertebrae and the rib cage. Furthermore, fusions of cranial nerves IX and X and defects in cranial nerve V were apparent in some Lmo4(-/-) and Lmo4(+/-) mice. Remarkably, Deaf-1 mutants displayed phenotypic abnormalities similar to those observed in Lmo4 mutants. These included exencephaly, transformation of cervical segments, and rib cage abnormalities. In contrast to Lmo4 nullizygous mice, nonexencephalic Deaf-1 mutants remained healthy. No defects in the sphenoid bone or cranial nerves were apparent. Thus, Lmo4 and Deaf-1 mutant mice exhibit overlapping as well as distinct phenotypes. Our data indicate an important role for these two transcriptional regulators in pathways affecting neural tube closure and skeletal patterning, most likely reflecting their presence in a functional complex in vivo.
Mol Cell Biol 2004 Mar
PMID:Defective neural tube closure and anteroposterior patterning in mice lacking the LIM protein LMO4 or its interacting partner Deaf-1. 1496 86


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