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

Therapeutic vaccination against cancer-associated antigens represents an attractive option for cancer therapy in view of the comparatively low toxicity and, so far, excellent safety profile of this treatment. Nevertheless, it is now recognized that the vaccination strategies used for prophylactic vaccinations against infectious diseases cannot necessarily be used for therapeutic cancer vaccination. Cancer patients are usually immunosuppressed, and most cancer-associated antigens are self antigens. Therefore, various immunostimulation techniques are under investigation in an effort to bolster immune systems and to overcome immune tolerance to self antigens. Various strategies to stimulate antigen presentation, T-cell reactivity and innate immune activity are under investigation. Similarly, strategies to produce an immunological 'danger signal' at the site of the tumor itself are under evaluation, as it is recognized that while tumor-specific T-cells can be activated at the site of vaccination, they require appropriate signals to be attracted to a tumor. The detection, evaluation and quantification of specific immune responses generated by vaccination with cancer-associated antigens is another important area of therapeutic cancer vaccine evaluation receiving much attention and novel strategies. Multiple clinical trials have been undertaken to evaluate therapeutic vaccines in patients. Aggressive protocols such as those combining specific stimulation of T-cells and chemotherapy or strategies to block immune regulation are having some success.
Curr Opin Mol Ther 2004 Feb
PMID:Therapeutic cancer vaccines. 1501 80

To investigate the extent to which in vivo mutation spectra might reflect the intrinsic specificities of active mutators, genetic and biochemical assays were used to analyse the DNA target specificities of cytidine deaminases of the APOBEC family. The results reveal the critical importance of nucleotides immediately 5' of the targeted C for the specificity of all three enzymes studied (AID, APOBEC1 and APOBEC3G). At position -1, APOBEC1 showed a marked preference for dT, AID for dA/dG and APOBEC3G a strong preference for dC. Furthermore, AID and APOBEC3G showed distinct dependence on the nucleotide at position -2 with dA/dT being favoured by AID and dC by APOBEC3G. Most if not all activity of the recombinant deaminases on free dC could be attributed to low-level contamination by host enzymes. The target preference of APOBEC3G supports it being a major but possibly not sole contributor to HIV hypermutation without making it a dominant contribution to general HIV sequence variation. The specificity of AID as deduced from the genetic assay (which relies on inactivation of sacB of Bacillus subtilis) agrees well with that deduced by Pham et al. using an in vitro assay although we postulate that major intrinsic mutational hotspots in immunoglobulin V genes in vivo might reflect favoured sites of AID action being generated by proximal DNA targets located on opposite DNA strands. The target specificity of AID also accords with the spectrum of mutations observed in B lymphoma-associated oncogenes. The possibility of deaminase involvement in non-lymphoid human tumours is hinted at by tissue-specific differences in the spectra of dC transitions in tumour-suppressor genes. Thus, the patterns of hypermutation in antibodies and retroviruses owe much to the intrinsic sequence preferences of the AID/APOBEC family of DNA deaminases: analogous biases might also contribute to the spectra of cancer-associated mutation.
J Mol Biol 2004 Mar 26
PMID:Comparison of the differential context-dependence of DNA deamination by APOBEC enzymes: correlation with mutation spectra in vivo. 1501 79

Mutations in the adenomatous polyposis coli (APC) protein occur early in colon cancer and correlate with chromosomal instability. Here, we show that depletion of APC from cystostatic factor (CSF) Xenopus extracts leads to a decrease in microtubule density and changes in tubulin distribution in spindles and asters formed in such extracts. Addition of full-length APC protein or a large, N-terminally truncated APC fragment to APC-depleted extracts restored normal spindle morphology and the intact microtubule-binding site of APC was necessary for this rescue. These data indicate that the APC protein plays a role in the formation of spindles that is dependent on its effect on microtubules. Spindles formed in cycled extracts were not sensitive to APC depletion. In CSF extracts, spindles predominantly formed from aster-like intermediates, whereas in cycled extracts chromatin was the major site of initial microtubule polymerization. These data suggest that APC is important for centrosomally driven spindle formation, which was confirmed by our finding that APC depletion reduced the size of asters nucleated from isolated centrosomes. We propose that lack of microtubule binding in cancer-associated mutations of APC may contribute to defects in the assembly of mitotic spindles and lead to missegregation of chromosomes.
Mol Biol Cell 2004 Jun
PMID:The adenomatous polyposis coli protein is required for the formation of robust spindles formed in CSF Xenopus extracts. 1507 72

A highly parallel replica exchange method (REM) that couples with a newly developed molecular dynamics algorithm particle-particle particle-mesh Ewald (P3ME)/RESPA has been proposed for efficient sampling of protein folding free energy landscape. The algorithm is then applied to two separate protein systems, beta-hairpin and a designed protein Trp-cage. The all-atom OPLSAA force field with an explicit solvent model is used for both protein folding simulations. Up to 64 replicas of solvated protein systems are simulated in parallel over a wide range of temperatures. The combined trajectories in temperature and configurational space allow a replica to overcome free energy barriers present at low temperatures. These large scale simulations reveal detailed results on folding mechanisms, intermediate state structures, thermodynamic properties and the temperature dependences for both protein systems.
J Mol Graph Model 2004 May
PMID:Exploring the protein folding free energy landscape: coupling replica exchange method with P3ME/RESPA algorithm. 1509 40

The spectrum of human antigens allows a monitoring of various pathological processes such as autoimmune disorders and tumorigenesis. Serological analysis of cDNA expression libraries (SEREX) is now used to search for new cancer-associated antigens, which are potential diagnostic markers or targets for immunotherapy of cancer. The results obtained for several solid tumors are reviewed. Groups of antigens detectable by SEREX, causes of immunogenicity of autoantigens, and prospective implication of antigens in diagnostics and monitoring of cancer are discussed.
Mol Biol (Mosk)
PMID:[Serological study of a repertoire of human cancer antigens and autoantigens]. 1512 27

The BRCT repeats in BRCA1 are essential for its tumor suppressor activity and interact with phosphorylated protein targets containing the sequence pSer-X-X-Phe, where X indicates any residue. The structure of the tandem BRCA1 BRCT repeats bound to an optimized phosphopeptide reveals that the N-terminal repeat harbors a conserved BRCT phosphoserine-binding pocket, while the interface between the repeats forms a hydrophobic groove that recognizes the phenylalanine. Crystallographic and biochemical data suggest that the structural integrity of both binding sites is essential for peptide recognition. The diminished peptide-binding capacity observed for cancer-associated BRCA1-BRCT variants may explain the enhanced cancer risks associated with these mutations.
Nat Struct Mol Biol 2004 Jun
PMID:Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. 1513 3

GroEL encapsulates nonnative substrate proteins in a central cavity capped by GroES, providing a safe folding cage. Conventional models assume that a single timer lasting approximately 8 s governs the ATP hydrolysis-driven GroEL chaperonin cycle. We examine single molecule imaging of GFP folding within the cavity, binding release dynamics of GroEL-GroES, ensemble measurements of GroEL/substrate FRET, and the initial kinetics of GroEL ATPase activity. We conclude that the cycle consists of two successive timers of approximately 3 s and approximately 5 s duration. During the first timer, GroEL is bound to ATP, substrate protein, and GroES. When the first timer ends, the substrate protein is released into the central cavity and folding begins. ATP hydrolysis and phosphate release immediately follow this transition. ADP, GroES, and substrate depart GroEL after the second timer is complete. This mechanism explains how GroES binding to a GroEL-substrate complex encapsulates the substrate rather than allowing it to escape into solution.
Mol Cell 2004 May 21
PMID:GroEL mediates protein folding with a two successive timer mechanism. 1514 92

A mutation in the mouse tub gene causes a phenotype characterized by maturity-onset obesity, blindness and deafness. The role of the intact tubby protein and the pathogenesis resulting in the phenotype of tub/tub mice remain largely unknown. In this study, we have investigated whether obese tub/tub mice exhibit altered expression levels for agouti-related protein (AGRP) or glutamic acid decarboxylase-65 (GAD65) in body weight-regulating neurons of the hypothalamic arcuate nucleus. In situ hybridization revealed that AGRP, but not GAD65 mRNA levels, were significantly lower in obese tub/tub mice as compared to tub/+ mice. The lower levels of AGRP mRNA in the arcuate nucleus of tub/tub mice were paralleled by lower fluorescence intensity and numbers of AGRP- and neuropeptide Y (NPY)-immunoreactive (ir) nerve fibers and terminals in the arcuate, ventromedial, dorsomedial hypothalamic nuclei and perifornical and lateral hypothalamic areas. No obvious differences in GAD65-ir nerve fibers and terminals could be detected. Measurements of daily food intake revealed that tub/tub mice displayed progressively higher food consumption as compared to lean tub/+ littermates over a 15-day observation period. When moved to an unfamiliar environment, e.g. a novel cage, daily food intake was initially lower in tub/tub mice than in tub/+ mice suggesting that tub/tub mice may be more sensitive to psychogenic stress. The results together show that tub/tub mice are hyperphagic and exhibit, within the hypothalamic arcuate nucleus, a depressed expression of neuropeptides involved in the regulation of feeding behavior.
Brain Res Mol Brain Res 2004 Jun 18
PMID:Down-regulated expression of agouti-related protein (AGRP) mRNA in the hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice. 1519 30

To identify neuronal substrates involved in NO/stress interactions we used Fos expression as a marker and examined the pattern of neuronal activation in response to swim stress in nNOS knock-out (nNOS-/-) and wild-type (WT) mice. Forced swimming enhanced Fos expression in WT and nNOS-/- mice in several brain regions, including cortical, limbic and hypothalamic regions. Differences in the Fos response between the two groups were observed in a limited set (6 out of 42) of these brain areas only: nNOS-/- mice displayed increased stressor-induced Fos expression in the medial amygdala, periventricular hypothalamic nucleus, supraoptic nucleus, CA1 field of the hippocampus, dentate gyrus and infralimbic cortex. No differences were observed in regions including the septum, central amygdala, periaqueductal grey and locus coeruleus. During forced swimming, nNOS-/- mice displayed reduced immobility duration, while no differences in general locomotor activity were observed between the groups in the home cage and during the open field test. The findings indicate that deletion of nNOS alters stress-coping ability during forced swimming and leads to an altered pattern of neuronal activation in response to this stressor in specific parts of the limbic system, hypothalamus and the medial prefrontal cortex.
Cell Mol Life Sci 2004 Jun
PMID:Genetic functional inactivation of neuronal nitric oxide synthase affects stress-related Fos expression in specific brain regions. 1519 73

Several distinct strategies have been used to modulate the expression of cancer-associated genes, including antisense oligonucleotides, small interfering RNAs (siRNAs), and artificial transcriptional factors. One major cause for chemotherapeutic treatment failure in cancer is the overexpression of P-glycoprotein, the product of the multidrug resistance gene MDR1. In this study, we tested the ability of siRNAs to inhibit MDR1 gene expression. We evaluated the efficiency of chemically synthesized dsRNAs as well as vector-based hairpin siRNAs and investigated the behavior of clones of multidrug-resistant NCI/ADR-RES breast carcinoma cells stably transfected with hairpin siRNA vectors. The effects of siRNA on the MDR phenotype were compared with those elicited by antisense oligonucleotides or by designed transcription factors targeting the MDR1 promoter. These studies suggest that there are several comparably effective strategies for inhibiting MDR1 expression.
Mol Pharmacol 2004 Aug
PMID:Strategies for inhibition of MDR1 gene expression. 1526 17


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