Point mutations of the P53 gene, human hepatocellular carcinoma and aflatoxins

The tumor suppressor p53 exerts important protective functions towards DNA-damaging agents. Its inactivation by allelic deletions or point mutations within the P53 gene as well as complex formation of wildtype p53 with cellular or viral proteins is a common and crucial event in carcinogenesis. Mutations increase the half-life of the p53 protein allowing the immunohistochemical detection and anti-p53 antibody formation. Distinct G to T point mutations in codon 249 leading to a substitution of the basic amino acid arginine by the neutral amino acid serin are responsible for the altered functionality of the mutant gene product and were originally identified in 8 of 16 Chinese and 5 of 10 African HCC patients. Both groups are frequently exposed to mycotoxin contaminations of their food. Today an average P53 gene mutation rate of 25% is assumed for high-aflatoxin B1-exposure regions. This is double the rate observed in low-aflatoxin B1-exposure countries. Although many HCC patients displaying P53 mutations also suffer from HBV infection, which itself can lead to rearrangements of P53 coding regions or induce the synthesis of viral proteins possibly interacting with p53, the specific G to T transversion within codon 249 of the P53 gene seems to directly reflect the extent of aflatoxin B1 exposure

Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of pâ unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radicalâ trapping antioxidants; more so than the phenols from which they are derivedâ or transformed toâ despite the fact that they do not possess a labile Hâ atom for transfer to the peroxyl radicals that propagate autoxidation.Chinonmethidâ Dimere wurden durch milde anodische Oxidation vermittelt durch eine preiswerte und leicht verfügbare Aminbase mit exzellenter Ausbeute und Regiokontrolle hergestellt. Diese Strategie ermöglicht raschen Zugang zu Zwischenprodukten für die katalytische Synthese von Phenylpropenoidâ Oligomeren und bietet ein neues Werkzeug für die Totalsynthese dieser komplexen Moleküle.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/1/ange201810870.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/2/ange201810870_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/3/ange201810870-sup-0001-misc_information.pd

Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of pâ unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radicalâ trapping antioxidants; more so than the phenols from which they are derivedâ or transformed toâ despite the fact that they do not possess a labile Hâ atom for transfer to the peroxyl radicals that propagate autoxidation.Quinone methide dimers are prepared via mild anodic oxidation mediated by a cheap and readily available amine base with excellent yield and regiocontrol. This strategy provides rapid access to intermediates for the synthesis of phenylpropenoid oligomers in a catalytic fashion, providing a new tool for the total synthesis of these complex molecules.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/1/anie201810870-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/2/anie201810870_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/3/anie201810870.pd

Phosphorylation regulates targeting of cytoplasmic dynein to kinetochores during mitosis

Cytoplasmic dynein functions at several sites during mitosis; however, the basis of targeting to each site remains unclear. Tandem mass spectrometry analysis of mitotic dynein revealed a phosphorylation site in the dynein intermediate chains (ICs) that mediates binding to kinetochores. IC phosphorylation directs binding to zw10 rather than dynactin, and this interaction is needed for kinetochore dynein localization. Phosphodynein associates with kinetochores from nuclear envelope breakdown to metaphase, but bioriented microtubule (MT) attachment and chromosome alignment induce IC dephosphorylation. IC dephosphorylation stimulates binding to dynactin and poleward streaming. MT depolymerization, release of kinetochore tension, and a PP1-γ mutant each inhibited IC dephosphorylation, leading to the retention of phosphodynein at kinetochores and reduced poleward streaming. The depletion of kinetochore dynactin by moderate levels of p50(dynamitin) expression disrupted the ability of dynein to remove checkpoint proteins by streaming at metaphase but not other aspects of kinetochore dynein activity. Together, these results suggest a new model for localization of kinetochore dynein and the contribution of kinetochore dynactin

Inhibition of the Pim1 oncogene results in diminished visual function

Our objective was to profile genetic pathways whose differential expression correlates with maturation of visual function in zebrafish. Bioinformatic analysis of transcriptomic data revealed Jak-Stat signalling as the pathway most enriched in the eye, as visual function develops. Real-time PCR, western blotting, immunohistochemistry and in situ hybridization data confirm that multiple Jak-Stat pathway genes are up-regulated in the zebrafish eye between 3-5 days post-fertilisation, times associated with significant maturation of vision. One of the most up-regulated Jak-Stat genes is the proto-oncogene Pim1 kinase, previously associated with haematological malignancies and cancer. Loss of function experiments using Pim1 morpholinos or Pim1 inhibitors result in significant diminishment of visual behaviour and function. In summary, we have identified that enhanced expression of Jak-Stat pathway genes correlates with maturation of visual function and that the Pim1 oncogene is required for normal visual function.Jun Yin, Lisa Shine, Francis Raycroft, Sudhakar Deeti, Alison Reynolds, Kristin M. Ackerman, Antonino Glaviano, Sean O'Farrell, Olivia O'Leary, Claire Kilty, Ciaran Kennedy, Sarah McLoughlin, Megan Rice, Eileen Russell, Desmond G. Higgins, David R. Hyde, Breandan N. Kenned

Targeting cancer cell death with a bcl-x S adenovirus

Transformation is a complex cellular process that requires several genetic abnormalities. In many cases, one of these abnormalities is an inhibition of PCD, which provides a selective advantage for tumor cells. This has been recently shown in an in vivo model, where overexpression of Bcl-x L is a crucial step in the progression from hyperplasia to neoplasia and is accompanied by a significant decrease in tumor apoptosis [56].Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46936/1/281_2004_Article_BF00787225.pd