A CRAF/glutathione-S-transferase P1 complex sustains autocrine growth of cancers with and mutations.

The Ras/RAF/MEK/ERK pathway is an essential signaling cascade for various refractory cancers, such as those with mutant (m) and (m). However, there are unsolved ambiguities underlying mechanisms for this growth signaling thereby creating therapeutic complications. This study shows that a vital component of the pathway CRAF is directly impacted by an end product of the cascade, glutathione transferases (GST) P1 (GSTP1), driving a previously unrecognized autocrine cycle that sustains proliferation of m and m cancer cells, independent of oncogenic stimuli.

Drug- and Drug Abuse-Associated Hyperbilirubinemia: Experience With Atazanavir.

Hyperbilirubinemia is a common finding in individuals with a history of substance abuse. Although this may indicate a serious disorder of liver function, this is not always the case. An understanding of bilirubin formation, metabolism, and transport can provide a helpful approach to dealing with these patients.

Reaction mechanisms of allicin and allyl-mixed disulfides with proteins and small thiol molecules.

Allylsulfides from garlic are chemopreventive agents. Entering cells they are expected to initially interact with glutathione. Accordingly, reaction mechanisms of the product, S-allylthio-glutathione, with model proteins and thiols were analyzed in cell free systems.

The proximal promoter governs germ cell-specific expression of the mouse glutathione transferase mGstm5 gene.

To explain the tissue-selective expression patterns of a distinct subclass of glutathione S-transferase (GST), transgenic mice expressing EGFP under control of a 2 kb promoter sequence in the 5'-flanking region of the mGstm5 gene were produced. The intent of the study was to establish whether the promoter itself or whether posttranscriptional mechanisms, particularly at the levels of mRNA translation and stability or protein targeting, based on unique properties of mGSTM5, determine the restricted expression pattern. Indeed, the transgene expression was limited to testis as the reporter was not detected in somatic tissues such as brain, kidney or liver, indicating that the mGstm5 proximal promoter is sufficient to target testis-specific expression of the gene.

Transition state model and mechanism of nucleophilic aromatic substitution reactions catalyzed by human glutathione S-transferase M1a-1a.

An active site His107 residue distinguishes human glutathione S-transferase hGSTM1-1 from other mammalian Mu-class GSTs. The crystal structure of hGSTM1a-1a with bound glutathione (GSH) was solved to 1.9 A resolution, and site-directed mutagenesis supports the conclusion that a proton transfer occurs in which bound water at the catalytic site acts as a primary proton acceptor from the GSH thiol group to transfer the proton to His107.

A subclass of mu glutathione S-transferases selectively expressed in testis and brain.

A subclass of glutathione S-transferases (GSTs), exemplified by the human hGSTM3 and rodent GSTM5 subunits, has properties that distinguish it from other Mu class GSTs. Thus, they originate from single copy genes that are in an inverted order and, apart from the coding regions, share little sequence homology relative to the others in the Mu cluster. The genes for this M3/M5 subgroup encode for proteins that are in many ways unique, including their extended lengths with key amino acid substitutions.

Nomenclature for mammalian soluble glutathione transferases.

The nomenclature for human soluble glutathione transferases (GSTs) is extended to include new members of the GST superfamily that have been discovered, sequenced, and shown to be expressed. The GST nomenclature is based on primary structure similarities and the division of GSTs into classes of more closely related sequences. The classes are designated by the names of the Greek letters: Alpha, Mu, Pi, etc.

Diverse expression profiles of glutathione-S-transferase subunits in mammalian urinary bladders.

The hGSTM1 null genotype has been associated with increased susceptibility to urinary bladder cancer. However, the extent to which the GSTM1 subunit actually contributes to GST activities in mammalian urinary bladders is not clear. For adult mice, urinary bladders exhibited GST activity which was among the highest observed in the tissues tested.

Glutathione S-transferase hGSTM3 and ageing-associated neurodegeneration: relationship to Alzheimer's disease.

Glutathione S-transferases (GSTs) are detoxification enzymes that can counter ageing-associated oxidative and chemical stresses. The transcript of a distinct subclass of human GSTs (hGSTM3) was shown by RNA blot analysis to be widely distributed in different regions of adult brain. HPLC profiles indicated that the hGSTM3 subunit was the second most abundant GST subunit in brain.

Selective expression of glutathione S-transferase genes in the murine gastrointestinal tract in response to dietary organosulfur compounds.

A short-term feeding regimen was designed to analyze the effects of compounds such as diallyl disulfide (DADS), diallylthiosulfinate (allicin) from garlic and butylated hydroxyanisole (BHA) on glutathione S-transferase (GST) expression in the gastrointestinal tract and liver of male mice. After animals were force-fed these compounds, tissue GSTs were purified and individual subunits resolved by HPLC and identified on the basis of mass spectrometry (ESI MS) and immunoreactivity data. The effects of DADS and allicin on GST expression were especially prominent in stomach and small intestine, where there were major coordinate changes in GST subunit profiles.