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J Lanfear

Publications and source records attributed to J Lanfear.

11 recordsLinked to original sources
PubMed1997

Chemopreventive and growth inhibitory effects of selenium.

There is very convincing evidence that a high dietary level of selenium substantially reduces the incidence of a wide variety of animal cancers. The human epidemiological evidence is less clear cut, but overall suggests that selenium may be protective: the evidence is strongest in men in relation to gastro-intestinal cancers. There is evidence that dietary selenium compounds reduce the formation of DNA adducts by carcinogens. Selenium compounds also inhibit growth in vitro and induce apoptosis. In general, there is a good correlation between the effectiveness of selenium compounds in chemoprevention and growth inhibition, implying that the mechanisms of growth inhibition and chemoprevention may be similar and that a major factor in the chemopreventive effects of selenium compounds in vivo is their ability to retard outgrowth of pre-malignant cells. Various hypotheses have been advanced as to how selenium compounds might prevent tumour cell growth. One is that they cause apoptosis by inducing oxidative stress. However, we have shown that the most potent selenium compound, selenodiglutathione (SDG), a natural metabolite of selenite, does not induce oxidative stress, at least not in the same way as other oxidants such as H2O2 and diamide. Firstly, a partially selenium-resistant variant cell line does not show increased resistance to H2O2. Moreover, SDG does not induce widespread tyrosine phosphorylation, including MAP and SAP kinases, like other oxidants such as H2O2 and diamide and its effects are not reversed by pretreatment with the tyrosine kinase inhibitor, herbimycin. Our experiments with the selenium-resistant variant suggest that a novel selenium-binding protein may be involved in growth inhibition by selenium.

Anticarcinogenic Agents↗
PubMed1995

Altered selenium-binding protein levels associated with selenium resistance.

Our previous studies have sought to elucidate the mechanism by which selenium inhibits cell growth since the mechanisms involved may be relevant to the chemopreventive properties of selenium. In a previous report, we described the isolation of a selenium-resistant cell line, B19, from a selenium-sensitive parental cell line, C57. In this report we identify biochemical changes that may be responsible for conferring selenium resistance. Altered selenium uptake and intracellular glutathione concentrations were eliminated as possible modes of resistance since these two parameters were similar between the two cell lines. However, when the selenium-containing protein complements of the two cell lines were compared by labelling with [75Se]selenite, both increases and decreases in a number of selenium-labelling proteins were found in the B19 cells. The most striking differences were the presence of two 72 kDa selenium-labelling proteins in B19 cells which could not be detected in C57 cells. The levels of a number of mRNAs encoding antioxidant or detoxification enzymes were also compared between the two cell lines but only minor changes were found. This work suggests that further analysis of the 72 kDa selenium-labelling proteins may reveal insights into the mechanisms of growth inhibition by selenium.

Animals↗
PubMed1995

The selenium metabolite selenodiglutathione induces cell death by a mechanism distinct from H2O2 toxicity.

Our previous studies have implicated the selenium metabolite selenodiglutathione (SDG) in the growth inhibitory effects of selenite in vitro. Other work has suggested that reactive oxygen species, the superoxide anion and hydrogen peroxide, may be implicated in selenite toxicity. In this study the mechanism of growth inhibition by SDG and H2O2 has been compared in a mammary cell line, C57. Both SDG and H2O2 had a rapid effect on C57 cells and markedly reduced cloning efficiency within 1 h. However, the mechanisms involved seem to be different, as judged by the following observations: (i) An SDG-resistant cell line (B19) derived from C57 cells is cross-resistant to selenite, but not H2O2; (ii) SDG reduces the levels of the mRNAs for phospholipid hydroperoxide glutathione peroxidase and cytosolic glutathione peroxidase, whereas H2O2 has no effect; (iii) SDG induces both 560 kb and 50 kb DNA fragments, whereas H2O2 only induces 560 kb DNA fragments. This is of interest, since formation of high molecular weight DNA fragments has been recognized as a characteristic of apoptosis.

Animals↗
PubMed1994

The selenium metabolite selenodiglutathione induces p53 and apoptosis: relevance to the chemopreventive effects of selenium?

Selenodiglutathione (SDG), the initial metabolite of selenite, is shown to be a more powerful inhibitor of cell growth in vitro than selenite itself. This has been established both with mouse erythroleukaemia (MEL) cells and an ovarian cell line (A2780) which is known to contain wild-type p53. Other seleno-compounds, such as selenomethyl selenocysteine (SMS) and dimethyl selenoxide (DMS), which are potent chemopreventive agents and are known to be metabolized to methylated selenium derivatives directly rather than via SDG, are also growth inhibitory to both MEL and A2780 cells, although less so than SDG or selenite. However, cells growth-inhibited by DMS are more viable than cells growth-inhibited to the same extent by SDG or selenite, suggesting that the methylated seleno-compounds may inhibit cell growth in a different manner from that of SDG or selenite. Our studies of the mechanism of growth inhibition by SDG, have established two facts. First, SDG induces p53 protein levels in cells that contain wild-type p53 (A2780 cells), suggesting that SDG induces the DNA damage-recognition pathway. Secondly, SDG induces apoptosis in MEL cells, as judged by flow cytometry and formation of nucleosomal DNA ladders. However, since p53 mutations have been found to be targetted events in all MEL cells examined, our evidence suggests that induction of apoptosis by SDG is not absolutely dependent on the p53 response pathway.

Animals↗
PubMed1993

Different patterns of regulation of the genes encoding the closely related 56 kDa selenium- and acetaminophen-binding proteins in normal tissues and during carcinogenesis.

A full-length cDNA encoding a 56 kDa liver protein recently implicated in the detoxification of acetaminophen (AP56) has been cloned by virtue of its similarity to the 56 kDa selenium-binding protein (SP56): in fact, the deduced AP56 amino acid sequence differs at only 14 residues from SP56. Isolation of genomic DNA recombinants from a Balb/c mouse cosmid genomic DNA library shows that SP56 and AP56 are encoded by two different genes. Using reverse transcription/PCR with oligonucleotide primers that distinguish the AP56 and SP56 mRNAs shows that the SP56 mRNA is highly expressed in liver, kidney and, to a lesser extent, lung; whereas the AP56 mRNA is mainly expressed in liver. Both mRNAs tend to be down-regulated in liver cell lines but remain high in DEN-induced liver tumours in vivo. The relevance of these findings is evaluated in terms of the postulated functions of the two proteins in mediating the anti-carcinogenic effects of selenium and detoxification mechanisms.

Acetaminophen↗
PubMed1991

Cloning of segment polarity gene homologues from the unsegmented brachiopod Terebratulina retusa (Linnaeus).

We have used the polymerase chain reaction (PCR) to amplify, clone and sequence homologues of the Drosophila segment polarity genes engrailed (en), cubitus interruptus Dominant (ciD) and wingless (wg) from the genome of the brachiopod, Terebratulina retusa (Linnaeus). The deduced translation products of brachiopod en and ciD share high levels of sequence identity with their Drosophila homologues. The brachiopod wg-related clone is divergent from Drosophila wg, although clearly a member of the wg/Wnt gene family. These results indicate that structural diversity of Drosophila segment polarity genes has been evolutionarily conserved in a divergent, ancient and unsegmented animal phylum.

Amino Acid Sequence↗
PubMed1991

Cloning of fish zinc-finger genes related to Krox-20 and Krox-24.

Southern hybridization suggests that the zebrafish genome contains multiple zinc-finger genes related to the putative mouse developmental genes, Krox-20 and Krox-24. The polymerase chain reaction was employed to amplify and clone the zinc-finger regions of genes related to Krox-20, from two fish species and, for comparison, mouse, hamster and fox. DNA sequence analyses suggest that the genes cloned include the guppy homologue of Krox-20 and the zebrafish homologue of Krox-24, and that these genes diverged prior to the separation of the lineages leading to teleosts and to mammals.

Amino Acid Sequence↗
PubMed1991

The molecular evolution of ZFY-related genes in birds and mammals.

We report the isolation and nucleotide sequence determination of clones derived from five ZFY-related zinc-finger genes from birds and mammals. These sequences are analyzed with reference to the previously published human genes, ZFX and ZFY, and mouse genes, Zfx, Zfa, Zfy-1, and Zfy-2. The analysis indicates that ZFY-related genes are highly conserved in birds and mammals, and that the rate of nucleotide substitution in the Y-linked genes is not as high as predicted. However, the mouse Zfy-1 and Zfy-2 genes are markedly divergent members of the ZFY gene family; we suggest this relates to X-inactivation of the mouse gene Zfx.

Amino Acid Sequence↗