The p53 tumor suppressor gene: structure, function and mechanism of action.
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Animals↗
Biomedical subjects
P Reisdorf
Publications and source records attributed to P Reisdorf.
Mechanisms of p53-induced apoptosis: in search of genes which are regulated during p53-mediated cell death.
The tumor suppressor gene p53 is a major player in the protection of cells from DNA damage. In the majority of human cancers, p53 is functionally inactivated--mostly by mutations but also by interaction with viral or cellular proteins. Wild-type p53 is involved in essential functions such as DNA repair, transcription, genomic stability, senescence, cell cycle control and apoptosis. It was shown to be a sequence-specific transcriptional activator, and this activity appears to be necessary to impose growth arrest. A major target gene which participates in p53-mediated growth arrest is p21/Waf1, an inhibitor of cyclin-dependent kinases. Whether or not transcriptional activation of target genes is required for p53-mediated apoptosis may depend on the cell type and external factors, and the mechanism of cell death induction is not clear yet. We have employed clones of the M1 myeloid leukemic cell line expressing a temperature-sensitive p53 mutant to study genes which are regulated during p53-induced apoptosis.
Animals↗
The MBR1 gene from Saccharomyces cerevisiae is activated by and required for growth under sub-optimal conditions.
The MBR1 gene was isolated as a multicopy suppressor of the phenotype on glycerol medium of a Saccharomyces cerevisiae strain mutant for the Hap2/3/4/5 transactivator complex. In this paper, we show that Mbr1p is a limiting factor for growth on glycerol medium under the following sub-optimal culture conditions: in late growth phase, at low temperature, at high external pH or in the presence of 1,10-phenanthroline. Moreover, deletion of MBR1 protects cells against stress, whilst overexpression of this gene has the opposite effect. MBR1 expression is induced in the late growth phase and is negatively controlled by the cAMP-dependent protein kinase A (PKA). Both activation of PKA or overexpression of SOK1 or SCH9-two genes isolated as multicopy suppressors of a PKA null mutant-suppress the mbr1 growth defect. Our results indicate that Mbr1p is not an essential element of any one of these pathways. Deletion of SAC1, a gene implicated in vesicular transport, in association with MBR1 deletion, causes synthetic lethality. A possible role of Mbr1p in intracellular trafficking is discussed.
Bacterial Proteins↗
MBR1 and MBR3, two related yeast genes that can suppress the growth defect of hap2, hap3 and hap4 mutants.
Two new yeast genes, named MBR1 and MBR3, were isolated as multicopy suppressors of the growth defect of a strain lacking the HAP2 transcriptional activator. Both genes when overexpressed can also suppress the growth defect of hap3 and hap4 null mutants. However, overexpression of MBR1 cannot substitute for the HAP2/3/4 complex in activation of the CYC1 gene. Nucleotide sequencing of MBR1 and MBR3 revealed that these two genes encode serine-rich, hydrophilic proteins with regions of significant homology. The functional importance of one of these conserved regions was shown by mutagenesis. Disruption of MBR1 leads to a partial growth defect on glycerol medium. Disruption of MBR3 has no major effect but the double disruptant shows a synthetic phenotype suggesting that the MBR1 and MBR3 gene products participate in common function.
Amino Acid Sequence↗
Enhanced in vivo monooxygenase activities of mammalian P450s in engineered yeast cells producing high levels of NADPH-P450 reductase and human cytochrome b5.
We have engineered yeast genomic DNA to construct a set of strains producing various relative amounts of yeast NADPH-P450 reductase (Yred) and human cytochrome b5 (Hb5). Expression of cDNAs encoding human P450 1A1, 1A2, 3A4, 19A and mouse P450 1A1 in the different oxido-reduction backgrounds thus constituted were achieved after strain transformation by plasmid-based P450-encoding expression cassettes. The results indicate that the level of Yred strongly affects all activities tested. In contrast, the amount of Hb5 affects activities in a manner that is dependent both on the P450 isoform considered and the Yred level. In a strain containing optimized amounts of Hb5 and Yred, human P450 3A4-specific testosterone-6 beta-hydroxylase activity can be enhanced as much as 73-fold in comparison with the activity observed in a wild-type strain. Bioconversion of sterols or xenobiotics was easily achieved in vivo using this new co-expression system.
Animals↗
Epitope-tagging vectors designed for yeast.
In order to facilitate the process of epitope-tagging of yeast proteins, we have constructed two Saccharomyces cerevisiae-Escherichia coli shuttle vectors that allow fusion of a sequence encoding an epitope of the human c-myc protein at the 3' end of any gene. An example of the use of this technique is presented.
Amino Acid Sequence↗
Individual differences in bridging inference processes.
The role of individual differences in bridging-inference processing was studied. Students (n = 135) read passages of short to moderate length. After each one, they answered corresponding questions about inferences that bridged causally related ideas that were either near or far apart in the text. The main hypothesis was that local bridging-inference processing is facilitated by the reader's predisposition to access pertinent knowledge during comprehension. Regression analyses provided support for this proposal and indicated that greater working-memory capacity and vocabulary knowledge promote inference processing. The following relationships between the predictors and inference processing were proposed: Knowledge access promotes the co-occurrence in working memory of the text ideas and knowledge needed to compute the bridge. Working-memory capacity enhances the likelihood that needed antecedent ideas will be available to the bridging processes. Vocabulary knowledge may promote inference processing because unfamiliar word meanings place more demands on working-memory resources than do familiar meanings.
Adult↗