New rapamycin derivatives by precursor-directed biosynthesis.
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Carboxylic Acids↗
Biomedical subjects
Su Metcalfe
Publications and source records attributed to Su Metcalfe.
The interaction of p53 with the nuclear matrix is mediated by F-actin and modulated by DNA damage.
The tumour suppressor protein p53 is localized in the cell nucleus where it serves to initiate cellular responses to a variety of stresses, particularly DNA damage and has the capacity to transactivate stress response genes. An emerging body of evidence indicates that its action is also exerted through direct protein-protein interactions. An approach to understanding p53 function has been to analyse its positioning in relation to nuclear structures and we have shown that p53 can associate with the nuclear matrix. A potential nuclear matrix component for this association is actin. Here we show that p53 interacts with nuclear F-actin and we map the domains involved in this interaction. Using fluorescence resonance energy transfer, we demonstrate that the partition of p53 between F-actin bound and unbound forms is not constant, but is modulated by the presence of DNA damage, which increases binding. Our results indicate that the dynamic interaction of p53 with the nuclear matrix has to be considered for a full understanding of the mechanisms of the p53-mediated cellular response to DNA damage.
3T3 Cells↗
Genetic control of IL-1beta bioactivity through differential regulation of the IL-1 receptor antagonist.
Regulation of IL-1 bioactivity by the IL-1 receptor antagonist (IL-1Ra) is critical for the preservation of normal vascular structure and function in mice. In humans, IL-1 bioactivity may be further fine-tuned by genetic polymorphisms. We recently proposed that an intronic polymorphism of the human gene encoding the IL-1R antagonist (IL1RN) is a genetic risk factor for the development of chronic cardiac allograft rejection. Here we aimed to establish a physiological basis for this susceptibility. Plasma and peripheral blood mononuclear cells (PBMC) were obtained from 55 healthy human volunteers, whose genotypes for four polymorphisms of IL1 family genes (IL1B, IL1R1 and IL1RN) were determined by PCR. IL-1beta and IL-1Ra production and release in PBMC cultures were studied by flow cytometry and ELISA. Functional and genotypic data were pooled and analyzed first by multivariate and, subsequently, by univariate statistical tests. We were able to confirm our observed association of IL1RN genotype with chronic cardiac allograft rejection using multivariate statistics. IL1RN genotype also emerged as the principal regulator of both constitutive and stimulated IL-1Ra and IL-1beta release. Allele IL1RN*2 was consistently associated with higher IL-1Ra and lower IL-1beta release, in a dosage-dependent manner. Conversely, IL1RN*2 carriage was associated with reduced production of the intracellular isoform of IL-1Ra. These genotypic effects were only observed with prolonged culture prior to stimulation and were not appreciably influenced by the presence of exogenous modulators of IL-1beta production. We conclude that IL1RN genotype is the principal determinant of IL-1beta bioactivity within theIL1 gene cluster in humans and discuss its putative role in disease.
Adult↗