分子遺伝医学

The mdm2 gene encodes several protein isoforms with different molecular weights (p90, p80, p76 and p57). MDM2 p90 (usually considered to be the major MDM2 protein) binds to and inactivates P53. We have recently shown that growth inhibition of MCF-7 human breast cancer cells by progesterone is associated with P53 down-regulation. In this work, we analyzed the expression pattern of MDM2 proteins in three human breast cancer cell lines by western blotting with anti-MDM2 antibodies. We found a prominent expression of MDM2 p57 protein in cell lines which have non-functional P53 protein (T47D and MDA-MB-231) as compared to the p90, p80 isoforms, whereas p90 was the major protein isoform in MCF-7 cells that contain functional P53 protein. When MCF-7 cells were treated with 100 nM of progesterone, MDM2 p90 was inhibited but the highly expressed MDM2 p57 isoform was not. The inhibition of MDM2 p90 protein by progesterone was abrogated in MCF-7 cells transfected with a P53 expressing vector. To our knowledge, this is the first report linking progesterone-induced growth inhibition with down-regulation of the MDM2 protein. We present evidence that reestablishing of P53 expression by transient transfection of P53 cDNA in these cells enhances the expression level of MDM2 p90 isoform. The data indicate that expression of MDM2 p90 is regulated through a P53-dependent pathway in response to progesterone

Pakistanis belong to the South Asian population which has the highest known rate of coronary artery disease. Folic acid deficiency also appears to be highly prevalent in this population. Methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism decreases the activity of this enzyme and can be associated with mild to moderate hyperhomocysteinemia in homozygotes, particularly when there is folic acid deficiency, as well as with coronary artery disease. To assess the value of genotyping the MTHFR 677C>T dimorphism, we carried out a case-control study of dimorphism 677C>T for putative association with myocardial infarction (MI) among Pakistani nationals. We investigated a sample population of 622 Pakistanis consisting of 225 controls and 397 patients with clinical diagnosis of acute MI (AMI). MTHFR C677T alleles were determined by assays based on polymerase chain reaction and restriction endonuclease analysis. Frequencies of C alleles were 0.87 among controls and 0.86 among AMI patients. The MTHFR 677C>T dimorphism showed no association with MI (
2 = 0.25, 1df, P=0.62), serum levels of folate and vitamin B12 and plasma level of vitamin B6. A significant association, however, was found between homozygous 677T genotype and plasma levels of homocysteine. Multivariate analysis of the data showed that in case of log homocysteine, age and MTHFR genotypes were significantly different (P<0.001). In case of B12, smoking and age were found to be statistically significant (P<0.001), while in case of serum folate only smoking was found to be significant (P<0.001). The results indicate that MTHFR 677C>T polymorphism, though associated with homocysteine levels, confers no significant risk of coronary artery disease in the Pakistani population investigated here. We suggest that the higher incidence of AMI in South Asia occurs through mechanisms other than the MTHFR related pathways

Phenylephrine (PE) induces cardiac hypertrophy through multiple signaling pathways including pathways involving protein kinase C (PKC) activation. Docosahexaenoic acid (DHA), an omega-3 fatty acid, has been shown to reduce the PE-induced hypertrophic responses. However, the effects of DHA on PKC activation and translocation are controversial. The present study investigates the effect of DHA on PE-induced activation of PKC. The results indicate that PE induces PKC@ translocation (from cytosol to plasma membranes) and activation in cardiomyocytes during the hypertrophic responses. Although DHA itself has no significant effect on basal PKC translocation and activation, it effectively reduced PE-stimulated PKC translocation and activation. The results of the present study suggest a possible mechanism explaining how dietary fish oil may inhibit development of cardiac hypertrophy and therefore may be an attractive dietary agent for preventing cardiac hypertrophy in patients with heart failure

Y-box proteins belong to the cold shock domain family of proteins that are known to be involved in both transcriptional and translational control. Here, we give a brief overview of the structure, regulation and physiological functions of the Y-box proteins. This is followed by examining the role of Y-box protein 1 (YB-1), the most extensively studied of the Y-box protein in tumorigenesis, and its clinicopathological significance. YB-1 has the potential to be a prognostic marker and predictor of chemoresistance in human cancers.

Fc receptors (FcRs) are expressed on the surface of all types of cells of the immune system. They bind the Fc portion of immunoglobulin (Ig), thereby bridging specific antigen recognition by antibodies with cellular effector mechanisms. FcγRIIA, one of the three receptors for human IgG, is a low-affinity receptor for monomeric IgG, but binds IgG immune complexes efficiently. FcγRIIA is believed to play a major role in eliciting monocyte- and macrophage-mediated effector responses against blood-stage malaria parasites. A G → A single nucleotide polymorphism, which causes an arginine (R) to be replaced with histidine (H) at position 131, defines two allotypes which difer in their avidity for complexed human IgG₂ and IgG₃. Because FcγRIIA-H131 is the only FcγR allotype which interacts efficiently with human IgG₂, this polymorphism may determine whether parasite-specific IgG₂ may or may not elicit cooperation with cellular imune responses during blood-stage malaria infection. Here, we review data from four published case-control studies describing associations between FcγRIIA R/H131 polymorphism and malaria-related outcomes and discuss possible reasons for some incongruities found in these available results.