It has been previously described that p21 functions not only as a CDK inhibitor but also as a transcriptional co-repressor in some systems. To investigate the roles of p21 in transcriptional control, we studied the gene expression changes in two human cell systems. Using a human leukemia cell line (K562) with inducible p21 expression and human primary keratinocytes with adenoviral-mediated p21 expression, we carried out microarray-based gene expression profiling. We found that p21 rapidly and strongly repressed the mRNA levels of a number of genes involved in cell cycle and mitosis. One of the most strongly down-regulated genes was CCNE2 (cyclin E2 gene). Mutational analysis in K562 cells showed that the N-terminal region of p21 is required for repression of gene expression of CCNE2 and other genes. Chromatin immunoprecipitation assays indicated that p21 was bound to human CCNE2 and other p21-repressed genes gene in the vicinity of the transcription start site. Moreover, p21 repressed human CCNE2 promoter-luciferase constructs in K562 cells. Bioinformatic analysis revealed that the CDE motif is present in most of the promoters of the p21-regulated genes. Altogether, the results suggest that p21 exerts a repressive effect on a relevant number of genes controlling S phase and mitosis. Thus, p21 activity as inhibitor of cell cycle progression would be mediated not only by the inhibition of CDKs but also by the transcriptional down-regulation of key genes.

Background: Myc is an oncogenic transcription factor that is frequently deregulated in cancer, and Sin3b is a transcriptional regulator that recruits histone deacetylases. Results: A new interaction between the protein Sin3b and Myc that leads to Myc down-regulation is described. Conclusion: Sin3b-Myc interaction regulates Myc levels and activity. Significance: Sin3b adds a second level of control of Myc by directly regulating Myc levels.

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Chediak-Higashi syndrome (CHS) is an autosomal recessive disease characterized by the presence of abnormally large cytoplasmic organelles in all body granule producing cells. The molecular mechanism for this disease is still unknown. Functional disorders in membrane-related processes have been reported. Erythrocyte membranes from four CHS patients and 15 relatives including obligatory heterozygous were studied to examine potential alterations in the lipid and fatty acid profile of erythrocyte membranes associated with this syndrome. Plasma concentrations of cholesterol, triglycerides, phospholipids, and apolipoproteins AI and B100, and the lipid components of very low-, intermediate-, low- and high-density lipoproteins were also determined. CHS erythrocyte membranes were found to be enriched with lipids in relation to protein and to show: (1) an increase in cholesterol and choline-containing phospholipids (sphingomyelin and phosphatidylcholine) that predominate in the outer monolayer, which is higher than the increase in phosphatidylserine and phosphatidylethanolamine, that are chiefly limited to the inner monolayer in normal red blood cells; (2) a relative palmitic acid and saturated fatty acid increase and arachidonic acid and unsaturated fatty acid decrease, this resulting in a lower unsaturation index than controls. Changes in CHS erythrocyte membrane lipids seem to be unrelated to serum lipid disorders as plasma lipid and apolipoprotein concentrations were apparently in the normal range, with the exception of a modest hypertriglyceridemia in patients and relatives and a decreased concentration of HDL cholesterol in patients. These findings indicate that CHS erythrocyte membranes contain an abnormal lipid matrix with which membrane proteins are defectively associated. The anomalous CHS membrane composition can be explained on the postulated effects of the CHS1/Lyst gene.

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Objective: To determine the possible differences in lipid, thrombogenic and inflammatory marker concentrations and the presence of chronic and acute coronary artery disease (stable and unstable angina, respectively), comparing them with a group of control patients with normal coronary arteries. Material and Methods: This prospective cohort study included 125 patients with unstable angina, 189 with stable angina and a control group of 83 patients with normal coronary arteries. Marker concentrations were measured in all 3 groups. Logistic regression analysis was performed to determine whether such factors could predict unstable or stable angina. Results: Lipid parameter concentrations were similar in the 2 coronary disease groups and significantly lower than in controls. Haemostatic and inflammatory marker concentrations were higher in patients with coronary disease, but were statistically significant only when comparing unstable angina patients with normal controls. Unstable angina patients had significantly higher levels of lipoprotein (a) [Lp(a)], fibrinogen, C-reactive protein (CRP) and leucocytes. Multiple logistic regression analysis showed that CRP (OR 2.635, 95% CI 1.417–4.898), smoking (OR 3.416, 95% CI 1.773–6.584), leucocytes (OR 2.034, 95% CI 1.079–3.836) and Lp(a) (OR 2.269, 95% CI 1.188–4.334) were independent risk factors of unstable versus stable angina. Conclusions: Patients with unstable angina present a more atherogenic profile than patients with stable angina. Together with smoking, elevated Lp(a), CRP and leucocyte concentrations proved to be associated with the presence of unstable angina.

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