Résumé
BACKGROUND: The study was undertaken to understand the relationship between the functional proteomics of receptor-Ck and developmental stages of human atherosclerotic aortic wall. METHODS AND RESULTS: Gene expression study of 25 aortas was undertaken and the results revealed a gradual increase in receptor-Ck gene expression paralleled by the regulatory response of its effector genes coding for sterol response element-binding protein, p27, cyclin D, interleukin-6 and CD40 from a normal to atherosclerotic arterial wall (viz. fatty streak and fibrofatty/fibrous plaque). CONCLUSIONS: Based upon this and our earlier studies, we propose that cholesterol-specific receptor-Ck-dependent gene regulation may be of crucial importance in atherogenesis.
Sujets)
Aorte/physiopathologie , Protéines liant les séquences stimulatrices de type CCAAT/génétique , Protéines de transport/génétique , Maladie des artères coronaires/génétique , Cyclines/génétique , Protéines de liaison à l'ADN/génétique , Régulation de l'expression des gènes au cours du développement/génétique , Humains , Inde , Interleukine-6/génétique , Protéines des microfilaments/génétique , Adulte d'âge moyen , Protéines du muscle , Protéomique , Récepteurs aux lipoprotéines/génétique , Protéine-1 de liaison à l'élément de régulation des stérols , Facteur-3 associé aux récepteurs de TNF , Facteurs de transcription , Protéines et peptides associés aux récepteurs des facteurs de nécrose tumoraleRésumé
The study was addressed to explore the expression and functional activity of a novel cholesterol-specific cell surface receptor-Ck in a typical homozygous familial hypercholesterolemic family. Functional activity of receptor-Ck was characterized by its ability to downregulate Bcl-2 gene expression through a 47 kDa factor having an affinity for the sterol-regulatory element in the promoter region of this gene. The result of such a study revealed normal expression and functional activity of receptor-Ck accompanied by a lack of Apolipoprotein B-specific low-density lipoprotein receptor gene expression in the mononuclear cells derived from these patients. On the basis of these results, it is tempting to speculate that receptor-Ck may be involved in the maintenance of cellular cholesterol homeostasis observed in homozygous familial hypercholesterolemic patients.
Sujets)
Adolescent , Apolipoprotéines B/génétique , Régulation négative/génétique , Santé de la famille , Régulation de l'expression des gènes/génétique , Gènes bcl-2/génétique , Homozygote , Humains , Hyperlipoprotéinémie de type II/génétique , Mâle , Récepteurs aux lipoprotéines LDL/génétique , Récepteurs aux lipoprotéines/génétique , Facteurs de transcription/génétiqueRésumé
An important feature of malignant transformation of tumours is the loss of cholesterol feedback inhibition mechanism (cholesterol-feedback lesion) that regulates mevalonate pathway recognized to play a crucial role in cellular growth, death and differentiation. Recently, it was shown that Receptor-C(k)-dependent signalling regulates genes involved in maintaining cellular cholesterol homeostasis through a transcription factor sterol response element binding protein (SREBP) having affinity for sterol regulatory element (SRE) present in the promoter region of these genes. The present study revealed that CNS tumours exhibit overexpression of Receptor-C(k) gene product which was accompanied by their inability to express SREBP gene product and this phenomenon has the inherent capacity to initiate the cholesterol feedback lesion in these tumours. Based upon these and our earlier studies, we propose for the first time that this loss of cholesterol feedback control may be responsible for the initiation of these tumours.