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Identifier

000364012

Title

Μεταγραφική ρύθμιση γονιδίων που συμμετέχουν στον μεταβολισμό της HDL από πυρηνικούς υποδοχείς ορμονών και μέλη της οικογένειας Forkhead box (FOX)

Alternative Title

Negative cross talk between Forkhead box (FOX) and hormone nuclear receptors: Implication for the regulation of genes involved in HDL metabolism

Author

Κανάκη, Μαρία

Thesis advisor

Καρδάσης, Δημήτρης
Τσατσάνης, Χρήστος
Τζαμαρίας, Δημήτρης

Abstract

There is accumulating evidence that HDL levels in plasma are inversely related with the risk of developing coronary heart disease. Efforts are currently in progress to increase the expression of genes that are involved in the biosynthesis and metabolism of HDL, such as the apolipoproteins, the cholesterol and phospholipid transporters and the HDL remodeling enzymes. The transcriptional regulation of these genes is mediated mainly by members of the hormone nuclear receptor gene superfamily and especially by LXRs (Liver X Receptors). One of these LXR target genes is the ABCA1 transporter which plays a key role in the biogenesis of HDL by promoting the efflux of cellular cholesterol and phospholipids to lipid‐poor apolipoprotein A‐I. Recent data from our laboratory show that the hepatic transcription factor FOXA2, which belongs to the forkhead box (FOX) family, is a negative regulator of ABCA1 gene transcription in hepatic cells. FOXA2 binds to the ABCA1 promoter and inhibits the induction of ABCA1 gene by LXRa/RXRa heterodimers and their ligands (oxysterols and retinoids). The goal of the present master’s thesis was to study the mechanism of inhibition of ABCA1 gene transcription, as well as of other genes that are implicated in HDL metabolism, by FOXA2. To achieve this goal, we investigated potential physical interactions between FOXA2 and the nuclear receptor LXRa by utilizing protein‐protein interaction assays in vitro and ex vivo. We found that these transcription factors interact physically and this interaction may account for the negative cross talk between LXR and FOXA2 on the ABCA1 gene. The domain of LXRa that is responsible for the interaction with FOXA2 is the DNA binding domain plus an additional small region of the A/B domain. LXRa also interacts physically with FOXO1, which is another member of the FOX transcription factor family that resembles FOXA2 in its negative regulation by the insulin/AKT/PKB pathway. Furthermore, we showed that FOXA2 interacts physically with other members of the nuclear receptor family such as RARα, HNF4α, LXRβ, FXR, TRβ1, RXRα and may thus act as a general regulator of the activity of hormone nuclear receptors and their target genes. This was established by showing that FOXA2 inhibits apolipoprotein CIII and AI gene induction by HNF4a. A second goal of this thesis was the construction of plasmid vectors that express shRNAs for the nuclear receptors LXRα and LXRβ. The ultimate goal is to identify genes that are specifically regulated by one or the other LXR isoform and their utilization as tools to increase plasma HDL levels. Overall, understanding the mechanisms that regulate the expression of ABCA1 and of other genes involved in HDL metabolism, is anticipated to lead to the development of new molecules that will increase HDL levels and will decrease the risk of developing atherosclerosis and coronary heart disease.

Language

Greek

Subject

ABCA1

FOXA1

FOXA2

LXRa

LXRb

Suppressive regulation

Κατασταλτική ρύθμιση

Issue date

2011-03-18