Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ‐F1 homologue

Abstract

Nuclear receptors are master regulators of metazoan gene expression with crucial roles during development and in adult physiology. Fushi tarazu factor 1 (FTZ-F1) subfamily members are ancient orphan receptors with homologues from Drosophila to human that regulate diverse gene expression programs important for developmental processes, reproduction and cholesterol homeostasis in an apparently ligand-independent manner. Thus, developmental and tissue-specific cofactors may be particularly important in modulating the transcriptional activities of FTZ-F1 receptors. In Drosophila, the homeodomain protein Fushi tarazu acts as a cofactor for FTZ-F1 (NR5A3), leading to the hypothesis that a similar type of homeodomain cofactor-nuclear receptor relationship might exist in vertebrates. In this study, we have identified and characterized the homeodomain protein Prox1 as a co-repressor for liver receptor homologue 1 (LRH1/NR5A2), a master regulator of cholesterol homeostasis in mammals. Our study suggests that interactions between LRH1 and Prox1 may fulfil roles both during development of the enterohepatic system and in adult physiology of the liver.

Repression of interferon-γ expression in T cells by Prospero-related Homeobox protein

“…Despite its vital functions in the development of many organs and tissues and the fact that it possesses a putative homeoprospero DBD at the C-terminus, Prox1 has not been shown convincingly to bind directly to target gene DNA. Instead, previous work by others and our group has shown that Prox1 functions as a corepressor of nuclear receptor LRH-1 in the regulation of lipid catabolism-related genes [23,24]. In such a regulation mechanism, Prox1 associates with target gene promoter through binding to LRH-1, which in turn directly binds to specific binding sites on the promoter.…”

“…However, our results showed that repression by PPARγ is not significantly affected when DCS and PCS are removed from the promoter (Figure 3), indicating that c-Jun-related mechanisms may not play a major part in PPARγ-dependent repression. On the Prox1 side, its corepressor activity on other target genes has been attributed to the repression domain ( Figure 5A), which has been reported to recruit histone deacetylase 3 (HDAC3) [24]. HDAC3 activity is related to negative epigenetic regulation of gene transcription.…”

“…PPARγ is a nuclear receptor that has been identified as a trans-repressor of IFN-γ expression in Jurkat T cells [16]. Previous work by others and us has shown that Prox1 acts as a corepressor for another nuclear receptor LRH-1 by binding directly to LRH-1 to repress target gene transcription [23,24]. This led us to speculate whether similar mechanisms exist between Prox1 and PPARγ in the repression of IFN-γ expression.…”

“…Although Prox1 is a key regulator in development, very few target genes whose expression is directly affected by Prox1 have been reported. Work conducted by our lab and another group showed that, in adult hepatocytes, Prox1 acts as a corepressor of the nuclear receptor liver receptor homologue 1 (LRH-1) to regulate cholesterol catabolism [23,24].…”

Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7α-hydroxylase gene transcription

“…However, it is not known whether bile acids or drugs affect Prox1 interaction with FTF, HNF4␣, or PXR. Another recent report (28) shows that Prox1 interacts with FTF and inhibits SHP gene expression and that Prox1 specifically interacts with histone deacetylase (HDAC)3. HDACs are known to form complexes with nuclear receptors and corepressors and inhibit gene transcription (13).…”