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Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The regulation of the CYP17A1 gene is complex. Induction of CYP17A1 has been found to be cAMP mediated and testosterone can suppress the induction of the enzyme. It has been shown that the regulation of homeodomain protein Pbx1 and protein kinase A interaction at −250/−241 is cAMP dependent. The 5′-flanking region of the CYP17A1 gene contains three functional SF1 elements that collectively mediate 25-fold or greater induction of promoter activity by SF1 (Hanley et al. 2001). In constructs containing all three functional SF1 elements, DAX1 inhibited this activation by at least 55%. In the presence of only one or two SF1 elements, DAX1 inhibition was lost although SF1 transactivation persisted.
Regulation of Cell Functions
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
Sequential expression of homeotic genes is associated with the early stages of limb bud outgrowth in the mouse, with each gene showing a graded transcript distribution along the antero-posterior axis.125 A homeodomain protein, GHF1, is required for pituitary cell proliferation in the mouse.126 Homeobox genes can organize a complete secondary body axis in the dorsal blastopore lip of the early Xenopus laevis gastrula.127 Analysis of HOX gene expression in human hematopoietic cell lines suggests that these genes are switched on or off in blocks at various stages of hematopoietic cell differentiation.128 Lineage- and stage-specific expression of HOX1 genes occurs in the human hematopoietic system.129 Modulation of HOX1 gene expression alters the phenotype of human hematopoietic cell lines.130 A coordinate regulation of HOX genes may play a very important role in lineage determination during early stages of hematopoiesis.
Introduction
Published in Emmanuel Opara, NUTRITION and DIABETES, 2005
Activation of intracellular repair and β-cell proliferation systems can also be considered among mechanisms rescuing oxidative damage of insulin secretion (see The GSIS-ROS Hypothesis and Repair Problems). Such agents are proposed for treatment of both type 1 and type 2 diabetes [71]. For example, Glucagon-like peptide-1 (GLP-1) agonists exert multiple effects on pancreatic β-cells [72]. Mounting evidence suggests that GLP-1 signaling stimulates β-cell proliferation acting through an activation of the homeodomain protein PDX-1 and IRS2 pathway [66, 71].
A transcriptional regulatory network of HNF4α and HNF1α involved in human diseases and drug metabolism
Published in Drug Metabolism Reviews, 2022
Jianxin Yang, Xue Bai, Guiqin Liu, Xiangyang Li
Hepatic gene expression usually requires a large number of liver-enriched transcription factors (LETFs) binding to promoters. LETFs like HNF4α and HNF1α play a major role in regulating drug absorption, distribution, metabolism, and excretion (ADME) genes in the liver and gastrointestinal tract, the major sites of drug metabolism (Gardner-Stephen and Mackenzie 2008). Extensive correlations exist among TFs, DMEs, and DTs (Wortham et al. 2007). One study showed that HNF4α, HNF1α, and pregnane X receptor (PXR) are central nodes in the gut-liver-kidney regulatory network composed of ADME genes, including DMEs and DTs; almost 70% of these genes are obviously regulated by HNF4α and approximately 60% are regulated by HNF1α and PXR (Rosenthal et al. 2019). In addition, HNF4α and HNF1α interact with other LETFs to co-regulate ADME genes. For example, HNF4α and HNF1α regulate the expression of many UGTs, mainly through binding to cis-regulatory elements in the UGT promoter and enhancer (Hu et al. 2014). HNF4α cooperates with caudal-related homeodomain protein 2 (CDX2) in the regulation of UGT1A8, UGT1A9, and UGT1A10 expression in colon cancer cell lines (Mubarokah et al. 2018). HNF1α is also required for the UGT1A9 promoter to respond to HNF4α (Gardner-Stephen and Mackenzie 2007). Therefore, HNF4α and HNF1α are central factors in the regulation of drug metabolism-related genes (Figure 3). Main ADME (Phase I, II, III) genes regulated by HNF4α and HNF1α is summarized in Table 2.
SIX6-related anophthalmia/microphthalmia: second report on a deletion in a consanguineous family
Published in Ophthalmic Genetics, 2021
Asha Deepthi, Omar Fakhoury, Mohamad Daher, Alicia Gambarini, Stephany El-Hayek, André Megarbane
Proteins encoded by members of the SIX gene family are characterized by two evolutionarily conserved domains – a DNA binding homeobox nucleic acid recognition domain (HD) and an upstream SIX domain (SIX1 SD) that mediates protein-protein interactions (1). Generally, HDs are 60 amino acids in length and consist of a recognition helix, which has critical amino acid residues in close contact at position 47, 50, 51 and 54 (11). These residues were shown to be conserved among all the SIX proteins in flies and mice (1). The deletion reported here is predicted to affect codon 178 of Homeodomain protein SIX6, at position 51 of SIX6 HD (https://joiningdata.com/lollipops/index.html). We also compare here two previously reported variants (Figure 3) – p.Leu37Pro (c.110 T > C) and p.Thr165Ala (c.493A>G) that affect the upstream SIX domain and the HD domain, respectively.
Advances in the molecular biology and pathogenesis of congenital central hypoventilation syndrome—implications for new therapeutic targets
Published in Expert Opinion on Orphan Drugs, 2018
Simona Di Lascio, Roberta Benfante, Silvia Cardani, Diego Fornasari
Normal PHOX2B is a 314-amino acid protein that harbors a homeodomain and two polyalanine stretches of respectively 9 and 20 residues within the C-terminal domain (Figure 1). From a functional point of view, it is well established that the homeodomain is a highly conserved 60-residue region that contains the DNA-binding motif; furthermore, and in line with what has been observed in other homeodomain proteins, it also contains nuclear localization signals, it is responsible for the formation of homo- and heterodimers (with other homeoproteins, including its paralogue PHOX2A), and it establishes protein–protein interactions [56,62]. The region downstream of the homeodomain (the C-terminal domain), which contains the two polyalanine stretches and is where the majority of NPARMs are located, is an important modulator of DNA binding, homeodomain-mediated dimerization, and solubility of the protein [62].