SREBP-2 and NF-Y are involved in the transcriptional regulation of squalene epoxidase.

The expression of squalene epoxidase (SE) is highly regulated transcriptionally by cholesterol. To elucidate these molecular mechanisms, we isolated the human and rat genomic clones. The entire human SE gene was about 24 kb long and organized into 11 exons with 10 introns. Unidirectional deletion analysis of the human 5(')-flanking region indicated that the sequence between -264 and -230 bp conferred cholesterol sensitivity on a reporter gene. This region contained a potential copy of consensus sterol regulatory element (SRE) sequence (CCACGCAAC) previously identified in the promoter of cholesterogenic and its related genes. The transcriptional activation observed under overexpression of sterol regulatory element binding protein-2 (SREBP-2) supported the functional role of the SRE sequence. Another deletion analysis showed that the sequence -207 to -192 bp was also active and it contained nuclear factor Y (NF-Y) binding site. Both sites might play critical roles in sterol mediated regulation of SE gene.

[1]  R. Hammer,et al.  Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα , 1998, Cell.

[2]  J. Sakakibara,et al.  Nucleotide sequence of a cDNA for mouse squalene epoxidase. , 1995, Biochimica et biophysica acta.

[3]  J. Sakakibara,et al.  Molecular Cloning and Expression of Rat Squalene Epoxidase (*) , 1995, The Journal of Biological Chemistry.

[4]  J. Sakakibara,et al.  Purification and characterization of recombinant squalene epoxidase. , 1995, Journal of lipid research.

[5]  J. Gibbs.  Ras C-terminal processing enzymes—New drug targets? , 1991, Cell.

[6]  I. Shechter,et al.  Molecular Cloning and Functional Analysis of the Promoter of the Human Squalene Synthase Gene (*) , 1995, The Journal of Biological Chemistry.

[7]  D. Mangelsdorf,et al.  An oxysterol signalling pathway mediated by the nuclear receptor LXRα , 1996, Nature.

[8]  J. Goldstein,et al.  Regulation of the mevalonate pathway , 1990, Nature.

[9]  T. Kodama,et al.  Regulation of fatty acid synthase expression by cholesterol in human cultured cells. , 1996, Biochemical and biophysical research communications.

[10]  K. Dooley,et al.  Sterol Regulation of 3-Hydroxy-3-Methylglutaryl-coenzyme A Synthase Gene through a Direct Interaction Between Sterol Regulatory Element Binding Protein and the Trimeric CCAAT-binding Factor/Nuclear Factor Y* , 1998, The Journal of Biological Chemistry.

[11]  D. Lopez,et al.  Repression of the steroidogenic acute regulatory gene by the multifunctional transcription factor Yin Yang 1. , 2002, Endocrinology.

[12]  P. Edwards,et al.  YY1 Is a Negative Regulator of Transcription of Three Sterol Regulatory Element-binding Protein-responsive Genes* , 1999, The Journal of Biological Chemistry.

[13]  T. Satoh,et al.  Regulation of squalene epoxidase activity in rat liver. , 1990, Journal of lipid research.

[14]  D. Botstein,et al.  The transcriptional program in the response of human fibroblasts to serum. , 1999, Science.

[15]  T Kamei,et al.  Regulation of squalene epoxidase in HepG2 cells. , 1990, Journal of lipid research.

[16]  J. Sakakibara,et al.  Transcriptional Regulation of Squalene Epoxidase by Sterols and Inhibitors in HeLa Cells (*) , 1996, The Journal of Biological Chemistry.

[17]  J. R. Smith,et al.  Identification of nucleotides responsible for enhancer activity of sterol regulatory element in low density lipoprotein receptor gene. , 1990, The Journal of biological chemistry.

[18]  Y. Fukushima,et al.  Localization of the squalene epoxidase gene (SQLE) to human chromosome region 8q24.1. , 1997, Genomics.

[19]  R. Zenz,et al.  A novel sequence element is involved in the transcriptional regulation of expression of the ERG1 (squalene epoxidase) gene in Saccharomyces cerevisiae. , 2001, European journal of biochemistry.

[20]  Y. Paik,et al.  Cholesterol Biosynthesis from Lanosterol , 1999, The Journal of Biological Chemistry.

[21]  H. Sone,et al.  Sterol regulatory element-binding proteins induce an entire pathway of cholesterol synthesis. , 2001, Biochemical and Biophysical Research Communications - BBRC.

[22]  P. Edwards,et al.  Sterol regulatory element binding protein binds to a cis element in the promoter of the farnesyl diphosphate synthase gene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Rosenfeld,et al.  Sterol regulation of acetyl coenzyme A carboxylase: a mechanism for coordinate control of cellular lipid. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Timothy M. Willson,et al.  Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway* , 1997, The Journal of Biological Chemistry.

[25]  S. Chirala,et al.  Sterol regulation of human fatty acid synthase promoter I requires nuclear factor-Y- and Sp-1-binding sites. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Gelb,et al.  Geranylgeranylated proteins : Molecular and immunological approaches to the study of synaptic and axonal glycoproteins , 1992 .

[27]  M. Brown,et al.  Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. , 1983, Methods in enzymology.

[28]  P. Edwards,et al.  NF-Y Has a Novel Role in Sterol-dependent Transcription of Two Cholesterogenic Genes (*) , 1995, The Journal of Biological Chemistry.

[29]  T. Südhof,et al.  Sterol-dependent repression of low density lipoprotein receptor promoter mediated by 16-base pair sequence adjacent to binding site for transcription factor Sp1. , 1988, The Journal of biological chemistry.

[30]  R. Gardner,et al.  An Oxysterol-derived Positive Signal for 3-Hydroxy- 3-methylglutaryl-CoA Reductase Degradation in Yeast* , 2001, The Journal of Biological Chemistry.

[31]  X. Hua,et al.  Sterol-Regulated Release of SREBP-2 from Cell Membranes Requires Two Sequential Cleavages, One Within a Transmembrane Segment , 1996, Cell.