An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element.
An Alu element preceding the myeloperoxidase gene (MPO) contains four hexamer motifs related to the consensus recognition sequence for nuclear hormone receptors (AGGTCA), arranged as direct repeats with spacing of 2, 4, and 2 nucleotides (DR-2-4-2). Gel shift experiments and transient transfection assays demonstrate that these sequences include binding sites for retinoic acid and thyroid hormone receptors and function in vivo to activate transcription of a chloramphenicol acetyltransferase reporter gene. The first DR-2 elements of the series do not bind known receptors but do bind the SP1 transcription factor. Two alleles of the MPO gene exist that differ at one position within this element, resulting in one allele with and one without a strong SP1 binding site. The element with the SP1 site activates transcription by 25-fold in transient transfection assays, while the alternative allele confers severalfold less transcriptional activity. Most cases of acute myelocytic leukemia are homozygous for the allele with the SP1 binding site, suggesting this element plays an important role in regulating the MPO gene in myeloid leukemias. This MPO-Alu is a representative of an Alu subclass numbering approximately 400,000 copies, suggesting many genes may be regulated by such elements.
Piedrafita
F J
FJ
Sidney Kimmel Cancer Center, San Diego, California 92121, USA.
Molander
R B
RB
Vansant
G
G
Orlova
E A
EA
Pfahl
M
M
Reynolds
W F
WF
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D002522:Chlorocebus aethiops; D016384:Consensus Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008969:Molecular Sequence Data; D009195:Peroxidase / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis; D012091:Repetitive Sequences, Nucleic Acid; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D017931:DNA Primers; D004268:DNA-Binding Proteins; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D016329:Sp1 Transcription Factor; D009195:Peroxidase; D015500:Chloramphenicol O-Acetyltransferase