Upregulation of annexin A1 expression by butyrate in human colon adenocarcinoma cells: role of p53, NF-Y, and p38 mitogen-activated protein kinase.
Annexin A1 is a member of a phospholipid and calcium binding family of proteins; it is involved in anti-inflammation and in the regulation of differentiation, proliferation, and apoptosis. Here, we show the existence of a functional binding site for the tumor suppressor p53 near the proximal CCAAT box and the fact that the basal expression of annexin A1 in human colon adenocarcinoma cells is driven by p53 at the transcriptional level. Posttranscriptional mechanisms may also play an important role in maintaining constitutive annexin A1 expression. In addition, a p53/NF-Y complex is detected bound to the p53 binding site on its promoter. Butyrate is a natural product of fiber degradation in the colon and a key regulator of colonic epithelium homeostasis. We show that butyrate, a class I and II histone deacetylase inhibitor, induces transcriptional activation of annexin A1 expression correlated with differentiation. The effect of butyrate is mediated through a release of NF-Y from the proximal CCAAT box and an enhancement of p53 binding. The interaction of p53 with the promoter is dependent on p38 MAPK activity either in the absence or in the presence of butyrate. Further, activation of p38 MAPK by this agent is required to increase annexin A1 promoter activity and to increase protein expression.
Department of Biochemistry and Molecular Biology I, Faculty of Chemistry, Complutense University, 28040 Madrid, Spain.
E
E
Lecona
J I
JI
Barrasa
N
N
Olmo
B
B
Llorente
J
J
Turnay
M A
MA
Lizarbe
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D017305:Annexin A1 / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology*; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D017305:Annexin A1; D014408:Biomarkers, Tumor; D002087:Butyrates; D023081:CCAAT-Binding Factor; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C492061:NFYA protein, human; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D048051:p38 Mitogen-Activated Protein Kinases