title: Notch1-promoted TRPA1 expression in erythroleukemic cells suppresses erythroid but enhances megakaryocyte differentiation.
abstract: The Notch1 pathway plays important roles in modulating erythroid and megakaryocyte differentiation. To screen the Notch1-related genes that regulate differentiation fate of K562 and HEL cells, the expression of transient receptor potential ankyrin 1 (TRPA1) was induced by Notch1 receptor intracellular domain (N1IC), the activated form of Notch1 receptor. N1IC and v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1) bound to TRPA1 promoter region to regulate transcription in K562 cells. Transactivation of TRPA1 promoter by N1IC depended on the methylation status of TRPA1 promoter. N1IC and Ets-1 suppressed the DNA methyltransferase 3B (DNMT3B) level in K562 cells. Inhibition of TRPA1 expression after Notch1 knockdown could be attenuated by nanaomycin A, an inhibitor of DNMT3B, in K562 and HEL cells. Functionally, hemin-induced erythroid differentiation could be suppressed by TRPA1, and the reduction of erythroid differentiation of both cells by N1IC and Ets-1 occurred via TRPA1. However, PMA-induced megakaryocyte differentiation could be enhanced by TRPA1, and the surface markers of megakaryocytes could be elevated by nanaomycin A. Megakaryocyte differentiation could be reduced by Notch1 or Ets-1 knockdown and relieved by TRPA1 overexpression. The results suggest that Notch1 and TRPA1 might be critical modulators that control the fate of erythroid and megakaryocyte differentiation.
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Ji-Lin
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Yueh-Hsin
authors.initials: YH
authors.lastname: Ping
authors.affiliation: Department of Life Science, National Chung Cheng University, Chia-Yi 621, Taiwan.
authors.forename: Min-Jen
authors.initials: MJ
authors.lastname: Tseng
authors.affiliation: Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Yuan-I
authors.initials: YI
authors.lastname: Chang
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
authors.affiliation: School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Rong-Hong
authors.initials: RH
authors.lastname: Hsieh
authors.affiliation: Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.|Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Tien-Shun
authors.initials: TS
authors.lastname: Yeh
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019175:DNA Methylation; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D050784:Proto-Oncogene Protein c-ets-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074025:TRPA1 Cation Channel / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000097584:DNA Methyltransferase 3B; D000095622:Benzoisochromanequinones
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D009285:Naphthoquinones; D050784:Proto-Oncogene Protein c-ets-1; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000074025:TRPA1 Cation Channel; D000097584:DNA Methyltransferase 3B; C494041:ETS1 protein, human; C473350:TRPA1 protein, human; C008638:nanaomycin A; D000095622:Benzoisochromanequinones