title: Transcriptional repression of Cdc25B by IER5 inhibits the proliferation of leukemic progenitor cells through NF-YB and p300 in acute myeloid leukemia.
abstract: The immediately-early response gene 5 (IER5) has been reported to be induced by γ-ray irradiation and to play a role in the induction of cell death caused by radiation. We previously identified IER5 as one of the 2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (TMPP)-induced transcriptional responses in AML cells, using microarrays that encompassed the entire human genome. However, the biochemical pathway and mechanisms of IER5 function in regulation of the cell cycle remain unclear. In this study, we investigated the involvement of IER5 in the cell cycle and in cell proliferation of acute myeloid leukemia (AML) cells. We found that the over-expression of IER5 in AML cell lines and in AML-derived ALDH(hi) (High Aldehyde Dehydrogenase activity)/CD34(+) cells inhibited their proliferation compared to control cells, through induction of G2/M cell cycle arrest and a decrease in Cdc25B expression. Moreover, the over-expression of IER5 reduced colony formation of AML-derived ALDH(hi)/CD34(+) cells due to a decrease in Cdc25B expression. In addition, over-expression of Cdc25B restored TMPP inhibitory effects on colony formation in IER5-suppressed AML-derived ALDH(hi)/CD34(+) cells. Furthermore, the IER5 reduced Cdc25B mRNA expression through direct binding to Cdc25B promoter and mediated its transcriptional attenuation through NF-YB and p300 transcriptinal factors. In summary, we found that transcriptional repression mediated by IER5 regulates Cdc25B expression levels via the release of NF-YB and p300 in AML-derived ALDH(hi)/CD34(+) cells, resulting in inhibition of AML progenitor cell proliferation through modulation of cell cycle. Thus, the induction of IER5 expression represents an attractive target for AML therapy.
authors: Department of Internal Medicine III, Hamamatsu University School of Medicine, Higashi-ku, Hamamatsu, Shizuoka, Japan. satonaka@hama-med.ac.jp
authors: Satoki
authors: S
authors: Nakamura
authors: Yasuyuki
authors: Y
authors: Nagata
authors: Lin
authors: L
authors: Tan
authors: Tomonari
authors: T
authors: Takemura
authors: Kiyoshi
authors: K
authors: Shibata
authors: Michio
authors: M
authors: Fujie
authors: Shinya
authors: S
authors: Fujisawa
authors: Yasutaka
authors: Y
authors: Tanaka
authors: Mitsuo
authors: M
authors: Toda
authors: Reiko
authors: R
authors: Makita
authors: Kenji
authors: K
authors: Tsunekawa
authors: Manabu
authors: M
authors: Yamada
authors: Mayumi
authors: M
authors: Yamaoka
authors: Junko
authors: J
authors: Yamashita
authors: Kazunori
authors: K
authors: Ohnishi
authors: Mitsuji
authors: M
authors: Yamashita
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D002469:Cell Separation; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014410:Tumor Stem Cell Assay; D020687:cdc25 Phosphatases / Q000235:genetics*
chemical_list: D018952:Antigens, CD34; D023081:CCAAT-Binding Factor; C118926:IER5 protein, human; D017874:Immediate-Early Proteins; C492063:NFYB protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D020687:cdc25 Phosphatases