title: PML-retinoic acid receptor alpha inhibits PML IV enhancement of PU.1-induced C/EBPepsilon expression in myeloid differentiation.
abstract: PML and PU.1 play important roles in myeloid differentiation. PML-deficient mice have an impaired capacity for terminal maturation of their myeloid precursor cells. This finding has been explained, at least in part, by the lack of PML action to modulate retinoic acid-differentiating activities. In this study, we found that C/EBPepsilon expression is reduced in PML-deficient mice. We showed that PU.1 directly activates the transcription of the C/EBPepsilon gene that is essential for granulocytic differentiation. The type IV isoform of PML interacted with PU.1, promoted its association with p300, and then enhanced PU.1-induced transcription and granulocytic differentiation. In contrast to PML IV, the leukemia-associated PML-retinoic acid receptor alpha fusion protein dissociated the PU.1/PML IV/p300 complex and inhibited PU.1-induced transcription. These results suggest a novel pathogenic mechanism of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukemia.
authors.affiliation: Molecular Oncology Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-Chome, Chuo-Ku, Tokyo 104-0045, Japan. hityoshi@gan2.res.ncc.go.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tagata
authors.forename: Takuo
authors.initials: T
authors.lastname: Katsumoto
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohnishi
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Issay
authors.initials: I
authors.lastname: Kitabayashi
mesh_terms: D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D042381:Granulocyte Precursor Cells / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D038042:Myelopoiesis; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D050881:E1A-Associated p300 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099232:Proto-Oncogene Protein Spi-1; C489468:Cebpe protein, mouse; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070790:CEBPE protein, human; C070576:PML protein, human; C494360:EP300 protein, human