title: GCN5 acetylates and regulates the stability of the oncoprotein E2A-PBX1 in acute lymphoblastic leukemia.
abstract: The t(1;19) translocation in pediatric pre-B-cell acute lymphoblastic leukemia (ALL) fuses the genes, which encode the transcriptional activator E2A and homeobox pre-B-cell leukemia transcription factor 1 (PBX1), resulting in expression of the chimeric transcription factor E2A-PBX1. E2A-PBX1 can promote cell transformation both in vitro and in vivo; however, the mechanisms by which E2A-PBX1 contributes to malignancy merit further investigation. In the current work we report, for the first time, a physical and functional interaction between the SPT3-TAFII31-GCN5L acetylase (STAGA) complex and E2A-PBX1. STAGA, and its acetyltransferase subunit GCN5, directly interacted with the E2A portion of E2A-PBX1. GCN5 acetylated E2A-PBX1 and increased the stability of E2A-PBX1 protein in cells. Moreover, the GCN5 inhibitor α-methylene-γ-butyrolactone 3 (MB-3) decreased E2A-PBX1 acetylation and E2A-PBX1 protein levels in leukemic cells, indicating that GCN5 inhibitors have potential value as therapeutic agents for ALL. In addition, we show that the E3 ubiquitin ligase HDM2 potentiates the degradation of E2A-PBX1. We suggest that dynamic regulation of E2A-PBX1 protein levels in vivo has a fundamental role in ALL.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Holmlund
authors.forename: M J
authors.initials: MJ
authors.lastname: Lindberg
authors.forename: D
authors.initials: D
authors.lastname: Grander
authors.forename: A E
authors.initials: AE
authors.lastname: Wallberg
mesh_terms: D000107:Acetylation; D015153:Blotting, Western; D002648:Child; D051548:Histone Acetyltransferases; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011427:Propiophenones / Q000494:pharmacology; D011485:Protein Binding; D060066:Protein Interaction Maps; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D051548:Histone Acetyltransferases; D018398:Homeodomain Proteins; D046912:Multiprotein Complexes; D015514:Oncogene Proteins, Fusion; D011427:Propiophenones; D051736:Proto-Oncogene Proteins c-mdm2; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C089847:E2A-Pbx1 fusion protein; C005543:MB 3; C497206:MDM2 protein, human