Oligomeric self-association contributes to E2A-PBX1-mediated oncogenesis
Somervaille, Tim CP
AffiliationDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA
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AbstractThe PBX1 homeodomain transcription factor is converted by t(1;19) chromosomal translocations in acute leukemia into the chimeric E2A-PBX1 oncoprotein. Fusion with E2A confers potent transcriptional activation and constitutive nuclear localization, bypassing the need for dimerization with protein partners that normally stabilize and regulate import of PBX1 into the nucleus, but the mechanisms underlying its oncogenic activation are incompletely defined. We demonstrate here that E2A-PBX1 self-associates through the PBX1 PBC-B domain of the chimeric protein to form higher-order oligomers in t(1;19) human leukemia cells, and that this property is required for oncogenic activity. Structural and functional studies indicate that self-association facilitates the binding of E2A-PBX1 to DNA. Mutants unable to self-associate are transformation defective, however their oncogenic activity is rescued by the synthetic oligomerization domain of FKBP, which confers conditional transformation properties on E2A-PBX1. In contrast to self-association, PBX1 protein domains that mediate interactions with HOX DNA-binding partners are dispensable. These studies suggest that oligomeric self-association may compensate for the inability of monomeric E2A-PBX1 to stably bind DNA and circumvents protein interactions that otherwise modulate PBX1 stability, nuclear localization, DNA binding, and transcriptional activity. The unique dependence on self-association for E2A-PBX1 oncogenic activity suggests potential approaches for mechanism-based targeted therapies.
CitationLin CH, Wang Z, Duque-Afonso J, Wong SH, Demeter J, Loktev AV, et al. Oligomeric self-association contributes to E2A-PBX1-mediated oncogenesis. Sci Rep. 2019 Mar 20;9(1):4915.
- [Identification of proteins associated with transcription factors HOXA9 and E2A-PBX1 by tandem affinity purification].
- Authors: Shestakova EA, Boutin M, Bourassa S, Bonneil E, Bijl JJ
- Issue date: 2017 May-Jun
- An inhibitory switch derepressed by pbx, hox, and Meis/Prep1 partners regulates DNA-binding by pbx1 and E2a-pbx1 and is dispensable for myeloid immortalization by E2a-pbx1.
- Authors: Calvo KR, Knoepfler P, McGrath S, Kamps MP
- Issue date: 1999 Dec 23
- The Hox cooperativity motif of the chimeric oncoprotein E2a-Pbx1 is necessary and sufficient for oncogenesis.
- Authors: Chang CP, de Vivo I, Cleary ML
- Issue date: 1997 Jan
- Transformation properties of the E2a-Pbx1 chimeric oncoprotein: fusion with E2a is essential, but the Pbx1 homeodomain is dispensable.
- Authors: Monica K, LeBrun DP, Dedera DA, Brown R, Cleary ML
- Issue date: 1994 Dec
- Both Pbx1 and E2A-Pbx1 bind the DNA motif ATCAATCAA cooperatively with the products of multiple murine Hox genes, some of which are themselves oncogenes.
- Authors: Lu Q, Knoepfler PS, Scheele J, Wright DD, Kamps MP
- Issue date: 1995 Jul