Abstract |
The chimeric oncoprotein E2a-Pbx1 results from fusion of the E2A and PBX1 genes following t(1;19) chromosomal translocations in B cell precursor acute leukemias. Experimentally B cell progenitors do not tolerate constitutive expression of E2a-Pbx1 which contrasts with transformation of several other cell types following its stable expression both in vitro and in vivo. To further investigate the effects of E2a-Pbx1 on the B cell progenitors, we conditionally expressed E2a-Pbx1 under control of a metal response element in hematopoietic precursor cell lines in vitro. Inducible expression of E2a-Pbx1 resulted in cell death with the morphologic and molecular features of apoptosis. A structure-function analysis demonstrated that induction of apoptosis was not a dominant-negative effect of the E2a moiety but, rather, required the DNA-binding homeodomain of Pbx1. E2a-Pbx1-induced apoptosis proceeded through a BCL2-responsive checkpoint eventuating in PARP inactivation but did require p53. Constitutive expression of E2a-Pbx1 did not induce apoptosis or continued cycling of Rat-1 fibroblasts in low serum conditions. These studies demonstrate that E2a-Pbx1 initiates programmed cell death of hematopoietic precursers by a mechanism that requires its chimeric transcriptional properties, but, unlike other nuclear oncoproteins, is independent of p53.
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Authors | K S Smith, Y Jacobs, C P Chang, M L Cleary |
Journal | Oncogene
(Oncogene)
Vol. 14
Issue 24
Pg. 2917-26
(Jun 19 1997)
ISSN: 0950-9232 [Print] England |
PMID | 9205098
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Homeodomain Proteins
- Oncogene Proteins, Fusion
- Proto-Oncogene Proteins c-bcl-2
- Recombinant Fusion Proteins
- Transcription Factors
- Tumor Suppressor Protein p53
- E2A-Pbx1 fusion protein
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Topics |
- Animals
- Apoptosis
(drug effects, physiology)
- B-Lymphocytes
(cytology, physiology)
- Cell Cycle
(physiology)
- Cell Line
- Fibroblasts
(cytology)
- HL-60 Cells
(metabolism, physiology)
- Hematopoietic Stem Cells
(cytology, drug effects, physiology)
- Homeodomain Proteins
(genetics, pharmacology, physiology)
- Humans
- Oncogene Proteins, Fusion
(genetics, pharmacology, physiology)
- Proto-Oncogene Proteins c-bcl-2
(physiology)
- Rats
- Recombinant Fusion Proteins
(genetics, pharmacology, physiology)
- Structure-Activity Relationship
- Transcription Factors
(physiology)
- Transfection
- Tumor Suppressor Protein p53
(physiology)
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