Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2.

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.

• 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.)

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

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)