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

Kevin S. Smith, Yakop Jacobs, Ching-Pin Chang, Michael L. Cleary

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2917-2926
Number of pages10
JournalOncogene
Volume14
Issue number24
DOIs
StatePublished - 1997
Externally publishedYes

Fingerprint

Oncogene Proteins
B-Lymphoid Precursor Cells
Apoptosis
Cell Death
Genetic Translocation
Response Elements
Leukemia
Fibroblasts
Metals
Cell Line
DNA
Serum
Genes
In Vitro Techniques

Keywords

  • Apoptosis
  • Homeodomain
  • Inducible oncoprotein
  • Translocation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2. / Smith, Kevin S.; Jacobs, Yakop; Chang, Ching-Pin; Cleary, Michael L.

In: Oncogene, Vol. 14, No. 24, 1997, p. 2917-2926.

Research output: Contribution to journalArticle

Smith, Kevin S. ; Jacobs, Yakop ; Chang, Ching-Pin ; Cleary, Michael L. / Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2. In: Oncogene. 1997 ; Vol. 14, No. 24. pp. 2917-2926.
@article{abd78cf81fbe47dabdaf373c54cbb496,
title = "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.",
keywords = "Apoptosis, Homeodomain, Inducible oncoprotein, Translocation",
author = "Smith, {Kevin S.} and Yakop Jacobs and Ching-Pin Chang and Cleary, {Michael L.}",
year = "1997",
doi = "10.1038/sj.onc.1201249",
language = "English (US)",
volume = "14",
pages = "2917--2926",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "24",

}

TY - JOUR

T1 - Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2

AU - Smith, Kevin S.

AU - Jacobs, Yakop

AU - Chang, Ching-Pin

AU - Cleary, Michael L.

PY - 1997

Y1 - 1997

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Homeodomain

KW - Inducible oncoprotein

KW - Translocation

UR - http://www.scopus.com/inward/record.url?scp=0030849122&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030849122&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1201249

DO - 10.1038/sj.onc.1201249

M3 - Article

VL - 14

SP - 2917

EP - 2926

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 24

ER -