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PMID: 11179217 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Dimerization with PEBP2beta protects RUNX1/AML1 from ubiquitin-proteasome-mediated degradation.

The EMBO journal ·Vol. 20 ·No. 4 ·2001-02-15 ·Pages 723-33

Huang G, Shigesada K, Ito K, Wee HJ, Yokomizo T, Ito Y

Abstract

The RUNX family genes are the mammalian homologs of the Drosophila genes runt and lozenge, and members of this family function as master regulators of definitive hematopoiesis and osteogenesis. The RUNX genes encode the alpha subunit of the transcription factor PEBP2/CBF. The beta subunit consists of the non-RUNX protein PEBP2beta. We found that RUNX1/AML1, which is essential for hematopoiesis, is continuously subjected to proteolytic degradation mediated by the ubiquitin-proteasome pathway. When PEBP2beta is present, however, the ubiquitylation of RUNX1 is abrogated and this causes a dramatic inhibition of RUNX1 proteolysis. Heterodimerization between PEBP2beta and RUNX1 thus appears to be an essential step in the generation of transcriptionally competent RUNX1. Consistent with this notion, RUNX1 was barely detected in PEBP2beta(-/-) mouse. CBF(PEBP2)beta- SMMHC, the chimeric protein associated with inv(16) acute myeloid leukemia, was found to protect RUNX1 from proteolytic degradation more efficiently than PEBP2beta. These results reveal a hitherto unknown and major role of PEBP2beta, namely that it regulates RUNX1 by controlling its turnover. This has allowed us to gain new insights into the mechanism of leukemogenesis by CBFbeta-SMMHC.

MeSH Terms
Amino Acid Sequence Amino Acid Substitution Animals Base Sequence Core Binding Factor Alpha 2 Subunit Cysteine Endopeptidases/metabolism Cysteine Proteinase Inhibitors/pharmacology DNA-Binding Proteins/chemistry,metabolism Dimerization Hydrolysis Mice Molecular Sequence Data Multienzyme Complexes/metabolism Proteasome Endopeptidase Complex Proto-Oncogene Proteins Sequence Homology, Amino Acid Transcription Factor AP-2 Transcription Factors/chemistry,metabolism Ubiquitins/metabolism
Chemicals
Core Binding Factor Alpha 2 Subunit Cysteine Proteinase Inhibitors DNA-Binding Proteins Multienzyme Complexes Proto-Oncogene Proteins Runx1 protein, mouse Transcription Factor AP-2 Transcription Factors Ubiquitins Cysteine Endopeptidases Proteasome Endopeptidase Complex
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Huang G
Laboratory of Cell Regulation, Department of Viral Oncology, and Molecular Genetics, Institute for Virus Research, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Shigesada K
Ito K
Wee H J
Yokomizo T
Ito Y
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38 references, click to expand
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/20.4.723
Published
2001-02-15
Pages
723-33
Language
English
Region
England
NLM ID
8208664
PMCID
PMC145428
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/20.4.723 PMC Full Text View journal details
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