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PMID: 14559995 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

PU.1 and pRB interact and cooperate to repress GATA-1 and block erythroid differentiation.

Molecular and cellular biology ·Vol. 23 ·No. 21 ·2003-11-00 ·Pages 7460-74

Rekhtman N, Choe KS, Matushansky I, Murray S, Stopka T, Skoultchi AI

Abstract

PU.1 and GATA-1 are two hematopoietic specific transcription factors that play key roles in development of the myeloid and erythroid lineages, respectively. The two proteins bind to one another and inhibit each other's function in transcriptional activation and promotion of their respective differentiation programs. This mutual antagonism may be an important aspect of lineage commitment decisions. PU.1 can also act as an oncoprotein since deregulated expression of PU.1 in erythroid precursors causes erythroleukemias in mice. Studies of cultured mouse erythroleukemia cell lines indicate that one aspect of PU.1 function in erythroleukemogenesis is its ability to block erythroid differentiation by repressing GATA-1 (N. Rekhtman, F. Radparvar, T. Evans, and A. I. Skoultchi, Genes Dev. 13:1398-1411, 1999). We have investigated the mechanism of PU.1-mediated repression of GATA-1. We report here that PU.1 binds to GATA-1 on DNA. We localized the repression activity of PU.1 to a small acidic N-terminal domain that interacts with the C pocket of pRB, a well-known transcriptional corepressor. Repression of GATA-1 by PU.1 requires pRB, and pRB colocalizes with PU.1 and GATA-1 at repressed GATA-1 target genes. PU.1 and pRB also cooperate to block erythroid differentiation. Our results suggest that one of the mechanisms by which PU.1 antagonizes GATA-1 is by binding to it at GATA-1 target genes and tethering to these sites a corepressor that blocks transcriptional activity and thereby erythroid differentiation.

MeSH Terms
Animals Binding Sites Cell Differentiation/physiology Cell Line Cell Lineage DNA-Binding Proteins/metabolism Erythroid Precursor Cells/physiology Erythroid-Specific DNA-Binding Factors GATA1 Transcription Factor Gene Expression Regulation Genes, Reporter Humans Mice Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins/metabolism Recombinant Fusion Proteins/metabolism Retinoblastoma Protein/metabolism Trans-Activators/metabolism Transcription Factors/metabolism Transcription, Genetic
Chemicals
DNA-Binding Proteins Erythroid-Specific DNA-Binding Factors GATA1 Transcription Factor GATA1 protein, human Gata1 protein, mouse Proto-Oncogene Proteins Recombinant Fusion Proteins Retinoblastoma Protein Trans-Activators Transcription Factors proto-oncogene protein Spi-1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Rekhtman Natasha
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Choe Kevin S
Matushansky Igor
Murray Stuart
Stopka Tomas
Skoultchi Arthur I
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.21.7460-7474.2003
Published
2003-11-00
Pages
7460-74
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC207581
Subset
IM
Grants
NCI NIH HHS · 2P30CA13330 · United States
NCI NIH HHS · 5R37CA16368 · United States
NIGMS NIH HHS · 5T32GM07288-25 · United States
NIGMS NIH HHS · T32 GM007288 · United States
NCI NIH HHS · P30 CA013330 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.21.7460-7474.2003 PMC Full Text View journal details
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