Molecular and Cellular Biology, April 2000, p. 2297-2307, Vol. 20, No. 7
Department of Molecular Genetics, Weizmann
Institute of Science, Rehovot 76000,1 and
Department of Cell Research and Immunology, Tel Aviv
University, Tel Aviv,3 Israel, and
Laboratory of Experimental and Computational Biology, DBS,
National Cancer Institute, Frederick, Maryland
217022
Received 20 July 1999/Returned for modification 16 September
1999/Accepted 7 December 1999
AML1/RUNX1 belongs to the runt domain transcription factors that
are important regulators of hematopoiesis and osteogenesis. Expression
of AML1 is regulated at the level of transcription by two promoters,
distal (D) and proximal (P), that give rise to mRNAs bearing two
distinct 5' untranslated regions (5'UTRs) (D-UTR and P-UTR). Here we
show that these 5'UTRs act as translation regulators in vivo. AML1
mRNAs bearing the uncommonly long (1,631-bp) P-UTR are poorly
translated, whereas those with the shorter (452-bp) D-UTR are readily
translated. The low translational efficiency of the P-UTR is attributed
to its length and the cis-acting elements along it.
Transfections and in vitro assays with bicistronic constructs demonstrate that the D-UTR mediates cap-dependent translation whereas
the P-UTR mediates cap-independent translation and contains a
functional internal ribosome entry site (IRES). The IRES-containing bicistronic constructs are more active in hematopoietic cell lines that
normally express the P-UTR-containing mRNAs. Furthermore, we show that
the IRES-dependent translation increases during megakaryocytic differentiation but not during erythroid differentiation, of K562 cells. These results strongly suggest that the function of the P-UTR
IRES-dependent translation in vivo is to tightly regulate the
translation of AML1 mRNAs. The data show that AML1 expression is
regulated through usage of alternative promoters coupled with IRES-mediated translation control. This IRES-mediated translation regulation adds an important new dimension to the fine-tuned control of
AML1 expression.
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Transcription-Coupled Translation Control of
AML1/RUNX1 Is Mediated by Cap- and Internal Ribosome Entry
Site-Dependent Mechanisms
*
Corresponding author. Mailing address: Department of
Molecular Genetics, The Weizmann Institute of Science, Rehovot 76000, Israel. Phone: 972-8-9343972. Fax: 972-8-9344108. E-mail:
Yoram.Groner{at}weizmann.ac.il.
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