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Molecular and Cellular Biology, April 2000, p. 2297-2307, Vol. 20, No. 7
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

Amir Pozner,1 Dalia Goldenberg,1 Varda Negreanu,1 Shu-Yun Le,2 Orna Elroy-Stein,3 Ditsa Levanon,1 and Yoram Groner1,*

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.

* 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.

Molecular and Cellular Biology, April 2000, p. 2297-2307, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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