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Molecular and Cellular Biology, May 2000, p. 2959-2969, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Negative and Translation Termination-Dependent Positive Control of FLI-1 Protein Synthesis by Conserved Overlapping 5' Upstream Open Reading Frames in Fli-1 mRNA

Sandrine Sarrazin, Joëlle Starck, Colette Gonnet, Alexandre Doubeikovski,dagger Fabrice Melet, and François Morle*

Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, 69622 Villeurbanne, France

Received 6 December 1999/Returned for modification 18 January 2000/Accepted 2 February 2000

The proto-oncogene Fli-1 encodes a transcription factor of the ets family whose overexpression is associated with multiple virally induced leukemias in mouse, inhibits murine and avian erythroid cell differentiation, and induces drastic perturbations of early development in Xenopus. This study demonstrates the surprisingly sophisticated regulation of Fli-1 mRNA translation. We establish that two FLI-1 protein isoforms (of 51 and 48 kDa) detected by Western blotting in vivo are synthesized by alternative translation initiation through the use of two highly conserved in-frame initiation codons, AUG +1 and AUG +100. Furthermore, we show that the synthesis of these two FLI-1 isoforms is regulated by two short overlapping 5' upstream open reading frames (uORF) beginning at two highly conserved upstream initiation codons, AUG -41 and GUG -37, and terminating at two highly conserved stop codons, UGA +35 and UAA +15. The mutational analysis of these two 5' uORF revealed that each of them negatively regulates FLI-1 protein synthesis by precluding cap-dependent scanning to the 48- and 51-kDa AUG codons. Simultaneously, the translation termination of the two 5' uORF appears to enhance 48-kDa protein synthesis, by allowing downstream reinitiation at the 48-kDa AUG codon, and 51-kDa protein synthesis, by allowing scanning ribosomes to pile up and consequently allowing upstream initiation at the 51-kDa AUG codon. To our knowledge, this is the first example of a cellular mRNA displaying overlapping 5' uORF whose translation termination appears to be involved in the positive control of translation initiation at both downstream and upstream initiation codons.

* Corresponding author. Mailing address: Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, 43 Blvd. du 11 Novembre 1918, 69622 Villeurbanne, France. Phone: 33 04 72 43 13 75. Fax: 33 04 72 44 05 55. E-mail: morle{at}cismsun.univ-lyon1.fr.

dagger Present address: UPR 9051, Hôpital Saint-Louis, 75010 Paris, France.

Molecular and Cellular Biology, May 2000, p. 2959-2969, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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