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J. Biol. Chem., Vol. 281, Issue 28, 19145-19155, July 14, 2006

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Spi-1/PU.1 Oncoprotein Affects Splicing Decisions in a Promoter Binding-dependent Manner^*

From the Institut Curie, INSERM U528, Paris 75248, France

The expression of the Spi-1/PU.1 transcription factor is tightly regulated as a function of the hematopoeitic lineage. It is required for myeloid and B lymphoid differentiation. When overexpressed in mice, Spi-1 is associated with the emergence of transformed proerythroblasts unable to differentiate. In the course of a project undertaken to characterize the oncogenic function of Spi-1, we found that Spi-1 interacts with proteins of the spliceosome in Spi-1-transformed proerythroblasts and participates in alternative splice site selection. Because Spi-1 is a transcription factor, it could be hypothesized that these two functions are coordinated. Here, we have developed a system allowing the characterization of transcription and splicing from a single target. It is shown that Spi-1 is able to regulate alternative splicing of a pre-mRNA for a gene whose transcription it regulates. Using a combination of Spi-1 mutants and Spi-1-dependent promoters, we demonstrate that Spi-1 must bind and transactivate a given promoter to favor the use of the proximal 5' alternative site. This establishes that Spi-1 affects splicing decisions in a promoter binding-dependent manner. These results provide new insight into how Spi-1 may act in the blockage of differentiation by demonstrating that it can deregulate gene expression and also modify the nature of the products generated from target genes.

Received for publication, November 8, 2005 , and in revised form, May 11, 2006.

^* This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and Institut Curie, the Ligue contre le Cancer (Comité de Paris), and the Association pour la Recherche contre le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: 26 rue d'Ulm, 75248 Paris Cedex 05, France. Tel.: 33-1-42-34-66-48; Fax: 33-1-42-34-66-50; E-mail: guillouf.christel{at}curie.fr. ²To whom correspondence may be addressed. E-mail: framoreau{at}curie.fr.

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