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Human Molecular Genetics Advance Access originally published online on December 8, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 3 323-334
DOI: 10.1093/hmg/ddh024

Expression and molecular characterization of alternative transcripts of the ARHGEF5/TIM oncogene specific for human breast cancer

Marie-Anne Debily1, Alessandra Camarca2, Marina Ciullo1, Claudine Mayer3, Sandrine El Marhomy1, Ismaila Ba1, Abdelali Jalil4, Annamaria Anzisi5, John Guardiola2 and Dominique Piatier-Tonneau1,*

1Génomique Fonctionnelle et Biologie Systémique en Santé, FRE 2571, Centre National de la Recherche Scientifique, 7 rue Guy Moquet, 94801 Villejuif, France, 2Institute of Genetics and Biophysics ‘A. Buzzati Traverso’, Consiglio Nazionale delle Ricerche, via G. Marconi 10, 80125 Naples, Italy, 3Laboratoire de Minéralogie-Cristallographie de Paris, Université Paris 6, 4 place Jussieu, 75252 PARIS Cedex 05, France, 4U 487 INSERM, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France and 5Department of Oncology E, National Cancer Institute, via Mariano Semmola, 80131 Naples, Italy

Received September 16, 2003; Accepted November 24, 2003

The ARHGEF5/TIM oncogene belongs to the Dbl family of guanine nucleotide exchange factors (GEFs) for Rho GTPases. It is well established that Rho-GEFs play an important role in tumorigenesis and metastasis through the activation of their substrates, the Rho GTPases. Little is known about ARHGEF5/TIM oncogene expression and cellular functions. Because of its localization close to the common fragile site FRA7I, which has been shown to be responsible for an inverted duplication of the 7q34–q35 region in breast carcinoma cells, we examined the expression of the ARHGEF5/TIM oncogene in normal and tumoral breast tissue. We report here the identification of five novel ARHGEF5/TIM alternative transcripts specifically expressed in breast tumors. These variant transcripts were characterized by the absence of one or several exons, all coding for the catalytic Dbl-homology domain and generating modified or truncated predicted variant proteins. The variant transcripts were predominantly expressed in breast carcinoma cell lines and in the most aggressive primary breast carcinomas, suggesting they may play a role in breast tumor progression. Moreover, we demonstrate that the expression of recombinant ARHGEF5/TIM protein in transfected COS-7 and NIH-3T3 cells generated a loss of actin stress fibers and the formation of membrane ruffles and filopodia. This pattern suggests that ARHGEF5/TIM activates Rac1, Cdc42 or RhoG rather than RhoA, as previously demonstrated in in vitro guanine nucleotide exchange assays. We anticipate that the activation of the ARHGEF5/TIM oncogene, possibly by the variant isoforms detected here, may play an important role in proliferative breast disease.

* To whom correspondence should be addressed at: FRE 2571 CNRS, 7 rue Guy Moquet, BP 8, 94801 Villejuif Cedex, France. Tel: +33 149583496; Fax: +33 149583509; Email: piatier{at}vjf.cnrs.fr


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