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Distinct expression patterns and transforming properties of multiple isoforms of Ost, an exchange factor for RhoA and Cdc42

Oncogene volume 18, pages 4742–4755 (1999)Cite this article

Abstract

A search for transforming genes expressed in brain led to the identification of a novel isoform of Ost, an exchange factor for RhoA and Cdc42. In addition to the Dbl-homology (DH) and pleckstrin-homology (PH) domains identified in the original Ost, this isoform contained a SH3 domain and a novel HIV-Tat related (TR) domain. The presence or absence of these domains in Ost defined multiple isoforms of the protein. RT – PCR and in situ hybridization analysis revealed that these isoforms were generated by tissue-specific and developmentally restricted alternative splicing events. Whereas deletion of the N-terminus activated the transforming properties of Ost, the presence of the SH3 domain reduced the transforming activity of the protein. This inhibition was relieved by the presence of a TR domain, which contained a potential SH3 ligand sequence. The transforming activity of all Ost isoforms was inhibited by dominant negative forms of the Rho family proteins. Expression of Ost isoforms potently induced the formation of actin stress fibers and filopodia as well as JNK activity and AP1- and SRF-regulated transcriptional pathways. Ost transfectants also displayed elevated levels of cyclins A and D1, suggesting that the de-regulation of these cyclins is linked to Ost-mediated transformation.

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Acknowledgements

We thank Dr Jacalyn Pierce for support, Jason Long, Eva Gordon and Veena Kapoor for technical assistance and Dr Aykut Uren for advice on cyclin induction experiments. We are also grateful to Dr Stuart Aaronson who supported the construction of the luciferase reporter constructs. Genbank accession numbers: AF 130463 (TR domain), AF 133734 (BI domain), AF 133735 (SH3 domain).

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Author notes

  1. Matthew V Lorenzi

    Present address: Target Discovery Department, Zeneca Pharmaceuticals, PO Box 15437, 1800 Concord Pike, Wilmington, 19850, Delaware, USA

  2. Yasuhiro Hori

    Present address: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 5-2-3 Tokorodai, Tsukuba, Ibaraki, 300-26, Japan

Authors and Affiliations

  1. Laboratory of Cellular and Molecular Biology, National Cancer Institute, Building 37 Room 1E24; 37 Convent Dr. MSC 4255, Bethesda, 20892, Maryland, USA

    Matthew V Lorenzi, Paola Castagnino, Qiong Chen, Yasuhiro Hori & Toru Miki

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Lorenzi, M., Castagnino, P., Chen, Q. et al. Distinct expression patterns and transforming properties of multiple isoforms of Ost, an exchange factor for RhoA and Cdc42. Oncogene 18, 4742–4755 (1999). https://doi.org/10.1038/sj.onc.1202851

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