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 Previous Article

Molecular and Cellular Biology, December 2002, p. 8375-8387, Vol. 22, No. 23
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.23.8375-8387.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vivo Interference with Skp1 Function Leads to Genetic Instability and Neoplastic Transformation

Roberto Piva,1,2 Jian Liu,1,2 Roberto Chiarle,1,2 Antonello Podda,1,2 Michele Pagano,1 and Giorgio Inghirami1,2*

Department of Pathology and NYU Cancer Institute,1 Division of Hematopathology, New York University School of Medicine, New York, New York 100162

Received 12 March 2002/ Returned for modification 16 June 2002/ Accepted 19 August 2002

Skp1 is involved in a variety of crucial cellular functions, among which the best understood is the formation together with Cul1 of Skp1-cullin-F-box protein ubiquitin ligases. To investigate the role of Skp1, we generated transgenic (Tg) mice expressing a Cul1 deletion mutant (Cul1-N252) able to sequestrate and inactivate Skp1. In vivo interference with Skp1 function through expression of the Cul1-N252 mutant into the T-cell lineage results in lymphoid organ hypoplasia and reduced proliferation. Nonetheless, after a period of latency, Cul1-N252 Tg mice succumb to T-cell lymphomas with high penetrance (>80%). Both T-cell depletion and the neoplastic phenotype of Cul1-N252 Tg mice are largely rescued in Cul1-N252, Skp1 double-Tg mice, indicating that the effects of Cul1-N252 are due to a sequestration of the endogenous Skp1. Analysis of Cul1-N252 lymphomas demonstrates striking karyotype heterogeneity associated with c-myc amplification and c-Myc overexpression. We show that the in vitro expression of the Cul1-N252 mutant causes a pleiotrophic phenotype, which includes the formation of multinucleated cells, centrosome and mitotic spindle abnormalities, and impaired chromosome segregation. Our findings support a crucial role for Skp1 in proper chromosomal segregation, which is required for the maintenance of euploidy and suppression of transformation.

* Corresponding author. Mailing address: Department of Pathology and NYU Cancer Institute, New York University School of Medicine, 550 First Ave., MSB 503, New York, NY 10016. Phone: (212) 263-7768. Fax: (212) 263-7712. E-mail: inghig01{at}med.nyu.edu.

Molecular and Cellular Biology, December 2002, p. 8375-8387, Vol. 22, No. 23
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.23.8375-8387.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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