In vivo interference with Skp1 function leads to genetic instability and neoplastic transformation

Roberto Piva, Jian Liu, Roberto Chiarle, Antonello Podda, Michele Pagano, Giorgio Inghirami

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8375-8387
Number of pages13
JournalMolecular and Cellular Biology
Volume22
Issue number23
DOIs
StatePublished - Dec 1 2002
Externally publishedYes

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Transgenic Mice
SKP Cullin F-Box Protein Ligases
T-Lymphocytes
Phenotype
Centrosome
Chromosome Segregation
Spindle Apparatus
Penetrance
T-Cell Lymphoma
Cell Lineage
Ligases
Ubiquitin
Karyotype
Lymphoma
Maintenance

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

In vivo interference with Skp1 function leads to genetic instability and neoplastic transformation. / Piva, Roberto; Liu, Jian; Chiarle, Roberto; Podda, Antonello; Pagano, Michele; Inghirami, Giorgio.

In: Molecular and Cellular Biology, Vol. 22, No. 23, 01.12.2002, p. 8375-8387.

Research output: Contribution to journalArticle

Piva, Roberto ; Liu, Jian ; Chiarle, Roberto ; Podda, Antonello ; Pagano, Michele ; Inghirami, Giorgio. / In vivo interference with Skp1 function leads to genetic instability and neoplastic transformation. In: Molecular and Cellular Biology. 2002 ; Vol. 22, No. 23. pp. 8375-8387.
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