In vivo interference with Skp1 function leads to genetic instability and neoplastic transformation.
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.
Piva
Roberto
R
Department of Pathology and NYU Cancer Institute. Division of Hematopathology, New York University School of Medicine, New York, New York 10016, USA.
Liu
Jian
J
Chiarle
Roberto
R
Podda
Antonello
A
Pagano
Michele
M
Inghirami
Giorgio
G
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D018385:Centrosome / Q000378:metabolism; D044842:Cullin Proteins; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D008221:Lymphoid Tissue / Q000166:cytology / Q000473:pathology / Q000502:physiology; D008223:Lymphoma / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009154:Mutation; D010453:Peptide Synthases / Q000378:metabolism; D010641:Phenotype; D044786:S-Phase Kinase-Associated Proteins; D044843:SKP Cullin F-Box Protein Ligases; D008941:Spindle Apparatus / Q000378:metabolism; D015996:Survival Rate; D013601:T-Lymphocytes / Q000502:physiology
D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D044786:S-Phase Kinase-Associated Proteins; D044843:SKP Cullin F-Box Protein Ligases; D010453:Peptide Synthases