Role of the F-box protein Skp2 in lymphomagenesis.
The F-box protein Skp2 (S-phase kinase-associated protein 2) positively regulates the G(1)-S transition by controlling the stability of several G(1) regulators, such as the cell cycle inhibitor p27. We show here that Skp2 expression correlates directly with grade of malignancy and inversely with p27 levels in human lymphomas. To directly evaluate the potential of Skp2 to deregulate growth in vivo, we generated transgenic mice expressing Skp2 targeted to the T-lymphoid lineage as well as double transgenic mice coexpressing Skp2 and activated N-Ras. A strong cooperative effect between these two transgenes induced T cell lymphomas with shorter latency and higher penetrance, leading to significantly decreased survival when compared with control and single transgenic animals. Furthermore, lymphomas of Nras single transgenic animals often expressed higher levels of endogenous Skp2 than tumors of double transgenic mice. This study provides evidence of a role for an F-box protein in oncogenesis and establishes SKP2 as a protooncogene causally involved in the pathogenesis of lymphomas.
Department of Pathology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, 550 First Avenue, MSB 548, New York, NY 10016, USA.
E
E
Latres
R
R
Chiarle
B A
BA
Schulman
N P
NP
Pavletich
A
A
Pellicer
G
G
Inghirami
M
M
Pagano
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009124:Muscle Proteins; D044786:S-Phase Kinase-Associated Proteins
D018797:Cell Cycle Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D044786:S-Phase Kinase-Associated Proteins; C058992:Tagln protein, mouse