Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease.
BCR-ABL is proposed to impair cell-cycle control by disabling p27, a tumor suppressor that inhibits cyclin-dependent kinases. We show that in cell lines p27 expression is inversely correlated with expression of SKP2, the F-box protein of SCF(SKP2) (SKP1/Cul1/F-box), the E3 ubiquitin ligase that promotes proteasomal degradation of p27. Inhibition of BCR-ABL kinase causes G(1) arrest, down-regulation of SKP2, and accumulation of p27. Ectopic expression of wild-type SKP2, but not a mutant unable to recognize p27, partially rescues cell-cycle progression. A similar regulation pattern is seen in cell lines transformed by FLT3-ITD, JAK2(V617F), and TEL-PDGFRbeta, suggesting that the SKP2/p27 conduit may be a universal target for leukemogenic tyrosine kinases. Mice that received transplants of BCR-ABL-infected SKP2(-/-) marrow developed a myeloproliferative syndrome but survival was significantly prolonged compared with recipients of BCR-ABL-expressing SKP2(+/+) marrow. SKP2(-/-) leukemic cells demonstrated higher levels of nuclear p27 than SKP2(+/+) counterparts, suggesting that the attenuation of leukemogenesis depends on increased p27 expression. Our data identify SKP2 as a crucial mediator of BCR-ABL-induced leukemogenesis and provide the first in vivo evidence that SKP2 promotes oncogenesis. Hence, stabilization of p27 by inhibiting its recognition by SCF(SKP2) may be therapeutically useful.
Division of Hematology & Oncology, Oregon Health & Science University Cancer Institute, Portland, OR 97239, USA.
Anupriya
A
Agarwal
Thomas G P
TG
Bumm
Amie S
AS
Corbin
Thomas
T
O'Hare
Marc
M
Loriaux
Jonathan
J
VanDyke
Stephanie G
SG
Willis
Jutta
J
Deininger
Keiichi I
KI
Nakayama
Brian J
BJ
Druker
Michael W
MW
Deininger
D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D016044:Fusion Proteins, bcr-abl; D015870:Gene Expression; D016313:Genes, abl; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl