Absence of SKP2 expression attenuates BCR-ABL–induced myeloproliferative disease

Abstract

BCR-ABL is proposed to impair cell-cycle control by disabling p27, a tumor suppressor that inhibits cyclin-dependent ki-nases. 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 ubiq-uitin 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-PDGFR, suggesting that the SKP2/p27 conduit may be a universal target for leukemogenic ty-rosine 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 attenu-ation 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. (Blood.

A novel activating, germline JAK2 mutation, JAK2R564Q, causes familial essential thrombocytosis

“…17 Activation of signal transducer and activator of transcription 5 (STAT5) by JAK2V 617 F also leads to increased transcription of Skp2, a subunit of ubiquitin E3 ligase, which further promotes p27/Kip1 degradation. 18,19 Moreover, the normal control on overexuberant cell growth, mediated by the suppressor of cytokine signaling 3 (SOCS3), which acts to regulate JAK2 activity, is also abrogated by JAK2V 617 F in BaF/3 cells. disease pathogenesis have yet not been performed for many of these mutant kinases.…”

Regulation of p27Kip1by mitogen-induced tyrosine phosphorylation

“…65 In addition to p27, Skp2 expression can also be regulated by JAKV617F, where the protein is transcriptionally induced by activated STAT5. 87,88 Interestingly, shRNA-mediated knockdown of JAK2V617F leads to loss of p27-Y88 phosphorylation and stabilization of p27 without changes in Skp2 levels, indicating that p27 regulation by JAK2V617F can occur independently from Skp2 regulation.…”

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

“…Skp2 has been characterized to exhibit its oncogenic function via targeting of its substrates including p27 (7,8), p21 (9), p57 (10) and Forkhead box protein O1 (FOXO1) (11,12). Engineered mouse models revealed that conditional depletion of Skp2 in mice suppressed tumor growth in T cell lineage (13), B cell lineage (14), bone marrow (15), liver (16,17), breast (18), prostate (19) and skin cancer (20). Consistently, upregulation of Skp2 in mice enhanced tumor growth in lymphoma (21), prostate cancer (19) and breast tumor (18).…”