Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease
Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease
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DOI：
10.1182/blood-2007-09-113860
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发表时间：
2008-09-01
期刊：
影响因子：
20.3
通讯作者：
Deininger, Michael W.
中科院分区：
文献类型：
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作者：
Agarwal, Anupriya;Bumm, Thomas G. P.;Deininger, Michael W.
BCR-ABL被认为是通过使p27（一种抑制细胞周期蛋白依赖性激酶的肿瘤抑制因子）失活而损害细胞周期控制。我们发现，在细胞系中，p27的表达与SKP 2的表达呈负相关，SKP 2是SCFSKP 2的F-box蛋白（SKP 1/Cul 1/F-box），是促进p27蛋白酶体降解的E3泛素连接酶。抑制BCR-ABL激酶导致G阻滞、SKP 2下调和p27蓄积。野生型SKP 2的异位表达，而不是不能识别p27的突变体，部分挽救了细胞周期进程。在FLT 3-ITD、JAK 2（V617 F）和TEL-PDGFR β转化的细胞系中观察到类似的调控模式，表明SKP 2/p27管道可能是致白细胞增多性酪氨酸激酶的通用靶标。接受BCR-ABL感染的SKP 2（-/-）骨髓移植的小鼠出现骨髓增殖综合征，但与接受BCR-ABL表达的SKP 2（+/+）骨髓移植的小鼠相比，存活时间显著延长。SKP 2（-/-）白血病细胞比SKP 2（+/+）白血病细胞表现出更高水平的核p27，这表明白血病发生的减弱依赖于p27表达的增加。我们的数据确定SKP 2作为BCR-ABL诱导的白血病发生的关键介质，并提供了SKP 2促进肿瘤发生的第一个体内证据。因此，通过抑制p27被SCFSKP 2识别来稳定p27可能在治疗上有用。
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 SCFSKP2 (SKP1/Cul1/F-box), the E3 ubiquitin ligase that promotes proteasomal degradation of p27. Inhibition of BCR-ABL kinase causes G, arrest, downregulation 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 beta, suggesting that the SKP2/p27 conduit may be a universal target for leukernogenic 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 SCFSKP2 may be therapeutically useful.