p27 deficiency cooperates with Bcl-2 but not Bax to promote T-cell lymphoma.
p27 deficiency cooperates with Bcl-2 but not Bax to promote T-cell lymphoma.
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DOI：
10.1371/journal.pone.0001911
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发表时间：
2008-04-02
期刊：
影响因子：
3.7
通讯作者：
Knudson CM
中科院分区：
文献类型：
--
作者：
Cheng N;van de Wetering CI;Knudson CM
Bcl2在肿瘤发生中的作用是复杂的，其表达可以延缓或加速肿瘤的发生。其促肿瘤活性归因于其特有的抗凋亡作用，而抗肿瘤作用归因于其抑制细胞增殖的作用。最近的研究表明，p27可能介导了Bcl2对细胞增殖的影响。我们推测p27可能通过抑制Bcl2家族成员的肿瘤形成而起作用。为了验证这一假设，我们研究了p27基因缺失的Lck-Bcl2和Lck-Bax38/1转基因小鼠的细胞周期抑制和淋巴瘤的发生。值得注意的是，p27缺失与Bcl2协同作用，增加了T细胞的增殖和自发性T细胞淋巴瘤的发生。在一年内，90%的小鼠患上了胸腺T细胞淋巴瘤。这一高外显率与仅在LCK-Bcl2或p27−/−小鼠中胸腺淋巴瘤的一年发病率为5%形成了鲜明对比。相比之下，p27缺陷对另一种T细胞淋巴瘤模型Lck-Bax38/1转基因小鼠的肿瘤形成没有影响。在组织学上，p27−/−LCK-Bcl2小鼠的淋巴瘤是淋巴母细胞性的，常累及多个器官，提示其具有侵袭性表型。有趣的是，在成熟的脾T细胞中，即使在没有p27的情况下，Bcl2也在很大程度上保留了其抗增殖功能。P27CDK2LCK-−/−-Bcl2小鼠T细胞表现出CDK2Thr-160磷酸化的延迟动力学。这种延迟与Cyclin D2和D3上调的延迟有关。这些数据显示了Bcl2家族、细胞增殖和肿瘤发生之间的复杂关系，并表明p27上调在表达Bcl2家族成员的T细胞的增殖延迟中并不是特别重要的。尽管如此，结果表明p27在Bcl2表达的背景下是一个关键的肿瘤抑制因子。
The effect of Bcl-2 on oncogenesis is complex and expression may either delay or accelerate oncogenesis. The pro-oncogenic activity is attributed to its well characterized anti-apoptotic function while the anti-oncogenic function has been attributed to its inhibition of cellular proliferation. Recent studies demonstrate that p27 may mediate the effects of Bcl-2 on cellular proliferation. We hypothesized that p27 may suppress tumor formation by Bcl-2 family members. To test this hypothesis, cell cycle inhibition and lymphoma development were examined in Lck-Bcl-2 and Lck-Bax38/1 transgenic mice deficient in p27. Strikingly, p27 deficiency synergistically cooperates with Bcl-2 to increase T cell hyperplasia and development of spontaneous T cell lymphomas. Within 1 year, >90% of these mice had developed thymic T cell lymphomas. This high penetrance contrasts with a one year incidence of <5% of thymic lymphoma in Lck-Bcl-2 or p27 −/− mice alone. In contrast, p27 deficiency had no effect on tumor formation in Lck-Bax38/1 transgenic mice, another model of T cell lymphoma. Histologically the lymphomas in p27 −/− Lck-Bcl-2 mice are lymphoblastic and frequently involve multiple organs suggesting an aggressive phenotype. Interestingly, in mature splenic T cells, Bcl-2 largely retains its anti-proliferative function even in the absence of p27. T cells from p27 −/− Lck-Bcl-2 mice show delayed kinetics of CDK2 Thr-160 phosphorylation. This delay is associated with a delay in the up regulation of both Cyclin D2 and D3. These data demonstrate a complex relationship between the Bcl-2 family, cellular proliferation, and oncogenesis and demonstrate that p27 up-regulation is not singularly important in the proliferative delay observed in T cells expressing Bcl-2 family members. Nonetheless, the results indicate that p27 is a critical tumor suppressor in the context of Bcl-2 expression.
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影响因子：
8
作者：
Greider, C;Chattopadhyay, A;Yang, E
通讯作者：
Yang, E
影响因子：
8
作者：
Cheng, NL;Janumyan, YM;Knudson, CM
通讯作者：
Knudson, CM
影响因子：
12.4
作者：
Luke, JJ;van de Wetering, CI;Knudson, CM
通讯作者：
Knudson, CM
影响因子：
4.4
作者：
Hadzic, T;Li, L;Knudson, CM
通讯作者：
Knudson, CM
DOI：
10.1073/pnas.82.21.7439
发表时间：
1985-01-01
影响因子：
11.1
作者：
CLEARY, ML;SKLAR, J
通讯作者：
SKLAR, J