TGF-β Induces Growth Arrest in Burkitt Lymphoma Cells via Transcriptional Repression of E2F-1
TGF-β Induces Growth Arrest in Burkitt Lymphoma Cells via Transcriptional Repression of E2F-1
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DOI：
10.1074/jbc.m808080200
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发表时间：
2009-01-16
影响因子：
4.8
通讯作者：
Inman, Gareth J.
中科院分区：
文献类型：
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作者：
Spender, Lindsay C.;Inman, Gareth J.
转化生长因子-β（TGF-β）是组织稳态的有效调节剂，并且可以充当肿瘤抑制剂和肿瘤促进剂。诱导细胞周期停滞的能力是TGF-β的肿瘤抑制功能的主要组成部分。肺、乳腺和皮肤上皮细胞对TGF-β信号传导的反应表现出共同的最小细胞生长抑制程序，涉及生长促进因子c-MYC、Id 1、Id 2和Id 3的抑制。c-MYC表达的丧失是这一过程中的关键事件，导致细胞周期蛋白依赖性激酶抑制剂CDKN 1A（p21）和CDKN 2B（p15）的去抑制，并最终导致生长停滞。然而，目前尚不清楚哪些反应是TGF-β介导的其他细胞类型生长停滞所必需的。在这里，在人类伯基特淋巴瘤细胞转化失调的c-MYC表达，我们证明，有效的TGF-β诱导的细胞抑制可以发生，尽管c-MYC水平的维护和缺乏p21和p15的诱导。TGF-β处理还导致Id 1和Id 2表达的诱导，而不是抑制。在这种情况下，生长停滞与E2 F-1的转录抑制相关，并且伯基特淋巴瘤细胞中E2 F-1的过表达在很大程度上克服了TGF-β介导的G（1）停滞表型。这些数据表明，c-MYC在淋巴瘤细胞中的失调不能克服TGF-β的肿瘤抑制功能，并且E2 F-1转录的抑制足以有效诱导细胞停滞。
Transforming growth factor-beta(TGF-beta) is a potent regulator of tissue homeostasis and can act as both a tumor suppressor and a tumor promoter. The ability to induce cell cycle arrest is a major component of the tumor suppressor function of TGF-beta. Lung, mammary, and skin epithelial cells exhibit a common minimal cytostatic program in response to TGF-beta signaling involving the repression of the growth-promoting factors c-MYC, Id1, Id2, and Id3. Loss of c-MYC expression is a pivotal event in this process, resulting in derepression of the cyclin-dependent kinase inhibitors CDKN1A (p21) and CDKN2B (p15) and ultimately leading to growth arrest. It is not clear, however, which responses are necessary for TGF-beta-mediated growth arrest in other cell types. Here, in human Burkitt lymphoma cells transformed by deregulated c-MYC expression, we demonstrate that efficient TGF-beta-induced cytostasis can occur despite both maintenance of c-MYC levels and a lack of p21 and p15 induction. TGF-beta treatment also results in induction, rather than repression, of Id1 and Id2 expression. In this context, growth arrest correlates with transcriptional repression of E2F-1, and overexpression of E2F-1 in Burkitt lymphoma cells largely overcomes the TGF-beta-mediated G(1) arrest phenotype. These data indicate that deregulation of c-MYC in lymphoma cells does not overcome the tumor suppressor function of TGF-beta and that repression of E2F-1 transcription is sufficient for the efficient induction of cytostasis.