SerpinB2 protection of retinoblastoma protein from calpain enhances tumor cell survival.
SerpinB2 protection of retinoblastoma protein from calpain enhances tumor cell survival.
复制标题
SERPINB2保护视网膜母细胞瘤免受钙蛋白酶的保护可增强肿瘤细胞的存活。
DOI：
10.1158/0008-5472.can-07-5850
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Antalis, Toni M.
中科院分区：
文献类型：
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作者：
Tonnetti, Laura;Netzel-Arnett, Sarah;Darnell, Grant A.;Hayes, Tamara;Buzza, Marguerite S.;Anglin, Ian E.;Suhrbier, Andreas;Antalis, Toni M.
肿瘤抑制视网膜母细胞瘤蛋白 Rb 通过与 E2F 转录因子结合，在细胞增殖调节和细胞凋亡敏感性中发挥关键作用。因基因毒性应激或炎症细胞因子而导致的 Rb 损失可以部分地通过消除 Rb 介导的促凋亡基因转录抑制来增强细胞死亡。在这里，我们表明，钙蛋白酶对 Rb 的切割通过蛋白酶体降解促进了 Rb 的损失，并且这可能发生在 TNFα 诱导的细胞凋亡过程中。细胞保护性 Rb 结合蛋白 SerpinB2（2 型纤溶酶原激活剂抑制剂；PAI-2）可保护 Rb 免受钙蛋白酶裂解，从而提高 Rb 水平并增强细胞存活率。染色质免疫沉淀测定表明，增加的 Rb 水平选择性增强 Rb 对促凋亡基因转录的抑制。 SerpinB2 的这种细胞保护作用可以通过 SerpinB2 缺陷小鼠对多阶段皮肤癌发生的易感性降低来说明，其中 Rb 依赖性细胞增殖在乳头状瘤发展开始期间与细胞凋亡竞争。这些数据将 SerpinB2 确定为细胞存活因子，可调节促凋亡信号转导的 Rb 抑制，并定义了选择性调节细胞内 Rb 水平的新翻译后机制。
The tumor suppressor retinoblastoma protein, Rb, plays a pivotal role in the regulation of cell proliferation and sensitivity to apoptosis through binding to E2F transcription factors. Loss of Rb in response to genotoxic stress or inflammatory cytokines can enhance cell death, in part, by eliminating Rb-mediated repression of proapoptotic gene transcription. Here we show that calpain cleavage of Rb facilitates Rb loss by proteasome degradation and that this may occur during TNFα induced apoptosis. The cytoprotective, Rb-binding protein, SerpinB2 (Plasminogen activator inhibitor type 2; PAI-2) protects Rb from calpain cleavage, increasing Rb levels and enhancing cell survival. Chromatin immunoprecipitation assays show that the increased Rb levels selectively enhance Rb- repression of proapoptotic gene transcription. This cytoprotective role of SerpinB2 is illustrated by reduced susceptibility of SerpinB2-deficient mice to multistage skin carcinogenesis, where Rb dependent cell proliferation competes with apoptosis during initiation of papilloma development. These data identify SerpinB2 as cell survival factor that modulates Rb-repression of proapoptotic signal transduction, and define a new post-translational mechanism for selective regulation of the intracellular levels of Rb.