Tissue transglutaminase protects against apoptosis by modifying the tumor suppressor protein p110 Rb.
Tissue transglutaminase protects against apoptosis by modifying the tumor suppressor protein p110 Rb.
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DOI：
10.1074/jbc.c200147200
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发表时间：
2002-06-07
影响因子：
4.8
通讯作者：
Cerione, RA
中科院分区：
文献类型：
--
作者：
Boehm, JE;Singh, U;Cerione, RA
组织转氨酶（TGase）参与调节包括细胞分化和凋亡在内的多种生物学事件。TGase的表达和活化在视黄酸（RA）的作用下上调，从而保护几种细胞系免受N-（4-羟基苯基）视黄酰胺（HPR）诱导的凋亡。目前对TGase的抗凋亡机制知之甚少。我们研究了TGase与视网膜母细胞瘤（Rb）蛋白的相互作用，该蛋白是TGase的底物，也与细胞存活功能有关。在经历HPR诱导的凋亡的细胞中，Rb被降解。当细胞用RA（TGase的重要调节剂）预处理时，这种降解被阻断。在体外研究表明，TGase保护Rb从半胱天冬酶诱导的降解在一个transamidation依赖性的方式。用来自Rb-/-小鼠的成纤维细胞进行的实验进一步证明，Rb的存在是TGase响应于RA处理而表现出抗凋亡活性所必需的。显微注射的Rb-/-细胞与transamidation缺陷的TGase突变体和Rb没有提供保护HPR诱导的凋亡。总之，这些发现表明，TGase通过转酰胺作用修饰Rb的能力是TGase提供抗凋亡损伤保护并确保细胞在分化期间保持活力的能力的基础。
Tissue transglutaminase (TGase) is involved in the regulation of several biological events including cellular differentiation and apoptosis. The expression and activation of TGase are up-regulated in response to retinoic acid (RA), leading to the protection of several cell lines against N-(4-hydroxyphenyl)retinamide (HPR)-induced apoptosis. The anti-apoptotic mechanisms of TGase are poorly understood at this time. We examined the interaction of TGase with the retinoblastoma (Rb) protein, a substrate of TGase that is also implicated in cell survival functions. In cells undergoing HPR-induced apoptosis, Rb is degraded. This degradation is blocked when cells are pretreated with RA, an important regulator of TGase. In vitro studies revealed that TGase protects Rb from caspase-induced degradation in a transamidation-dependent manner. Experiments performed with fibroblasts from Rb-/- mice further demonstrated that the presence of Rb was required for TGase to exhibit antiapoptotic activity in response to RA treatment. Microinjection of Rb-/- cells with a transamidation-defective TGase mutant and Rb afforded no protection from HPR-induced apoptosis. Taken together, these findings suggest that the ability of TGase to modify Rb via transamidation underlies the ability of TGase to provide protection against apoptotic insults and to ensure that cells remain viable during differentiation.