The small heat shock protein HspB2 is a novel anti-apoptotic protein that inhibits apical caspase activation in the extrinsic apoptotic pathway.
The small heat shock protein HspB2 is a novel anti-apoptotic protein that inhibits apical caspase activation in the extrinsic apoptotic pathway.
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DOI：
10.1007/s10549-010-0735-0
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发表时间：
2010-11
影响因子：
3.8
通讯作者：
Cryns, Vincent L.
中科院分区：
文献类型：
--
作者：
Oshita, Shayna E.;Chen, Feng;Kwan, Toni;Yehiely, Fruma;Cryns, Vincent L.
保守的小热休克蛋白（sHSP）家族的成员，如α B-晶体蛋白和HSP 27，在多种恶性肿瘤中组成性表达，并已与癌症的几个标志性特征，包括细胞凋亡抗性相关。与此相反，sHSP HspB 2/MKBP与α B-晶状体蛋白共享一个基因间启动子，被发现是强直性肌营养不良蛋白激酶的伴侣，以前没有涉及凋亡调控。在这里，我们描述了一个新的功能，热休克蛋白B2作为一种新的抑制剂的顶端半胱天冬酶激活的外源性凋亡途径。具体地说，我们证明了HspB 2在人乳腺癌细胞系的亚群中表达，并且HspB 2在乳腺癌细胞中的异位表达赋予对由TRAIL和TNF-α诱导的凋亡的抗性。我们还表明，热休克蛋白B2抑制外源性凋亡途径，抑制顶端半胱天冬酶-8和10的激活，从而阻断下游凋亡事件，如投标切割和半胱天冬酶-3激活。与这些体外作用一致，HspB 2减弱了TRAIL在乳腺癌原位异种移植模型中的抗肿瘤活性。总的来说，我们的研究结果揭示了一种新的功能，热休克蛋白B2作为一种抗凋亡蛋白，负调控顶端caspase激活的外源性凋亡途径。
Members of the conserved small heat shock protein (sHSP) family, such as αB-crystallin and Hsp27, are constitutively expressed in diverse malignancies and have been linked to several hallmark features of cancer including apoptosis resistance. In contrast, the sHSP HspB2/MKBP, which shares an intergenic promoter with αB-crystallin, was discovered as a chaperone of the myotonic dystrophy protein kinase and has not been previously implicated in apoptosis regulation. Here we describe a new function for HspB2 as a novel inhibitor of apical caspase activation in the extrinsic apoptotic pathway. Specifically, we demonstrate that HspB2 is expressed in a subset of human breast cancer cell lines and that ectopic expression of HspB2 in breast cancer cells confers resistance to apoptosis induced by both TRAIL and TNF-α. We also show that HspB2 inhibits the extrinsic apoptotic pathway by suppressing apical caspases-8 and 10 activation, thereby blocking downstream apoptotic events, such as Bid cleavage and caspase-3 activation. Consistent with these in vitro effects, HspB2 attenuates the anti-tumor activity of TRAIL in an orthotopic xenograft model of breast cancer. Collectively, our results reveal a novel function of HspB2 as an anti-apoptotic protein that negatively regulates apical caspase activation in the extrinsic apoptotic pathway.
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影响因子：
3.8
作者：
Ivanov, Olga;Chen, Feng;Cryns, Vincent L.
通讯作者：
Cryns, Vincent L.
影响因子：
4.8
作者：
Kischkel, FC;Lawrence, DA;Ashkenazi, A
通讯作者：
Ashkenazi, A
影响因子：
82.9
作者：
LeBlanc, H;Lawrence, D;Ashkenazi, A
通讯作者：
Ashkenazi, A
影响因子：
11.5
作者：
Lu, Meiling;Strohecker, Anne;Cryns, Vincent L.
通讯作者：
Cryns, Vincent L.
影响因子：
4.8
作者：
Chen, F;Arseven, OK;Cryns, VL
通讯作者：
Cryns, VL