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Abstract：
Epigenetic gene silencing of the tumor suppressor death-associated protein kinase 1 (DAPK1) is implicated in the progression of malignant gliomas. However, the mechanism underlying the repression of DAPK1 in gliomas remains elusive. In this study, we identified the existence of DAPK1-inositol 1,4,5-trisphosphate receptor (IP3R)-interacting protein (ITPRIP) -myosin regulatory light polypeptide 9 (MYL9) complex in malignant glioma cells. Lentivirus co-infection and coimmunoprecipitation showed that ITPRIP bound with the death domain (DD) of DAPK1 in vitro. Further, dissociating ITPRIP-DAPK1 interaction inhibited glioma tumor growth in vitro but not in vivo. Moreover, knockdown of ITPRIP or DAPK1 impaired the ternary complex formation, whereas MYL9 knockdown did not affect ITPRIP-DAPK1 association. We further found that ITPRIP recruited MYL9 to the kinase domain (KD) of DAPK1, and in turn impeded the phosphorylation of MYL9. Accordingly, interference of ITPRIP enhanced the suppressive effects of DAPK1-KD on glioma progression both in vitro and in vivo. Our results demonstrate that ITPRIP plays a crucial role in the inhibition of DAPK1 and enhancement of tumorigenic properties of malignant glioma cells.
摘要：
肿瘤抑制死亡相关蛋白激酶1（DAPK1）的表观遗传基因沉默与恶性神经胶质瘤的进展有关。然而,神经胶质瘤中DAPK1抑制的潜在机制仍然难以捉摸。在这项研究中,我们发现恶性神经胶质瘤细胞中存在DAPK1-肌醇1,4,5-三磷酸受体(IP3R)相互作用蛋白(ITPRIP)-肌球蛋白调节光多肽9(MYL9)复合物.慢病毒共感染和共免疫沉淀表明ITPRIP在体外与DAPK1的死亡结构域(DD)结合。Further,分离的ITPRIP-DAPK1相互作用在体外但不在体内抑制神经胶质瘤肿瘤的生长。此外，ITPRIP或DAPK1的敲低损害了三元复合物的形成，而MYL9敲低并不影响ITPRIP-DAPK1的关联。我们进一步发现ITPRIP将MYL9募集到DAPK1的激酶结构域（KD），进而阻碍了MYL9的磷酸化。因此，ITPRIP的干扰增强了DAPK1-KD在体外和体内对神经胶质瘤进展的抑制作用。我们的结果表明，ITPRIP在抑制DAPK1和增强恶性神经胶质瘤细胞的致瘤特性中起着至关重要的作用。
