College of Life Science, Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
Biochem Biophys Res Commun. 2011 Apr 29;408(1):84-8. doi: 10.1016/j.bbrc.2011.03.124. Epub 2011 Mar 31.
Human CAP10-like protein 46 kDa (hCLP46) is the homolog of Rumi, which is the first identified protein O-glucosyltransferase that modifies Notch receptor in Drosophila. Dysregulation of hCLP46 occurs in many hematologic diseases, but the role of hCLP46 remains unclear. Knockdown of hCLP46 by RNA interference resulted in decreased protein levels of endogenous Notch1, Notch intracellular domain (NICD) and Notch target gene Hes-1, suggesting the impairment of the Notch signaling. However, neither cell surface Notch expression nor ligand binding activities were affected. In addition, down-regulated expression of hCLP46 inhibited the proliferation of U937 cells, which was correlated with increased cyclin-dependent kinase inhibitor (CDKI) CDKN1B (p27) and decreased phosphorylation of retinoblastoma (RB) protein. We showed that lack of hCLP46 results in impaired ligand induced Notch activation in mammalian cell, and hCLP46 regulates the proliferation of U937 cell through CDKI-RB signaling pathway, which may be important for the pathogenesis of leukemia.
人源 CAP10 样蛋白 46kDa（hCLP46）是 Rumi 的同源物，Rumi 是在果蝇中首次被鉴定的 Notch 受体蛋白 O-糖基转移酶。hCLP46 在许多血液疾病中失调，但 hCLP46 的作用仍不清楚。RNA 干扰敲低 hCLP46 导致内源性 Notch1、Notch 细胞内结构域（NICD）和 Notch 靶基因 Hes-1 的蛋白水平降低，提示 Notch 信号受损。然而，细胞表面 Notch 表达或配体结合活性均不受影响。此外，下调 hCLP46 的表达抑制了 U937 细胞的增殖，这与细胞周期蛋白依赖性激酶抑制剂（CDKI）CDKN1B（p27）的增加和视网膜母细胞瘤（RB）蛋白磷酸化减少有关。我们表明，hCLP46 的缺失导致哺乳动物细胞中配体诱导的 Notch 激活受损，hCLP46 通过 CDKI-RB 信号通路调节 U937 细胞的增殖，这可能对白血病的发病机制很重要。
