NELL2 Function in the Protection of Cells against Endoplasmic Reticulum Stress

Continuous intra- and extracellular stresses induce disorder of Ca²⁺ homeostasis and accumulation of unfolded protein in the endoplasmic reticulum (ER), which results in ER stress. Severe long-term ER stress triggers apoptosis signaling pathways, resulting in cell death. Neural epidermal growth factor-like like protein 2 (NELL2) has been reported to be important in protection of cells from cell death-inducing environments. In this study, we investigated the cytoprotective effect of NELL2 in the context of ER stress induced by thapsigargin, a strong ER stress inducer, in Cos7 cells. Overexpression of NELL2 prevented ER stress-mediated apoptosis by decreasing expression of ER stress-induced C/EBP homologous protein (CHOP) and increasing ER chaperones. In this context, expression of anti-apoptotic Bcl-xL was increased by NELL2, whereas NELL2 decreased expression of pro-apoptotic proteins, such as cleaved caspases 3 and 7. This anti-apoptotic effect of NELL2 is likely mediated by extracellular signal-regulated kinase (ERK) signaling, because its inhibitor, U0126, inhibited effects of NELL2 on the expression of anti- and pro-apoptotic proteins and on the protection from ER stress-induced cell death.     

Neural Epidermal Growth Factor-Like Like Protein 2 (NELL2) Promotes Aggregation of Embryonic Carcinoma P19 Cells by Inducing N-Cadherin Expression

NELL2 was first identified as a mammalian homolog of chick NEL (Neural EGF-like) protein. It is almost exclusively expressed in neurons of the rat brain and has been suggested to play a role in neural differentiation. However, there is still no clear evidence for the detailed function of NELL2 in the differentiation of neurons. In this study, we identified NELL2 function during neural differentiation of mouse embryonic carcinoma P19 cells. Endogenous expression of NELL2 in the P19 cells increased in parallel with the neuronal differentiation induced by retinoic acid (RA). We found that the mouse NELL2 promoter contains RA response elements (RAREs) and that treatment with RA increased NELL2 promoter activity. Transfection of P19 cells with NELL2 expression vectors induced a dramatic increase in cell aggregation, resulting in the facilitation of neural differentiation. Moreover, NELL2 significantly increased N-cadherin expression in the P19 cell. These data suggest that NELL2 plays an important role in the regulation of neuronal differentiation via control of N-cadherin expression and cell aggregation.     

低、高频电针诱导原癌基因c－fos／c－jun和阿片肽基因表达及其关系的比较研究

本工作对低频（２Ｈｚ）和高频（１００Ｈｚ）电针引起大鼠中枢Ｆｏｓ／Ｊｕｎ表达和三类阿片肽基因表达进行了详细的比较研究,并用针对ｃ－ｆｏｓ／ｃ－ｊｕｎ的反义寡核苷酸（ＯＤＮｓ）对电针引起的Ｆｏｓ／Ｊｕｎ表达进行选择性阻断,然后观察阿片肽基因表达是否受到影响,以确定Ｆｏｓ／Ｊｕｎ复合物在电针引起阿片肽基因表达中的作用。主要结果如下：（１）２Ｈｚ和１００Ｈｚ电针引起脑内不同部位的Ｆｏｓ／Ｊｕｎ表达;（２）２Ｈｚ电针使前脑啡肽原（ＰＰＥ）ｍＲＮＡ表达大幅度增高,１００Ｈｚ电针也能增加ＰＰＥｍＲＮＡ的转录,但不如２Ｈｚ电针的作用显著;但１００Ｈｚ电针能使某些脑区的前强啡肽原（ＰＰＤ）基因转录加速,而２Ｈｚ电针没有这一作用;（３）用ｃ－ｆｏｓ／ｃ－ｊｕｎ反义ＯＤＮｓ特异地阻断Ｆｏｓ／Ｊｕｎ表达后,电针引起的ＰＰＤ转录加速被明显阻断,而ＰＰＥ表达不受影响。提示Ｆｏｓ／Ｊｕｎ是电针引起ＰＰＤ（而非ＰＰＥ）基因表达的转录因子。     

The neuronal EGF-related genes NELL1 and NELL2 are expressed in hemopoietic cells and developmentally regulated in the B lineage

NELL1 and NELL2 (neural epidermal growth factor-like 1 and 2) are recently described members of the epidermal growth factor gene family that have previously been shown to be expressed almost exclusively in brain tissue. Here we demonstrate regulated expression of NELL1 and NELL2 in human hematopoietic cells. Mature NELL1 mRNA is not detected in any normal hemopoietic cell type, although the gene is transcribed during a narrow window of pre-B cell development, and cell lines at the same developmental stage express the NELL1 mRNA. The related NELL2 gene is expressed by all nucleated peripheral blood cells examined (B, T, monocyte, and natural killer cells), but not in any of the bone marrow B lineage cells at earlier stages of development. However, leukemic cell lines corresponding to the same early differentiation stages express abundant NELL2 mRNA. These results suggest normal and possible oncogenic roles for the NELL proteins in hemopoietic cells.     

蛋白激酶MSK在表观遗传学调控中的作用及其生物学意义

丝裂原和应激激活的蛋白激酶(MSK)是一类核内丝/苏氨酸蛋白激酶,参与丝裂原激活蛋白激酶(MAPK)信号通路介导的下游基因转录调控和表观遗传学调控.首先,MSK是MAPK通路的下游媒介分子.在丝裂原或应激刺激下,p38或ERK激酶通过级联磷酸化激活MSK蛋白.然后,活化的MSK介导转录因子磷酸化活化和组蛋白H3的10位丝氨酸磷酸化.MSK介导的组蛋白H3磷酸化,可引发组蛋白乙酰化和甲基化修饰的动态变化,相互协同或拮抗,开放染色质结构,利于诱导型基因的表达.除组蛋白H3外,MSK直接磷酸化的下游底物还包括CREB、NF-κB等转录因子以及多个非转录相关蛋白.因此,MSK能在多层次调控基因表达和细胞功能,广泛参与肿瘤转化、炎症反应、神经突触可塑性以及心肌肥大等生物学事件.本文将简要介绍MSK蛋白的研究进展,探讨其在转录调控、表观遗传学修饰等生物学事件中的作用.