(肌)营养不良短小蛋白结合蛋白1(dystrobrevin-binding protein 1, dysbindin-1)是溶酶体相关细胞器生物发生复合体-1(biogenesis of lysosome-related organelles complex-1, BLOC-1)的一个亚基,在内体-溶酶体通路的货物运输中发挥一...(肌)营养不良短小蛋白结合蛋白1(dystrobrevin-binding protein 1, dysbindin-1)是溶酶体相关细胞器生物发生复合体-1(biogenesis of lysosome-related organelles complex-1, BLOC-1)的一个亚基,在内体-溶酶体通路的货物运输中发挥一定作用。Dysbindin-1在睾丸组织中的作用尚不明确。本文从前期已筛选到的dysbindin-1在小鼠睾丸组织中的潜在互作蛋白质中,选取2个RNA结合蛋白(RNA-binding proteins, RBPs)脆性X相关蛋白1(fragile X related protein 1, FXR1P)和Y盒结合蛋白2(Y-box binding protein 2, YBX2),用GST pull-down和内源性免疫沉淀的方法进行相互作用的验证。结果显示,dysbindin-1与FXR1P和YBX2存在相互作用,提示dysbindin-1在睾丸组织RNA的运输中可能发挥作用。展开更多
Pancreatic ductal adenocarcinoma （PDAC） represents a biggest challenge in clinic oncology due to its invasiveness and lack of tar- geted therapeutics. Our recent study showed that schizophrenia susceptibility factor...Pancreatic ductal adenocarcinoma （PDAC） represents a biggest challenge in clinic oncology due to its invasiveness and lack of tar- geted therapeutics. Our recent study showed that schizophrenia susceptibility factor dysbindin exhibited significant higher level in serum of PDAC patients. However, the functional relevance of dysbindin in PDAC is still unclear. Here, we show that dysbindin pro- motes tumor growth both in vitro and in vivo by accelerating the G1/S phase transition in cell cycle via PI3K/AKT signaling path- way. Mechanistically, dysbindin interacts with PI3K and stimulates the kinase activity of PI3K. Moreover, overexpression of dysbindin in PDAC is correlated with clinicopathological characteristics significantly, such as histological differentiation （P = 0.011） and tumor size （P = 0.007）. Kaplan-Meier survival curves show that patients with high dysbindin expression exhibit poorer overall survival, compared to those with low dysbindin expression （P 〈 0.001）. Multivariate analysis reveals that dysbindin is an independ- ent prognostic factor for pancreatic ductal adenocarcinoma （P = 0.001）. Thus, our findings reveal that dysbindin is a novel PI3K acti- vator and promotes PDAC progression via stimulation of PI3K/AKT. Dysbindin therefore represents a potential target for prognosis and therapy of PDAC.展开更多
The Drosophila homolog of schizophrenia susceptibility gene dysbindin(Ddysb)affects a range of behaviors through regulation of multiple neurotransmitter signals,including dopamine activity.To gain insights into mechan...The Drosophila homolog of schizophrenia susceptibility gene dysbindin(Ddysb)affects a range of behaviors through regulation of multiple neurotransmitter signals,including dopamine activity.To gain insights into mechanisms underlying Ddysb-dependent regulation of dopamine signal,we investigated interaction between Ddysb and Ebony,the Drosophilaβ-alanyl-monoamine synthase involved in dopamine recycling.We found that Ddysb was capable of regulating expression of Ebony in a bi-directional manner and its subcellular distribution.Such regulation is confined to glial cells.The expression level of ebony and its accumulation in glial soma depend positively on Ddysb activity,whereas its distribution in glial processes is bound to be reduced in response to any alterations of Ddysb from the normal control level,either an increase or decrease.An optimal binding ratio between Dysb and Ebony might contribute to such non-linear effects.Thus,Ddysb-dependent regulation of Ebony could be one of the mechanisms that mediate dopamine signal.展开更多
Schizophrenia （SCZ） is a complex disease that has been regarded as a neurodevelopmental, synaptic or epigenetic disorder. Here we provide evidence that neurodegeneration is implicated in SCZ. The DTNBP1 （dystrobrev...Schizophrenia （SCZ） is a complex disease that has been regarded as a neurodevelopmental, synaptic or epigenetic disorder. Here we provide evidence that neurodegeneration is implicated in SCZ. The DTNBP1 （dystrobrevin-binding protein 1） gene encodes dysbindin-1 and is a leading susceptibility gene of SCZ. We previously reported that the dysbindin-lC isoform regulates the survival of the hilar glutamatergic mossy cells in the dentate gyms, which controls the adult hippocampal neurogenesis. However, the underlying mechanism of hilar mossy cell loss in the dysbindin-l-deficient sandy （sdy） mice （a mouse model of SCZ） is unknown. In this study, we did not observe the apoptotic signals in the hilar mossy cells of the sdy mice by using the TUNEL assay and immunostaining of cleaved caspase-3 or necdin, a dysbindin-1- and p53-interacting protein required for neuronal survival. However, we found that the steady-state level of LC3- II, a marker of autophagosomes, was decreased in the hippocampal formation in the mice lacking dysbindin-lC. Furthermore, we observed a significant reduction of the cytosolic LC3-II puncta in the mossy cells of sdy mice. In addition, overexpression of dysbindin- 1C, but not 1A, in cultured cells increased LC3-II level and the LC3 puncta in the transfected cells. These results suggest that dysbindin- 1C deficiency causes impaired autophagy, which is likely implicated in the pathogenesis of SCZ.展开更多
文摘(肌)营养不良短小蛋白结合蛋白1(dystrobrevin-binding protein 1, dysbindin-1)是溶酶体相关细胞器生物发生复合体-1(biogenesis of lysosome-related organelles complex-1, BLOC-1)的一个亚基,在内体-溶酶体通路的货物运输中发挥一定作用。Dysbindin-1在睾丸组织中的作用尚不明确。本文从前期已筛选到的dysbindin-1在小鼠睾丸组织中的潜在互作蛋白质中,选取2个RNA结合蛋白(RNA-binding proteins, RBPs)脆性X相关蛋白1(fragile X related protein 1, FXR1P)和Y盒结合蛋白2(Y-box binding protein 2, YBX2),用GST pull-down和内源性免疫沉淀的方法进行相互作用的验证。结果显示,dysbindin-1与FXR1P和YBX2存在相互作用,提示dysbindin-1在睾丸组织RNA的运输中可能发挥作用。
文摘Pancreatic ductal adenocarcinoma （PDAC） represents a biggest challenge in clinic oncology due to its invasiveness and lack of tar- geted therapeutics. Our recent study showed that schizophrenia susceptibility factor dysbindin exhibited significant higher level in serum of PDAC patients. However, the functional relevance of dysbindin in PDAC is still unclear. Here, we show that dysbindin pro- motes tumor growth both in vitro and in vivo by accelerating the G1/S phase transition in cell cycle via PI3K/AKT signaling path- way. Mechanistically, dysbindin interacts with PI3K and stimulates the kinase activity of PI3K. Moreover, overexpression of dysbindin in PDAC is correlated with clinicopathological characteristics significantly, such as histological differentiation （P = 0.011） and tumor size （P = 0.007）. Kaplan-Meier survival curves show that patients with high dysbindin expression exhibit poorer overall survival, compared to those with low dysbindin expression （P 〈 0.001）. Multivariate analysis reveals that dysbindin is an independ- ent prognostic factor for pancreatic ductal adenocarcinoma （P = 0.001）. Thus, our findings reveal that dysbindin is a novel PI3K acti- vator and promotes PDAC progression via stimulation of PI3K/AKT. Dysbindin therefore represents a potential target for prognosis and therapy of PDAC.
基金supported by the National Basic Research Program of Ministry of Science and Technology of China(2009CB941301 and 2013CB835102)the Tsinghua University Initiative Scientific Research Program(20111080956,all to Zhong Yi)+1 种基金the China Postdoctoral Science Foundation(2012M510412)supported by the Postdoctoral Fellowship at Tsinghua-Peking Center for Life Sciences
文摘The Drosophila homolog of schizophrenia susceptibility gene dysbindin(Ddysb)affects a range of behaviors through regulation of multiple neurotransmitter signals,including dopamine activity.To gain insights into mechanisms underlying Ddysb-dependent regulation of dopamine signal,we investigated interaction between Ddysb and Ebony,the Drosophilaβ-alanyl-monoamine synthase involved in dopamine recycling.We found that Ddysb was capable of regulating expression of Ebony in a bi-directional manner and its subcellular distribution.Such regulation is confined to glial cells.The expression level of ebony and its accumulation in glial soma depend positively on Ddysb activity,whereas its distribution in glial processes is bound to be reduced in response to any alterations of Ddysb from the normal control level,either an increase or decrease.An optimal binding ratio between Dysb and Ebony might contribute to such non-linear effects.Thus,Ddysb-dependent regulation of Ebony could be one of the mechanisms that mediate dopamine signal.
基金partially supported by grants from the National Natural Science Foundation of China(Nos.91332116 and 31230046)the National Basic Research Program of China(No.2014CB942803)Chinese Academy of Sciences(No.KJZD-EW-L08)
文摘Schizophrenia （SCZ） is a complex disease that has been regarded as a neurodevelopmental, synaptic or epigenetic disorder. Here we provide evidence that neurodegeneration is implicated in SCZ. The DTNBP1 （dystrobrevin-binding protein 1） gene encodes dysbindin-1 and is a leading susceptibility gene of SCZ. We previously reported that the dysbindin-lC isoform regulates the survival of the hilar glutamatergic mossy cells in the dentate gyms, which controls the adult hippocampal neurogenesis. However, the underlying mechanism of hilar mossy cell loss in the dysbindin-l-deficient sandy （sdy） mice （a mouse model of SCZ） is unknown. In this study, we did not observe the apoptotic signals in the hilar mossy cells of the sdy mice by using the TUNEL assay and immunostaining of cleaved caspase-3 or necdin, a dysbindin-1- and p53-interacting protein required for neuronal survival. However, we found that the steady-state level of LC3- II, a marker of autophagosomes, was decreased in the hippocampal formation in the mice lacking dysbindin-lC. Furthermore, we observed a significant reduction of the cytosolic LC3-II puncta in the mossy cells of sdy mice. In addition, overexpression of dysbindin- 1C, but not 1A, in cultured cells increased LC3-II level and the LC3 puncta in the transfected cells. These results suggest that dysbindin- 1C deficiency causes impaired autophagy, which is likely implicated in the pathogenesis of SCZ.
