title: p75 neurotrophin receptor and its novel interaction partner, NIX, are involved in neuronal apoptosis after intracerebral hemorrhage.
abstract: Recently, NIX, a pro-apoptotic BH3-only protein, was found to be a novel p75 neurotrophin receptor (p75NTR) binding protein by screening a human fetal brain two-hybrid library in our laboratory. We further study the interaction of these two proteins and the possible roles of p75NTRand NIX in intracerebral hemorrhage (ICH)-induced neuronal death. Using the split-ubiquitin yeast two-hybrid system, we found that the "Copper" domain in p75NTRand the TM region in NIX were sufficient for the interaction of these two proteins. Co-immunoprecipitation and in vitro binding assays demonstrated the direct interaction between p75NTRand NIX. NIX protein was stabilized by p75NTRat post-translational levels. Moreover, p75NTRwas able to work together with NIX to promote apoptosis and affected the NIX-induced JNK-p53-Bax pathway in neuronal PC12 cells. Previous work has indicated that p75NTRand NIX are induced in neurons in human ICH and the rat ICH model, respectively. We confirm that both p75NTRand NIX levels were up-regulated in glutamate-treated primary cortical neurons (a cellular in vitro model for ICH) and in the rat ICH model. Glutamate exposure increased the association between p75NTRand NIX and elevated the activation of the JNK-p53-Bax pathway and neuronal apoptosis; all of these observations were similar in the rat ICH model. Importantly, p75NTRand NIX appeared to be involved in cortical neuronal apoptosis, because knockdown of p75NTRor NIX not only inhibited the JNK pathway but also impaired neuronal apoptosis. Thus, p75NTRand NIX may play critical roles in ICH-induced neuronal apoptosis in vitro and in vivo.
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China.
authors.forename: Jiabing
authors.initials: J
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, People's Republic of China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, People's Republic of China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 2005 Songhu Rd., Shanghai, 200438, People's Republic of China. kkhuo@fudan.edu.cn.
authors.forename: Keke
authors.initials: K
authors.lastname: Huo
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China. kekaifu_nt@126.com.
authors.forename: Kaifu
authors.initials: K
authors.lastname: Ke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C116838:BNIP3L protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D020800:Receptor, Nerve Growth Factor; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D051028:bcl-2-Associated X Protein; D018698:Glutamic Acid; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Intracerebral hemorrhage; JNK; NIX; Neuron; p75 neurotrophin receptor