title: Protein 4.1N acts as a potential tumor suppressor linking PP1 to JNK-c-Jun pathway regulation in NSCLC.
abstract: Protein 4.1N is a member of protein 4.1 family and has been recognized as a potential tumor suppressor in solid tumors. Here, we aimed to investigate the role and mechanisms of 4.1N in non-small cell lung cancer (NSCLC). We confirmed that the expression level of 4.1N was inversely correlated with the metastatic properties of NSCLC cell lines and histological grade of clinical NSCLC tissues. Specific knockdown of 4.1N promoted tumor cell proliferation, migration and adhesion in vitro, and tumor growth and metastasis in mouse xenograft models. Furthermore, we identified PP1 as a novel 4.1N-interacting molecule, and the FERM domain of 4.1N mediated the interaction between 4.1N and PP1. Further, ectopic expression of 4.1N could inactivate JNK-c-Jun signaling pathway through enhancing PP1 activity and interaction between PP1 and p-JNK. Correspondingly, expression of potential downstream metastasis targets (ezrin and MMP9) and cell cycle targets (p53, p21 and p19) of JNK-c-Jun pathway were also regulated by 4.1N. Our data suggest that down-regulation of 4.1N expression is a critical step for NSCLC development and that repression of JNK-c-Jun signaling through PP1 is one of the key anti-tumor mechanisms of 4.1N.
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.|Department of Medicine, University of California, Irvine, CA, USA.
authors.forename: Zi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Bianyin
authors.initials: B
authors.lastname: Ma
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Xiao
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.|Department of Biochemistry, College of Medicine, Jishou University, Jishou, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Medicine, University of California, Irvine, CA, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Yayue
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Shuming
authors.initials: S
authors.lastname: Sun
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Yanpeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Zhengzhou University, Zhengzhou, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Weng
authors.affiliation: College of Life Sciences, Zhengzhou University, Zhengzhou, China.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Ye
authors.affiliation: College of Life Sciences, Zhengzhou University, Zhengzhou, China.|Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA.
authors.forename: Xiuli
authors.initials: X
authors.lastname: An
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D009479:Neuropeptides; D017476:Receptors, Neuropeptide Y; D025521:Tumor Suppressor Proteins; C120557:erythrocyte membrane protein band 4.1-like 1; C109491:neuropeptide Y4 receptor; D048031:JNK Mitogen-Activated Protein Kinases
keywords: JNK/c-Jun pathway; PP1; non-small cell lung cancer; protein 4.1N; tumor suppressor