title: Regulation of global gene expression and cell proliferation by APP.
abstract: Down syndrome (DS), caused by trisomy of chromosome 21, is one of the most common genetic disorders. Patients with DS display growth retardation and inevitably develop characteristic Alzheimer's disease (AD) neuropathology, including neurofibrillary tangles and neuritic plaques. The expression of amyloid precursor protein (APP) is increased in both DS and AD patients. To reveal the function of APP and elucidate the pathogenic role of increased APP expression in DS and AD, we performed gene expression profiling using microarray method in human cells overexpressing APP. A set of genes are significantly altered, which are involved in cell cycle, cell proliferation and p53 signaling. We found that overexpression of APP inhibits cell proliferation. Furthermore, we confirmed that the downregulation of two validated genes, PSMA5 and PSMB7, inhibits cell proliferation, suggesting that the downregulation of PSMA5 and PSMB7 is involved in APP-induced cell proliferation impairment. Taken together, this study suggests that APP regulates global gene expression and increased APP expression inhibits cell proliferation. Our study provides a novel insight that APP overexpression may contribute to the growth impairment in DS patients and promote AD pathogenesis by inhibiting cell proliferation including neural stem cell proliferation and neurogenesis.
authors.affiliation: Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.|Ministry of Education Key Lab of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.|Department of Psychiatry, Jining Medical University, Jining, Shandong, 272067, China.
authors.forename: Yili
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Ministry of Education Key Lab of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Si
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Qin
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zou
authors.affiliation: Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.|Ministry of Education Key Lab of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Weihui
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.affiliation: Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.|Ministry of Education Key Lab of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Tingyu
authors.initials: T
authors.lastname: Li
authors.affiliation: Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.|Ministry of Education Key Lab of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.|Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C576985:PSMA5 protein, human; D046988:Proteasome Endopeptidase Complex