Amyloid-β precursor-like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress

• Published in: Oncogene Vol. 26; no. 52; pp. 7302 - 7312
• Main Authors: TANG, X, MILYAVSKY, M, GOLDFINGER, N, ROTTER, V
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 15.11.2007; Nature Publishing Group
• Subjects: Amyloid beta-Protein Precursor - antagonists & inhibitors; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Apoptosis; Biological and medical sciences; Cancer; Cell Death; Cell differentiation; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells, Cultured; Cellular Senescence - physiology; Cellular stress response; Chromatin Immunoprecipitation; DNA microarrays; Epithelial cells; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Genetic aspects; Genotoxicity; Humans; Immunoblotting; Kinases; Luciferases - metabolism; Lung - embryology; Lung - metabolism; Medical sciences; Molecular and cellular biology; Molecular genetics; Neuroblastoma; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neurodegenerative diseases; Neurology; Oligonucleotide Array Sequence Analysis; p53 Protein; Promoter Regions, Genetic; Properties; Regulatory sequences; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - pharmacology; Senescence; Transcription; Transcription, Genetic; Transcription. Transcription factor. Splicing. Rna processing; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Tumors of the nervous system. Phacomatoses; β-Amyloid; Israel; Nervous system diseases; Senescence; Transcription; Toxicity; Alzheimer disease; neuroblastoma and Alzheimer's disease; Genotoxicity; APLP1; Malignant tumor; Neuroblastoma; Carcinogenesis; Protein; Stress; Cerebral disorder; p53; TP53 Gene; Cell death; Central nervous system disease; Degenerative disease; Amyloid; Autonomic neuropathy; Cancer; Apoptosis; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210542

The tumor suppressor p53 is a key modulator of the cellular stress response, inducing cell-cycle arrest, apoptosis, senescence and cell differentiation. To evaluate further the molecular mechanism underlying p53 function, the transcriptional profiles of proliferating and senescent WI-38 cells, both wild-type p53 expressers and counterparts with an inactivated p53, were compared by DNA microarray analysis. In particular, the amyloid-beta precursor-like protein 1 (APLP1) is induced in senescent cells in a p53-dependent manner. APLP1 was confirmed to be a novel transcriptional target of p53 by in vivo and in vitro characterization of a p53 responsive element found in the first intron of the APLP1 gene locus. APLP1 knockdown experiments demonstrate that APLP1 is required for the proliferation of fibroblastic and epithelial cells. Moreover, depletion of APLP1 expression diminishes stress-induced apoptosis of neural cells, whereas ectopic APLP1 expression augments apoptosis. Based on these data, a mechanism is proposed whereby p53-dependent induction of APLP1 is involved in neural cell death, and which may exacerbate neuronal cell loss in some acute or chronic neurodegenerative disorders.