Control of transferrin expression by β-amyloid through the CP2 transcription factor.
Accumulation of β-amyloid protein (Aβ) is one of the most important pathological features of Alzheimer's disease. Although Aβ induces neurodegeneration in the cortex and hippocampus through several molecular mechanisms, few studies have evaluated the modulation of transcription factors during Aβ-induced neurotoxicity. Therefore, in this study, we investigated the transcriptional activity of transcription factor CP2 in neuronal damage mediated by Aβ (Aβ(1-42) and Aβ(25-35) ). An unbiased motif search of the transferrin promoter region showed that CP2 binds to the transferrin promoter, an iron-regulating protein, and regulates transferrin transcription. Ectopic expression of CP2 led to increased transferrin expression at both the mRNA and protein levels, whereas knockdown of CP2 down-regulated transferrin mRNA and protein expression. Moreover, CP2 trans-activated transcription of a transferrin reporter gene. An electrophoretic mobility shift assay and a chromatin immunoprecipitation assay showed that CP2 binds to the transferrin promoter region. Furthermore, the binding affinity of CP2 to the transferrin promoter was regulated by Aβ, as Aβ (Aβ(1-42) and Aβ(25-35) ) markedly increased the binding affinity of CP2 for the transferrin promoter. Taken together, these results suggest that CP2 contributes to the pathogenesis of Alzheimer's disease by inducing transferrin expression via up-regulating its transcription.
Jang
Sang-Min
SM
Department of Life Science (BK21 Program), College of Natural Sciences, Chung-Ang University, Seoul, Korea.
Kim
Jung-Woong
JW
Kim
Chul-Hong
CH
An
Joo-Hee
JH
Kang
Eun-Jin
EJ
Kim
Chul Geun
CG
Kim
Hyun-Jung
HJ
Choi
Kyung-Hee
KH
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D017124:Conserved Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D008156:Luciferases / Q000235:genetics; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014168:Transferrin / Q000235:genetics*; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D017931:DNA Primers; D004268:DNA-Binding Proteins; C501906:TFCP2 protein, human; D014157:Transcription Factors; D014168:Transferrin; D008156:Luciferases