ATF3 plays a protective role against toxicity by N-terminal fragment of mutant huntingtin in stable PC12 cell line.
Huntington's disease is a progressive neurodegenerative disorder caused by a polyglutamine expansion near the N-terminus of huntingtin. The mechanisms of polyglutamine neurotoxicity, and cellular responses are not fully understood. We have studied gene expression profiles by short oligo array using an inducible PC12 cell model expressing an N-terminal huntingtin fragment with expanded polyglutamine (Htt-N63-148Q). Mutant huntingtin Htt-N63 induced cell death and increased the mRNA and protein levels of activating transcription factor 3 (ATF3). Mutant Htt-N63 also significantly enhanced ATF3 transcriptional activity by a promoter-based reporter assay. Overexpression of ATF3 protects against mutant Htt-N63 toxicity and knocking down ATF3 expression reduced Htt-N63 toxicity in a stable PC12 cell line. These results indicated that ATF3 plays a critical role in toxicity induced by mutant Htt-N63 and may lead to a useful therapeutic target.
Liang
Yideng
Y
Division of Neurobiology, Department of Psychiatry, The Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe St., Baltimore, MD 21287, USA.
Jiang
Haibing
H
Ratovitski
Tamara
T
Jie
Chunfa
C
Nakamura
Masayuki
M
Hirschhorn
Ricky R
RR
Wang
Xiaofang
X
Smith
Wanli W
WW
Hai
Tsonwin
T
Poirier
Michelle A
MA
Ross
Christopher A
CA
D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015870:Gene Expression; D020869:Gene Expression Profiling; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection
D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C097188:polyglutamine