Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells.
Stress response gene ATF3 plays a pleiotropic role in determining cell fate in response to mitogenic or stress stimuli. An alternate promoter of the human ATF3 gene (designated P1 in this study) has recently been reported, which is located approximately 43.5 kb upstream of the previously reported P2 promoter. We showed here that the P1 promoter is highly conserved between human and mouse and is functional in response to various stimuli, whereas the P1 promoter was dominantly induced by serum and the P2 promoter was more efficiently activated in response to TGF-beta and oncogenic HRAS. The P1 promoter contains multiple transcriptional start sites, and the different 5'-UTRs markedly affected their translation in response to stress. In human prostate and Hodgkin Reed-Sternberg cancer cells with elevated expression of ATF3, the P1 promoter was constitutively activated and its chromatin structure was modified into active configuration. The differential usage of alternate promoters of the ATF3 gene at both transcriptional and translational level and the modification of chromatin structure may provide a novel mechanism for expressing ATF3 in determining cell fate during stress response and cancer.
Miyazaki
Keisuke
K
Department of Biochemical Genetics, Medical Research Institute and Laboratory of Genome Structure and Regulation, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
Inoue
Shoko
S
Yamada
Kazuhiko
K
Watanabe
Masashi
M
Liu
Qin
Q
Watanabe
Toshiki
T
Adachi
Mimi Tamamori
MT
Tanaka
Yujiro
Y
Kitajima
Shigetaka
S
D020121:5' Untranslated Regions; D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D017124:Conserved Sequence; D004249:DNA Damage; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D024363:Transcription Initiation Site; D015533:Transcriptional Activation
D020121:5' Untranslated Regions; C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D002843:Chromatin