Stress response gene ATF3 is a target of c-myc in serum-induced cell proliferation.
The c-myc proto-oncogene encodes a transcription factor that promotes cell cycle progression and cell proliferation, and its deficiency results in severely retarded proliferation rates. The ATF3 stress response gene encodes a transcription factor that plays a role in determining cell fate under stress conditions. Its biological significance in the control of cell proliferation and its crosstalk regulation, however, are not well understood. Here, we report that the serum response of the ATF3 gene expression depends on c-myc gene and that the c-Myc complex at ATF/CREB site of the gene promoter plays a role in mediating the serum response. Intriguingly, ectopic expression of ATF3 promotes proliferation of c-myc-deficient cells, mostly by alleviating the impeded G1-phase progression observed in these cells, whereas ATF3 knockdown significantly suppresses proliferation of wild-type cells. Our study demonstrates that ATF3 is downstream of the c-Myc signaling pathway and plays a role in mediating the cell proliferation function of c-Myc. Our results provide a novel insight into the functional link of the stress response gene ATF3 and the proto-oncogene c-myc.
Department of Biochemical Genetics, Medical Research Institute and Laboratory of Genome Structure and Regulation, School of Biomedical Science, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Kiyoshi
K
Tamura
Bayin
B
Hua
Susumu
S
Adachi
Isil
I
Guney
Junya
J
Kawauchi
Masaki
M
Morioka
Mimi
M
Tamamori-Adachi
Yujiro
Y
Tanaka
Yusaku
Y
Nakabeppu
Makoto
M
Sunamori
John M
JM
Sedivy
Shigetaka
S
Kitajima
D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D044967:Serum / Q000502:physiology*; D013312:Stress, Physiological / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases