Novel function of transcription factor ATF5: blockade of p53-dependent apoptosis induced by ionizing irradiation.
OBJECTIVE
To find a new molecule that affects p53-dependent radiosensitivity.


METHODS
A mouse sarcoma cell line, QRsP(p53+/+), was used. From this cell line, we established a radiosensitive clone and a radioresistant one. Colony assay, p53 gene transfer, a luciferase assay for p53 and p21, animal transplantation experiment, and DNA array analyses were performed.


RESULTS
Microarray showed marked reduction of a transcription factor, ATF5, both in vitro and in vivo for the radiosensitive clone. Interestingly, flow cytometric analysis demonstrated marked apoptosis for the radiosensitive clone by p53 cloned adenovirus infection. Luciferase reporter assay revealed that ATF5 suppressed the transactivational activity of p53 and p63. By ATF5 gene transfer, the radiosensitive clone regained resistance to both ionizing-radiation and Ad-p53 infection-induced cell death. Surprisingly, time-lapse cell migration observation revealed greater cell motility for ATF5-transfected radiosensitive clone.


CONCLUSIONS
It seems likely that ATF5 is a potent repressor of p53 and elevated expression of ATF5 in a tumor may relate to enhanced malignant phenotypes, such as radioresistance or greater cell motility.
Nishioka
Takeshi
T
Department of Biomedical Sciences and Engineering, Faculty of Health Sciences, Graduate School of Health Sciences, Hokkaido University, Sapporo, Japan. trout@hs.hokudai.ac.jp
Miyai
Yusuke
Y
Haga
Hisashi
H
Kawabata
Kazushige
K
Shirato
Hiroki
H
Homma
Akihiro
A
Shibata
Kenichiro
K
Yasuda
Motoaki
M
D051696:Activating Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D051696:Activating Transcription Factors; C471855:Atf5 protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53