Foxp3 expression in p53-dependent DNA damage responses.
The forkhead transcription factor, Foxp3, is thought to act as a master regulator that controls (suppresses) expression of the breast cancer oncogenes, SKP2 and HER-2/ErbB2. However, the mechanisms that regulate Foxp3 expression and thereby modulate tumor development remain largely unexplored. Here, we demonstrate that Foxp3 up-regulation requires p53 function, showing that Foxp3 expression is directly regulated by p53 upon DNA damage responses in human breast and colon carcinoma cells. Treatment with the genotoxic agents, doxorubicin or etoposide, induced Foxp3 expression in p53-positive carcinoma cells, but not in cells lacking p53 function. Furthermore, knock down of endogenous wild-type p53 using RNA interference abrogated Foxp3 induction by genotoxic agents, and exogenous expression of p53 in cells lacking p53 restored the responsiveness of Foxp3 to DNA-damaging stresses. In addition, Foxp3 knock down blunted the p53-mediated growth inhibitory response to DNA-damaging agents. These results suggest that induction of Foxp3 in the context of tumor suppression is regulated in a p53-dependent manner and implicate Foxp3 as a key determinant of cell fate in p53-dependent DNA damage responses.
Jung
Da-Jung
DJ
Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul 110-744, USA.
Jin
Dong-Hoon
DH
Hong
Seung-Woo
SW
Kim
Jee-Eun
JE
Shin
Jae-Sik
JS
Kim
Daejin
D
Cho
Byung-Joo
BJ
Hwang
Young-Il
YI
Kang
Jae-Seung
JS
Lee
Wang-Jae
WJ
D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage / Q000235:genetics*; D004317:Doxorubicin / Q000633:toxicity; D005047:Etoposide / Q000633:toxicity; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010766:Phosphorylation / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D005047:Etoposide; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2