IRF1 suppresses Ki-67 promoter activity through interfering with Sp1 activation.
Interferon regulatory factor 1 (IRF1) shows tumor-suppressor activity by suppressing proliferation of cancer cells. To exert its anti-proliferative effects, this factor must ultimately control transcription of several key genes that regulate cell cycle progression. Here, we showed that Ki-67 gene is a novel proliferation-related downstream target of IRF1. IRF1 repressed Ki-67 gene transcription in a dose-dependent manner in human Ketr-3 and 786-O renal carcinoma cells. We previously cloned the Ki-67 core promoter which contained two functional Sp1 binding sites. Mutation of the two Sp1 binding sites abrogated Sp1-dependent enhancement of Ki-67 promoter activity. Forced elevation of IRF1 decreased endogenous Sp1 protein level. However, there was no effect on Sp1 mRNA level after transfected with IRF1. Our findings establish a casual series of events that connect anti-proliferative effects of IRF1 with the Ki-67 gene, which encodes a key regulator of the G1/S phase transition. It suggests that the inhibitory effect on Ki-67 gene expression mediated by decreasing level of Sp1 protein might be a novel function of the anti-tumor activity of IRF1.
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, 221002 Jiangsu, People's Republic of China.
Feifei
F
Chen
Jian
J
Song
Jiehui
J
Di
Qing
Q
Zhang
Hui
H
Tian
Junnian
J
Zheng
D001665:Binding Sites; D015153:Blotting, Western; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000235:genetics* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D008156:Luciferases