Blockade of AP-1 activity by dominant-negative TAM67 can abrogate the oncogenic phenotype in latent membrane protein 1-positive human nasopharyngeal carcinoma.
Although activating protein-1 (AP-1) transcription factors play an important role in mediating metastasis for nasopharyngeal carcinoma (NPC), the biological and physiological functions of AP-1, in relation to the oncogenic phenotype of NPC, are not fully understood. Our previous study showed that the latent membrane protein 1 (LMP1) mediated a primary dimer form of c-jun and jun B. In this study, we used a NPC cell line that express a specific inhibitor of AP-1, a dominant-negative c-jun mutant (TAM67), to investigate the role of AP-1 in regulating the NPC oncogenic phenotype. First, we observed that TAM67 inhibited cell growth in vitro and in vivo. Next, with Western blotting, we discovered that TAM67 impaired the cyclin D1/cdk4 complex but had little effect on the cyclin E/cdk2 complex, concomitantly with inhibiting Rb phosphorylation. RT-PCR and luciferase assay results demonstrated that the levels of cyclin D1 mRNA and the promoter activity in TAM67 transfectants were reduced as compared with control cells. Thereby, we show that blockade of AP-1 transcriptional activity has a negative impact on cyclin D1 transcription. We obtained the first evidence that TAM67 prevented NPC growth both in vitro and in vivo. AP-1 appears to be a novel target for treating or preventing LMP1-positive NPC effectively.
Jin
Xin
X
Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China.
Song
Xin
X
Li
Lili
L
Wang
Zhenlian
Z
Tao
Yongguang
Y
Deng
Lin
L
Tang
Ming
M
Yi
Wei
W
Cao
Ya
Y
D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism* / Q000473:pathology; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; C439528:TAM67 peptide; D018808:Transcription Factor AP-1; D014763:Viral Matrix Proteins; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases