p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers.
FAT10 is a member of the ubiquitin-like modifier family of proteins and has been implicated to play important roles in antigen presentation, cytokine response, apoptosis and mitosis. We have recently demonstrated the upregulation of FAT10 gene expression in 90% of hepatocellular carcinoma patients. Here, we identified and characterized the promoter of the FAT10 gene to elucidate the mechanism of FAT10 gene expression. Notably, we found that the 5' untranslated region (5'UTR), from the transcription start site to 15 bases before the translational start site, displays significant promoter activity. Regions upstream of the 5'UTR (from +26 to -1997) do not confer any promoter activity. Curiously, FAT10 promoter activity and expression is significantly repressed in KB3-1 and HepG2 cells, which have wild-type p53, than in p53-negative Hep3B cells. The role of p53 in regulating FAT10 expression was evident by the significant downregulation (P<0.05) of FAT10 mRNA expression and promoter activity when wild-type p53 was transfected into p53-null Hep3B cells. Conversely, inhibiting p53 expression through siRNA against p53 significantly enhanced FAT10 expression and promoter activity. p53 was found to bind in vivo to the 5' half consensus sequence of p53-binding site located at the FAT10 promoter. Hence, we propose that FAT10 is a downstream target of p53 and dysregulation of FAT10 expression in p53-defective cells could contribute to carcinogenesis.
Zhang
D W
DW
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Jeang
K-T
KT
Lee
C G L
CG
D020121:5' Untranslated Regions / Q000502:physiology; D001483:Base Sequence; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D064246:Mad2 Proteins; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014452:Ubiquitins / Q000235:genetics*; D015854:Up-Regulation
D020121:5' Untranslated Regions; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C109184:UBD protein, human; D014452:Ubiquitins