Mitochondrial transcription factor A and its downstream targets are up-regulated in a rat hepatoma.
Mitochondrial transcription factor A is a key regulator involved in mitochondrial DNA transcription and replication. In a poorly differentiated rat hepatoma, Morris hepatoma 3924A, the mRNA and protein levels of this factor were elevated about 10- and 11-fold, respectively, relative to the host liver. The mRNA levels for the hepatoma cytochrome c oxidase I, II, and NADH dehydrogenase 5, 6, the downstream targets of Tfam, were augmented 10-, 8-, 5-, and 3-fold, respectively. Interestingly, Tfam was also found in the hepatoma nucleus. The mRNA levels for nuclear respiratory factor 1 and 2 (NRF-1 and -2), the proteins that are known to interact with specific regulatory elements on human TFAM promoter, were 5- and 3-fold higher, respectively, in the hepatoma relative to the host liver. Unlike the human promoter, the rat Tfam promoter did not form a specific complex with the NRF-1 in the liver or hepatoma nuclear extracts, which is consistent with the absence of an NRF-1 consensus sequence in the proximal rat promoter. A single specific complex formed between the rat promoter and the NRF-2 protein was comparable in the two extracts. The DNA binding activity of Sp1 in the hepatoma nuclear extract was 4-fold greater than that in the liver extract. In vivo genomic footprinting showed occupancy of NRF-2 and Sp1 consensus sites on the promoter of rat Tfam gene. Tfam was also up-regulated in other hepatoma cells. Together, these results show up-regulation of Tfam in some tumors, particularly the liver tumors. Further, the relatively high level of Sp1 binding to the promoter in the hepatoma could play a major role in the up-regulation of Tfam in these tumor cells.
Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Xiaocheng
X
Dong
Kalpana
K
Ghoshal
Sarmila
S
Majumder
Satya P
SP
Yadav
Samson T
ST
Jacob
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D051268:GA-Binding Protein Transcription Factor; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D007700:Kinetics; D008114:Liver Neoplasms, Experimental; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009245:NADH Dehydrogenase / Q000235:genetics; D051265:NF-E2-Related Factor 1; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D004268:DNA-Binding Proteins; D051268:GA-Binding Protein Transcription Factor; D024101:Mitochondrial Proteins; D051265:NF-E2-Related Factor 1; C495632:Nfe2l1 protein, rat; D009687:Nuclear Proteins; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D012333:RNA, Messenger; C489030:Tfam protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV