title: Negative transcriptional regulation of mitochondrial transcription factor A (TFAM) by nuclear TFAM.
abstract: The nuclear DNA-encoded mitochondrial transcription factor A (TFAM) is synthesized in cytoplasm and transported into mitochondria. TFAM enhances both transcription and replication of mitochondrial DNA. It is unclear, however, whether TFAM plays a role in regulating nuclear gene expression. Here, we demonstrated that TFAM was localized to the nucleus and mitochondria by immunostaining, subcellular fractionation, and TFAM-green fluorescent protein hybrid protein studies. In HT22 hippocampal neuronal cells, human TFAM (hTFAM) overexpression suppressed human Tfam promoter-mediated luciferase activity in a dose-dependent manner. The mitochondria targeting sequence-deficient hTFAM also repressed Tfam promoter activity to the same degree as hTFAM. It indicated that nuclear hTFAM suppressed Tfam expression without modulating mitochondrial activity. The repression required for nuclear respiratory factor-1 (NRF-1), but hTFAM did not bind to the NRF-1 binding site of its promoter. TFAM was co-immunoprecipitated with NRF-1. Taken together, we suggest that nuclear TFAM down-regulate its own gene expression as a NRF-1 repressor, showing that TFAM may play different roles depending on its subcellular localizations.
authors.affiliation: Department of Neuroscience, Department of Physiology, College of Medicine, Kyung Hee University, Seoul 130-731, Republic of Korea.
authors.forename: Eun Jin
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, Department of Physiology, College of Medicine, Kyung Hee University, Seoul 130-731, Republic of Korea.
authors.forename: Young Cheol
authors.initials: YC
authors.lastname: Kang
authors.affiliation: Department of Neuroscience, Department of Physiology, College of Medicine, Kyung Hee University, Seoul 130-731, Republic of Korea.
authors.forename: Wook-Ha
authors.initials: WH
authors.lastname: Park
authors.affiliation: Department of Neuroscience, Department of Physiology, College of Medicine, Kyung Hee University, Seoul 130-731, Republic of Korea.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Neuroscience, Department of Physiology, College of Medicine, Kyung Hee University, Seoul 130-731, Republic of Korea. Electronic address: ykpak@khu.ac.kr.
authors.forename: Youngmi Kim
authors.initials: YK
authors.lastname: Pak
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D051265:NF-E2-Related Factor 1 / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D051265:NF-E2-Related Factor 1; D012097:Repressor Proteins; C499631:TFAM protein, human; D014157:Transcription Factors
keywords: NRF-1; Nuclei; Promoter regulation; Repressor; TFAM