Identification of Rhit as a novel transcriptional repressor of human Mpv17-like protein with a mitigating effect on mitochondrial dysfunction, and its transcriptional regulation by FOXD3 and GABP.
Mpv17-like protein (M-LP) is a protein that has been suggested to be involved in the metabolism of reactive oxygen species. To elucidate the molecular basis of M-LP expression, we recently searched for regulatory elements of M-LP and identified a novel mouse KRAB-containing protein, Rhit (regulator of heat-induced transcription), as a repressor of the transcriptional regulation of M-LP. In this study, we identified zinc-finger protein 205 as a candidate human Rhit (RhitH) and subsequently confirmed its participation in transcriptional regulation of human M-LP (M-LPH). To clarify the functions of RhitH and M-LPH, we searched for cis-regulatory elements in the promoter region of RhitH and identified two transcription factors: forkhead box D3, as a negative regulatory element, and GA-binding protein, one of the key regulators of the mitochondrial electron transport system, as a positive regulatory element. Additionally, it was demonstrated that knockdown of RhitH or overexpression of M-LPH reduces the generation of intracellular H(2)O(2) and loss of mitochondrial membrane potential caused by an inhibitor of the respiratory chain, antimycin A. These results suggest that M-LPH functions to protect cells from oxidative stress and/or initiation of the mitochondrial apoptotic cascade under stressed conditions.
Division of Life Science, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan. riida@u-fukui.ac.jp
Reiko
R
Iida
Misuzu
M
Ueki
Toshihiro
T
Yasuda
D001483:Base Sequence; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D051858:Forkhead Transcription Factors / Q000502:physiology*; D051268:GA-Binding Protein Transcription Factor / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008565:Membrane Proteins / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; C503514:FOXD3 protein, human; D051858:Forkhead Transcription Factors; D051268:GA-Binding Protein Transcription Factor; C530370:MPV17 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C115821:ZNF205 protein, human; D008156:Luciferases