NRF-1 is the major transcription factor regulating the expression of the human TOMM34 gene.
The human TOMM34 gene encodes a cytosolic protein with chaperone-like activity that helps import some preproteins to the mitochondria by keeping them in an unfolded, import-compatible state. TOMM34 was found to be upregulated frequently in colorectal tumors, suggesting that it also has a role in the growth of cancer cells. In this context, TOMM34 is a potential target for novel anticancer drugs, and it might also be used in the diagnosis of colorectal cancer. Nuclear respiratory factors (NRFs) play an important role in governing the nuclear-mitochondrial interactions implicated in mitochondrial biogenesis. Our previous studies revealed that NRFs promote the expression of the major members of the mitochondrial transport machinery, TOMM70 and TOMM20. Here we report the existence of binding sites for NRF-1, Sp1, and NRF-2 in the 5' region of the human TOMM34 gene. We determined the effects of mutations at these sites on promoter activity in HeLa S3 and A204 cells, in conjunction with chromatin immunoprecipitation experiments, electrophoretic mobility shift assays, and in vivo methylation analysis of the promoter region. We conclude that NRF-1 is the main transcription factor regulating the expression of TOMM34. Sp1 interacts with NRF-1 to stimulate the promoter's full activity.
Blesa
José R
JR
Fundacion Centro de Investigacion Principe Felipe, Av. Autopista del Saler 16-3, Valencia, Spain. jrblesa@cipf.es
Prieto-Ruiz
Jesús A
JA
Abraham
Beth A
BA
Harrison
Bridget L
BL
Hegde
Anita A
AA
Hernández-Yago
José
J
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008969:Molecular Sequence Data; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D016329:Sp1 Transcription Factor; C108485:TOMM34 protein, human; D014157:Transcription Factors