title: DJ1 represses glycolysis and cell proliferation by transcriptionally up-regulating Pink1.
abstract: DnaJ-1 or hsp40/hdj-1 (DJ1) is a multi-functional protein whose mutations cause autosomal recessive early-onset Parkinson's disease (PD). DJ1 loss of function disrupts mitochondrial function, but the signalling pathway, whereby it interferes with energy metabolism, is unknown. In the present study, we found that mouse embryonic fibroblasts (MEFs) obtained from DJ1-null (dj1-/-) mice showed higher glycolytic rate than those from wild-type (WT) DJ1 (dj1+/+). This effect could be counteracted by the expression of the full-length cDNA encoding the WT DJ1, but not its DJ1-L166P mutant form associated with PD. Loss of DJ1 increased hypoxia-inducible factor-1α (Hif1α) protein abundance and cell proliferation. To understand the molecular mechanism responsible for these effects, we focused on phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-induced protein kinase-1 (Pink1), a PD-associated protein whose loss was recently reported to up-regulate glucose metabolism and to sustain cell proliferation [Requejo-Aguilar et al. (2014) Nat. Commun. 5, 4514]. Noticeably, we found that the alterations in glycolysis, Hif1α and proliferation of DJ1-deficient cells were abrogated by the expression of Pink1. Moreover, we found that loss of DJ1 decreased pink1 mRNA and Pink1 protein levels and that DJ1, by binding with Foxo3a (forkhead box O3a) transcription factor, directly interacted with the pink1 promoter stimulating its transcriptional activity. These results indicate that DJ1 regulates cell metabolism and proliferation through Pink1.
authors: *Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, Zacarías González, 2, 37007 Salamanca, Spain.
authors: Raquel
authors: R
authors: Requejo-Aguilar
authors: *Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, Zacarías González, 2, 37007 Salamanca, Spain.
authors: Irene
authors: I
authors: Lopez-Fabuel
authors: *Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, Zacarías González, 2, 37007 Salamanca, Spain.
authors: Daniel
authors: D
authors: Jimenez-Blasco
authors: *Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, Zacarías González, 2, 37007 Salamanca, Spain.
authors: Emilio
authors: E
authors: Fernandez
authors: *Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, Zacarías González, 2, 37007 Salamanca, Spain.
authors: Angeles
authors: A
authors: Almeida
authors: *Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, Zacarías González, 2, 37007 Salamanca, Spain.
authors: Juan P
authors: JP
authors: Bolaños
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015513:Oncogene Proteins; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D012333:RNA, Messenger; D000099202:PTEN-Induced Putative Kinase; C474033:FoxO3 protein, mouse; C497443:Hif1a protein, mouse; C503466:PARK7 protein, mouse