title: The kinesin superfamily protein KIF17 is regulated by the same transcription factor (NRF-1) as its cargo NR2B in neurons.
abstract: The kinesin superfamily of motor proteins is known to be ATP-dependent transporters of various types of cargoes. In neurons, KIF17 is found to transport vesicles containing the N-methyl-D-aspartate receptor NR2B subunit from the cell body specifically to the dendrites. These subunits are intimately associated with glutamatergic neurotransmission as well as with learning and memory. Glutamatergic synapses are highly energy-dependent, and recently we found that the same transcription factor, nuclear respiratory factor 1 (NRF-1), co-regulates energy metabolism (via its regulation of cytochrome c oxidase and other mitochondrial enzymes) and neurochemicals of glutamatergic transmission (NR1, NR2B, GluR2, and nNOS). The present study tested our hypothesis that NRF-1 also transcriptionally regulates KIF17. By means of in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation assays, promoter mutations, and real-time quantitative PCR, we found that NRF-1 (but not NRF-2) functionally regulates Kif17, but not Kif1a, gene. NRF-1 binding sites on Kif17 gene are highly conserved among mice, rats, and humans. Silencing of NRF-1 with small interference RNA blocked the up-regulation of Kif17 mRNA and proteins (and of Grin1 and Grin2b) induced by KCl-mediated depolarization, whereas over-expressing NRF-1 rescued these transcripts and proteins from being suppressed by TTX. Thus, NRF-1 co-regulates oxidative enzymes that generate energy and neurochemicals that consume energy related to glutamatergic neurotransmission, such as KIF17, NR1, and NR2B, thereby ensuring that energy production matches energy utilization at the molecular and cellular levels.
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Dhar
authors.forename: Margaret T T
authors.initials: MT
authors.lastname: Wong-Riley
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016547:Kinesins; D051267:NF-E2-Related Factor 2; D051266:Nuclear Respiratory Factor 1; D016194:Receptors, N-Methyl-D-Aspartate; C409642:KIF17 protein, mouse; C121001:NR2B NMDA receptor