Novel Nuclear Shuttle Proteins, HDBP1 and HDBP2, Bind to Neuronal Cell-specific cis-Regulatory Element in the Promoter for the Human Huntington's Disease Gene

Abstract

Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the HD gene, and the expression level of either normal or mutant huntingtin is implicated in the pathogenesis of HD. However, a molecular base of the HD gene transcription has not been elucidated as yet. In this study, we identified two proteins, HDBP1 and HDBP2, which bind to the promoter region for the HD gene using a yeast one-hybrid system. Amino acid sequence analysis of the proteins deduced the presence of nuclear localization signal, nuclear export signal, zinc finger, serine/ proline-rich region, and highly conserved C-terminal region. In vitro DNA binding assay indicated that the C-terminal conserved regions of the proteins were responsible for binding to the unique promoter DNA sequences of the HD gene. The DNA sequence protected from DNase I digestion was a 7-bp consensus sequence (GCCGGCG), which resides in triplicate at intervals of 13 bp within and proximal to the 20-bp direct repeat sequences of the HD promoter region. The mutation of 7-bp consensus sequence abolishes the HD promoter function in a neuronal cell line (IMR32). In human cultured cells, ectopically expressed green fluorescent protein-fused HDBP1 and HDBP2 localized in the cytoplasm, but both proteins totally shift from cytoplasm to nucleus by the treatment with an inhibitor of the nuclear export, leptomycin B, and mutagenesis of the putative nuclear export signals. Taken together, HDBP1 and HDBP2 are novel transcription factors shuttling between nucleus and cytoplasm and bind to the specific GCCGGCG, which is an essential cis-element for HD gene expression in neuronal cells.

Zebrafish as a Model for Monocarboxyl Transporter 8-Deficiency

“…Interestingly, we found that binding sites for the PURA, HDBP, and GATA transcription factors are conserved from fish to humans. Both the PURA and HDBP transcription factors have previously been associated with the development of the nervous system (56,57), and GATA is commonly present in regulatory elements of bloodrelated genes (58). The presence of these putative binding sites is consistent with the expression observed in the nervous and vascular systems, respectively.…”

A distinct inflammatory gene expression profile in patients with psoriatic arthritis

“…ZNF395 has been implicated in regulation of neuronal cell genes, and PI3KC2B has been implicated in epidermal differentiation, but no functions for these genes have been described in hematopoietic cells. 14,15 These results suggest that detection of whole-blood expression levels of a small group of genes may be useful for confirming a PsA clinical diagnosis.…”

The Glucose Transporter (GLUT4) Enhancer Factor Is Required for Normal Wing Positioning in Drosophila

“…Glut4EF ½also called the Huntington's disease gene regulatory regionbinding protein (HDBP) 1 (Tanaka et al 2004) and SLC2A4RG was originally characterized and named for its ability to bind to the enhancer of the Glucose Transporter 4 gene (Oshel et al 2000). Glut4EF proteins are also highly similar to papillomavirus binding factor (PBF) (Boeckle et al 2002), also called HDBP2 (Tanaka et al 2004), osteosarcoma antigen (Tsukahara et al 2004), and ZNF395 (Stoeckman et al 2006) (Figure 4A), and in our search of the database we found a previously uncharacterized human EST ZNF704 ½similar to the mouse EST Zfp704 (Blackshaw et al 2004), also called mouse glucocorticoid-induced gene 1 (Gig1) that was highly related to Glut4EF proteins and represents a third mammalian family member ( Figure 4A). Therefore, the gene disrupted in stretch mutants represents the Drosophila member of a new family of transcription factors conserved from Drosophila to mammals.…”