Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q02556 (DNA-binding domain)
 6,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIC1 (hypermethylated in cancer) and its close relative HRG22 (HIC1-related gene on chromosome 22) encode transcriptional repressors with five C(2)H(2) zinc fingers and an N-terminal BTB/POZ autonomous transcriptional repression domain that is unable to recruit histone deacetylases (HDACs). Alignment of the HIC1 and HRG22 proteins from various species highlighted a perfectly conserved GLDLSKK/R motif highly related to the consensus CtBP interaction motif (PXDLSXK/R), except for the replacement of the virtually invariant proline by a glycine. HIC1 strongly interacts with mCtBP1 both in vivo and in vitro through this conserved GLDLSKK motif, thus extending the CtBP consensus binding site. The BTB/POZ domain does not interact with mCtBP1, but the dimerization of HIC1 through this domain is required for the interaction with mCtBP1. When tethered to DNA by fusion with the Gal4 DNA-binding domain, the HIC1 central region represses transcription through interactions with CtBP in a trichostatin A-sensitive manner. In conclusion, our results demonstrate that HIC1 mediates transcriptional repression by both HDAC-independent and HDAC-dependent mechanisms and show that CtBP is a HIC1 corepressor that is recruited via a variant binding site.
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PMID:The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif. 1205 94

Hypermethylated in Cancer 1 (HIC1) is a human tumor suppressor gene located at chromosome 17p13.3 which is frequently hypermethylated and transcriptionally silent in many types of tumors. In addition, its location in the Miller-Dieker syndrome's (MDS) deletion region, its embryonic expression pattern in mice and the phenotype of the HIC1-deficient mice have provided strong evidence for its implication in this contiguous-gene syndrome. HIC1 encodes a five C2H2-type zinc finger transcriptional repressor belonging to the BTB/POZ family. We have isolated the true zebrafish orthologue of human HIC1 since it has a comparable intron-exon structure and since its predicted gene product, ZfHIC1 displays much higher sequence similarities in its overall sequence (737 residues) with human HIC1 (714 residues) than the 454 residues encoded by the only zebrafish HIC1 sequence (AF111712) described so far, which has been renamed ZfHIC1alpha. Notably, the C-terminal end and one zinc finger in the DNA-binding domain are missing in ZfHIC1alpha. As a consequence, ZfHIC1 proteins bind the human HIC1 consensus DNA-binding sequence in vitro, whereas ZfHIC1alpha cannot. Analyses of the expression pattern of ZfHIC1 and of its paralogue ZfHRG22 (HIC1 related gene on chromosome 22) show that they share expression domains with their respective orthologous vertebrate genes. ZfHRG22 is prominently expressed in the brain and in neural tissues. Interestingly, the predominant expression of ZfHIC1 in the mesenchyme of the head, around the nose and the eye and in the branchial arches is possibly consistent with some of the abnormalities seen in the HIC1-deficient mice and provides another clue for the implication of HIC1 in MDS.
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PMID:Identification and developmental expression of the zebrafish orthologue of the tumor suppressor gene HIC1. 1509 38