| Identity |
| Other names | ZBTB29 |
| HGNC (Hugo) | HIC1 |
| LocusID (NCBI) | 3090 |
| Location | 17p13.3. |
| Location_base_pair | Starts at 1959604 and ends at 1962981 bp from pter ( according to hg19-Feb_2009) [Mapping] |
| Local_order | Close to the D17S5/D17S30/YNZ22 micro satellite marker which is a highly polymorphic variable number of tandem repeats (VNTR) marker. Aberrant hypermethylation in tumours of a cluster of methylation-sensitive NotI restriction sites surrounding this marker allowed the positional cloning of HIC1 in 1995. Telomere, OVCA1/DPH2L1, OVCA2, HIC1, KIAA0732,......Centromere. |
| Note | OVCA1/DPH2L1 and OVCA2 are two tumour suppressor genes deleted in ovarian cancers. |
| DNA/RNA |
| Description | The HIC1 gene extends approximately 15 Kbp and consists of four exons. The first three exons 1a, 1b and 1c are alternative. Note that exon 1a is included in exon 1c. The major transcripts are derived from alternative promoters associated with exon 1a and 1b. Exon 1c is conserved in rodent genomes (rat and mice) but transcripts containing it are very minor. The fourth exon, exon 2, contains the coding region and the 3' untranslated region. An in-frame upstream ATG initiation codon is also found in exon 1b. This upstream reading frame is conserved in mice. |
| Transcription | 3.0Kb mRNA. |
| Pseudogene | No known pseudogene. |
| Protein |
| Description | 714 amino acids; around 80kDa; Transcription factor belonging to the BTB/POZ and Krüppel C2H2 zinc fingers family. There is no experimental evidence for the existence of a protein initiated by the upstream ATG (e.g. through the use of antipeptide specific antibodies). |
| Expression | Based on Northern Blots and RT-PCR experiments, HIC1 is widely expressed in various normal tissues. |
| Localisation | Nucleus. Localized on nuclear dots upon overexpression by transient transfection assays in COS-7 or HEK293 cells. In human primary fibroblats (WI38), the endogenous HIC1 proteins are localized in discrete nuclear structures called "HIC1 bodies". |
| Function | HIC1 is a transcriptional repressor belonging to the BTB/POZ and Krüppel C2H2 family (44 proteins in the human genome). HIC1 interacts with the corepressor CtBP through a conserved GLDLSKK motif in the central region. This central region also contains a SUMOylation site MK314HEP which is important for the transcriptional repression potential of HIC1. This K314 is also subject to a reversible acetylation/deacetylation implicating CBP/P300 and the NAD+ dependent class III deacetylase SIRT1. |
| Homology | HIC1 shares distant homology through the conserved BTB/POZ domain and C2H2 zinc fingers domain with several BTB/POZ transcriptional repressors. |
| Mutations |
| Epigenetics | There are a number of reports highlighting differences in promoter methylation status in primary human tumours (breast, ovaries, prostate, .....) compared to matched normal tissues, hence the name of the gene. |
| Germinal | No germinal coding sequence mutation have been described for HIC1. |
| Somatic | No somatic coding sequence mutations have been described for HIC1 with one exception. During the screening of a panel of 68 medulloblastomas using SSCP analyses, a 12-bp deletion in the second exon of HIC1 has been identified. This results in a deletion of 4 glycine residues in a stretch of 8 located just after the BTB/POZ domain. The other regions of the protein specially the downstream central region and the zinc fingers domain are not affected by this deletion. |
| Implicated in |
| Entity | medulloblastomas, breast tumours, ovary tumours, prostate tumours |
| Note | (see above) |
| Breakpoints |
| Note | No breakpoint in HIC1 identified so far. |
| To be noted |
| A paralog called HIC2, HRG22 or KIAA1020 is found on human chromosome 22. It is located in 22q11.2 in a region subject to translocations (BCRL-2 for Breakpoint Cluster Region-Like 2). But so far, there is no experimental evidence for a translocation implicating HRG22 or for its aberrant hypermethylation in tumours. |
| External links |
| Bibliography |
| p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. |
| Wales MM, Biel MA, el Deiry W, Nelkin BD, Issa JP, Cavenee WK, Kuerbitz SJ, Baylin SB |
| Nature medicine. 1995 ; 1 (6) : 570-577. |
| PMID 7585125 |
| Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors: the case of HIC-1 and gammaFBP-B. |
| Deltour S, Guerardel C, Leprince D |
| Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (26) : 14831-14836. |
| PMID 10611298 |
| Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome. |
| Grimm C, Sprle R, Schmid TE, Adler ID, Adamski J, Schughart K, Graw J |
| Human molecular genetics. 1999 ; 8 (4) : 697-710. |
| PMID 10072440 |
| Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome. |
| Carter MG, Johns MA, Zeng X, Zhou L, Zink MC, Mankowski JL, Donovan DM, Baylin SB |
| Human molecular genetics. 2000 ; 9 (3) : 413-419. |
| PMID 10655551 |
| Characterization of HRG22, a human homologue of the putative tumor suppressor gene HIC1. |
| Deltour S, Pinte S, Guİrardel C, Leprince D |
| Biochemical and biophysical research communications. 2001 ; 287 (2) : 427-434. |
| PMID 11554746 |
| Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53. |
| Guerardel C, Deltour S, Pinte S, Monte D, Begue A, Godwin AK, Leprince D |
| The Journal of biological chemistry. 2001 ; 276 (5) : 3078-3089. |
| PMID 11073960 |
| The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif. |
| Deltour S, Pinte S, Guerardel C, Wasylyk B, Leprince D |
| Molecular and cellular biology. 2002 ; 22 (13) : 4890-4901. |
| PMID 12052894 |
| Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. |
| Chen WY, Zeng X, Carter MG, Morrell CN, Chiu Yen RW, Esteller M, Watkins DN, Herman JG, Mankowski JL, Baylin SB |
| Nature genetics. 2003 ; 33 (2) : 197-202. |
| PMID 12539045 |
| Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. |
| Chen W, Cooper TK, Zahnow CA, Overholtzer M, Zhao Z, Ladanyi M, Karp JE, Gokgoz N, Wunder JS, Andrulis IL, Levine AJ, Mankowski JL, Baylin SB |
| Cancer cell. 2004 ; 6 (4) : 387-398. |
| PMID 15488761 |
| Identification of a second G-C-rich promoter conserved in the human, murine and rat tumor suppressor genes HIC1. |
| Pinte S, Guİrardel C, Deltour-Balerdi S, Godwin AK, Leprince D |
| Oncogene. 2004 ; 23 (22) : 4023-4031. |
| PMID 15007385 |
| The tumor suppressor gene HIC1 (hypermethylated in cancer 1) is a sequence-specific transcriptional repressor: definition of its consensus binding sequence and analysis of its DNA binding and repressive properties. |
| Pinte S, Stankovic-Valentin N, Deltour S, Rood BR, Guİrardel C, Leprince D |
| The Journal of biological chemistry. 2004 ; 279 (37) : 38313-38324. |
| PMID 15231840 |
| Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. |
| Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB |
| Cell. 2005 ; 123 (3) : 437-448. |
| PMID 16269335 |
| Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1. |
| Britschgi C, Rizzi M, Grob TJ, Tschan MP, Hşgli B, Reddy VA, Andres AC, Torbett BE, Tobler A, Fey MF |
| Oncogene. 2006 ; 25 (14) : 2030-2039. |
| PMID 16301995 |
| A L225A substitution in the human tumour suppressor HIC1 abolishes its interaction with the corepressor CtBP. |
| Stankovic-Valentin N, Verger A, Deltour-Balerdi S, Quinlan KG, Crossley M, Leprince D |
| The FEBS journal. 2006 ; 273 (13) : 2879-2890. |
| PMID 16762039 |
| HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies. |
| Valenta T, Lukas J, Doubravska L, Fafilek B, Korinek V |
| The EMBO journal. 2006 ; 25 (11) : 2326-2337. |
| PMID 16724116 |
| An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. |
| Stankovic-Valentin N, Deltour S, Seeler J, Pinte S, Vergoten G, Guİrardel C, Dejean A, Leprince D |
| Molecular and cellular biology. 2007 ; 27 (7) : 2661-2675. |
| PMID 17283066 |
| Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex. |
| Zhang Q, Wang SY, Fleuriel C, Leprince D, Rocheleau JV, Piston DW, Goodman RH |
| Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (3) : 829-833. |
| PMID 17213307 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 02-2007 | Dominique Leprince |
| Citation |
| This paper should be referenced as such : |
| Leprince D . HIC1 (Hypermethylated in Cancer 1). Atlas Genet Cytogenet Oncol Haematol. February 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HIC1ID40819ch17p13.html |
This paper is referenced by INIST as such : |
| http://documents.irevues.inist.fr/bitstream/2042/38437/1/02-2007-HIC1ID40819ch17p13.pdf [ Bibliographic record ] |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Sat Apr 28 15:08:49 CEST 2012 |
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