Alternative titles; symbols
HGNC Approved Gene Symbol: ING1
Cytogenetic location: 13q34 Genomic coordinates (GRCh38): 13:110,712,623-110,723,339 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q34 | Squamous cell carcinoma, head and neck, somatic | 275355 | 3 |
Garkavtsev et al. (1996) described a new strategy for the isolation of tumor suppressor genes. This strategy was based on subtractive hybridization followed by selection of transforming genetic suppressor elements. It was used to isolate a novel gene called ING1, which encodes a 33-kD, 294-amino acid protein that displays the characteristics of a tumor suppressor gene.
An erratum to Garkavtsev et al. (1996) reported that the initial sequence for ING1 was incorrect. The error appeared to have been the result of a compression introducing a frameshift and of the ING1 gene encoding several differentially spliced isoforms that contained a common 3-prime exon. The correct sequence is available at GenBank AF181849.
By SEREX (serologic analysis of recombinant tumor cDNA expression libraries) of a breast cancer cell cDNA library and a testis cDNA library using autologous and allogenic breast cancer sera, Jager et al. (1999) cloned ING1. They identified 4 splice variants that differ in their 5-prime regions. The predicted proteins encoded by variants A (279 amino acids), C (235 amino acids), and D (294 amino acids) share a common 233-amino acid C terminus but differ in their N termini. Variant B encodes an N-terminally truncated protein of 210 amino acids. Jager et al. (1999) evaluated the expression of variants A, B, and C by RT-PCR using variant-specific primers. Variant A was expressed in all normal tissues and cells examined, as well as in all breast cancer and melanoma cell lines examined. Variant B was expressed in testis, liver, and kidney, weakly expressed in colon and brain, and not expressed in breast and cultured melanocytes. Weak expression of variant B was detected in 4 of 6 breast cancer cell lines. Variant C was highly expressed in testis and weakly expressed in brain, but not expressed in breast, colon, kidney, or melanocytes. It was not expressed in breast cancer or melanoma cell lines.
Saito et al. (2000) analyzed the complete transcripts, primary structures, and expression of p33/ING1. They found 2 novel, related alternatively spliced transcripts encoding p24/ING1-ALT1 and p47/ING1-ALT2. These transcripts share C-terminal residues with the candidate tumor suppressors p33/ING1. The candidate tumor suppressors p33/ING1 and p24/ING1-ALT1 were coexpressed in a variety of fetal and adult human tissues, but p47/ING1-ALT2 was minimally expressed.
Garkavtsev et al. (1996) reported that expression of high levels of transfected constructs of ING1 inhibited growth, while chronic expression of antisense constructs promoted cell transformation. They observed reduced expression of ING1 in some breast cancer cell lines and mutation of ING1 in neuroblastoma cells. Garkavtsev et al. (1997) showed, using indirect immunofluorescence, that the p33(ING1) protein is located in the nucleus, which is consistent with its proposed role as a growth regulator.
Gunduz et al. (2000) demonstrated that the ING1 gene has 3 exons and that 4 mRNA variants are transcribed from 3 different promoter regions.
By fluorescence in situ hybridization, Garkavtsev et al. (1997) localized the ING1 gene to 13q33-q34. Using the radiation hybrid mapping technique, Zeremski et al. (1997) mapped ING1 to 13q34.
Of 34 informative cases of head and neck squamous cell carcinoma (275355), Gunduz et al. (2000) found that 68% of tumors showed loss of heterozygosity (LOH) at 13q33-q34, where the ING1 gene is located. Gunduz et al. (2000) identified 3 missense mutations and 3 silent changes in the ING1 gene in 6 of 23 tumors with allelic loss at the 13q33-q34 region. These missense mutations were found within the PHD finger domain and nuclear localization motif in the ING1 protein, probably abrogating its normal function. None of a total of 452 breast cancers, ovarian cancers, and cell lines examined exhibited tumor-specific somatic mutation. Because LOH at 13q33-q34 had been observed only in squamous cell carcinomas of the head and neck, Gunduz et al. (2000) suggested that the ING1 gene mutation may be restricted to this type of cancer.
In tumor tissue of a squamous cell carcinoma of the head and neck (275355), Gunduz et al. (2000) found a G-to-C change (TGC-TCC) in exon 2 of the ING1 gene resulting in a cys215-to-ser substitution. The cysteine substituted is 1 of 7 composing the C4HC3 motif of ING1. This change may affect the PHD finger and break the 3-dimensional structure of the ING1 protein, leading to loss of function.
In tumor tissue from a case of squamous cell carcinoma of the head and neck (275355), Gunduz et al. (2000) found an A-to-G change (AAC-AGC) in exon 2 of the ING1 gene resulting in an asn216-to-ser mutation. This mutation may affect the conformation of the zinc finger domain and the ING1 protein.
In tumor tissue from a case of squamous cell carcinoma of the head and neck (275355), Gunduz et al. (2000) found a C-to-A change (GCC-GAC) in exon 2 of the ING1 gene resulting in an ala192-to-asp substitution. This mutation may affect the nuclear localization signal and ultimately interfere in the accumulation of ING1 protein in the nucleus.
Garkavtsev, I., Demetrick, D., Riabowol, K. Cellular localization and chromosome mapping of a novel candidate tumor suppressor gene (ING1). Cytogenet. Cell Genet. 76: 176-178, 1997. [PubMed: 9186514] [Full Text: https://doi.org/10.1159/000134539]
Garkavtsev, I., Kazarov, A., Gudkov, A., Riabowol, K. Suppression of the novel growth inhibitor p33(ING1) promotes neoplastic transformation. Nature Genet. 14: 415-420, 1996. Note: Erratum: Nature Genet. 23: 373 only, 1999. [PubMed: 8944021] [Full Text: https://doi.org/10.1038/ng1296-415]
Gunduz, M., Ouchida, M., Fukushima, K., Hanafusa, H., Etani, T., Nishioka, S., Nishizaki, K., Shimizu, K. Genomic structure of the human ING1 gene and tumor-specific mutations detected in head and neck squamous cell carcinomas. Cancer Res. 60: 3143-3146, 2000. [PubMed: 10866301]
Jager, D., Stockert, E., Scanlan, M. J., Gure, A. O., Jager, E., Knuth, A., Old, L. J., Chen, Y.-T. Cancer-testis antigens and ING1 tumor suppressor gene product are breast cancer antigens: characterization of tissue-specific ING1 transcripts and a homologue gene. Cancer Res. 59: 6197-6204, 1999. [PubMed: 10626813]
Saito, A., Furukawa, T., Fukushige, S., Koyama, S., Hoshi, M., Hayashi, Y., Horii, A. p24/ING1-ALT1 and p47/ING1-ALT2, distinct alternative transcripts of p33/ING1. J. Hum. Genet. 45: 177-181, 2000. [PubMed: 10807544] [Full Text: https://doi.org/10.1007/s100380050206]
Zeremski, M., Horrigan, S. K., Grigorian, I. A., Westbrook, C. A., Gudkov, A. V. Localization of the candidate tumor suppressor gene ING1 to human chromosome 13q34. Somat. Cell Molec. Genet. 23: 233-236, 1997. [PubMed: 9330636] [Full Text: https://doi.org/10.1007/BF02721376]