HGNC Approved Gene Symbol: ING4
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:6,650,301-6,663,119 (from NCBI)
By searching for sequences similar to ING1 (601566) and ING2 (604215), followed by PCR and RACE of a placenta cDNA library, Shiseki et al. (2003) cloned ING4, which they called p29ING4. The deduced 249-amino acid protein contains a C-terminal plant homeodomain finger motif and 2 nuclear localization signals.
Shiseki et al. (2003) showed that overexpression of ING4 or ING5 (608525) in cancer cell lines diminished colony-forming efficiency, decreased cell population in S phase, and induced p53 (191170)-dependent apoptosis. Both ING4 and ING5 activated the WAF1 (116899) promoter and induced WAF1 expression. ING4 and ING5 physically interacted with p300 (602700), a member of histone acetyltransferase complexes, and with p53 in vivo, and they enhanced acetylation of p53 at lys382.
Garkavtsev et al. (2004) reported that ING4 is involved in regulating brain tumor growth and angiogenesis. Expression of ING4 was significantly reduced in gliomas as compared with normal human brain tissue, and the extent of reduction correlated with the progression from lower to higher grades of tumors. In mice, xenografts of human glioblastoma U87MG, which has decreased expression of ING4, grew significantly faster and had higher vascular volume fractions than control tumors. Garkavtsev et al. (2004) showed that ING4 physically interacts with the p65 (RelA; 164014) subunit of NFKB (see 164011), and that ING4 regulates brain tumor angiogenesis through transcriptional repression of NFKB-responsive genes, including IL8 (146930), IL6 (147620), COX2 (600262), and colony-stimulating factor 3 (138970). The authors concluded that ING4 has an important role in brain tumor pathogenesis.
A key component of the hypoxic response pathway is hypoxia-inducible factor (HIF; see 603348). Ozer et al. (2005) found that ING4 suppressed expression of HIF target genes under hypoxic conditions. ING4 directly interacted with HPH2 (EGLN1; 606425), a mediator of HIF stability, providing a mechanism for ING4 recruitment to HIF. ING4 association with HPH2 did not affect hydroxylase activity or HIF stability , but it suppressed HIF activity in a chromatin-dependent manner. Ozer et al. (2005) hypothesized that ING4, recruited to HIF by HPH2 under hypoxic conditions, acts as an adaptor protein to recruit transcriptional repressors to mediate HIF activity.
By immunopurifying HeLa cell proteins that associated with ING4, Doyon et al. (2006) found that ING4 was a component of a histone acetyltransferase complex containing HBO1 (MYST2; 609880). Using an in vitro acetyltransferase assay, they showed that the complex could acetylate lysines of the histone H4 (see 602822) N-terminal domain.
Zhang et al. (2010) presented evidence that microRNA-650 (MIR650; 615379) plays a role in human gastric cancer tumorigenicity. Using bioinformatic analysis, they identified a potential binding site for MIR650 in the 3-prime UTR of ING4. Transfection of MIR650 precursor into HEK293 cells reduced protein content of ING4, whereas inhibition of MIR650 increased expression of a reporter gene containing the ING4 3-prime UTR.
Kim et al. (2004) stated that the ING4 gene maps to chromosome 12p13.
Kim et al. (2004) devised a screen for genes that suppress the loss of contact inhibition elicited by overexpression of the protooncogene MYCN (164840). The initial application of this screen detected 9 distinctive suppressors within a representative human cDNA library. One of these genes was ING4, a potential tumor suppressor gene. Ectopic expression of ING4 suppressed the loss of contact inhibition elicited by either MYCN or MYC (190080) but had no direct effect on cellular proliferation. Pursuing the possibility that ING4 might be a tumor suppressor gene, Kim et al. (2004) found inactivating mutations in ING4 transcripts from various human cancer cell lines. In addition, they used comparative genomic hybridization to detect deletion of the ING4 locus in 10 to 20% of human breast cancer cell lines and primary breast tumors. Ectopic expression of ING4 attenuated the growth of the human breast tumor cell line T47D in soft agar. Kim et al. (2004) concluded that ING4 is a strong candidate as a tumor suppressor gene.
Doyon, Y., Cayrou, C., Ullah, M., Landry, A.-J., Cote, V., Selleck, W., Lane, W. S., Tan, S., Yang, X.-J., Cote, J. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Molec. Cell 21: 51-64, 2006. [PubMed: 16387653] [Full Text: https://doi.org/10.1016/j.molcel.2005.12.007]
Garkavtsev, I., Kozin, S. V., Chernova, O., Xu, L., Winker, F., Brown, E., Barnett, G. H., Jain, R. K. The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature 428: 328-332, 2004. [PubMed: 15029197] [Full Text: https://doi.org/10.1038/nature02329]
Kim, S., Chin, K., Gray, J. W., Bishop, J. M. A screen for genes that suppress loss of contact inhibition: identification of ING4 as a candidate tumor suppressor gene in human cancer. Proc. Nat. Acad. Sci. 101: 16251-16256, 2004. [PubMed: 15528276] [Full Text: https://doi.org/10.1073/pnas.0407158101]
Ozer, A., Wu, L. C., Bruick, R. K. The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc. Nat. Acad. Sci. 102: 7481-7486, 2005. [PubMed: 15897452] [Full Text: https://doi.org/10.1073/pnas.0502716102]
Shiseki, M., Nagashima, M., Pedeux, R. M., Kitahama-Shiseki, M., Miura, K., Okamura, S., Onogi, H., Higashimoto, Y., Appella, E., Yokota, J., Harris, C. C. p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. Cancer Res. 63: 2373-2378, 2003. [PubMed: 12750254]
Zhang, X., Zhu, W., Zhang, J., Huo, S., Zhou, L., Gu, Z., Zhang, M. MicroRNA-650 targets ING4 to promote gastric cancer tumorigenicity. Biochem. Biophys. Res. Commun. 395: 275-280, 2010. [PubMed: 20381459] [Full Text: https://doi.org/10.1016/j.bbrc.2010.04.005]