| Structural highlights
Function
[ING4_HUMAN] Component of the HBO1 complex which has a histone H4-specific acetyltransferase activity, a reduced activity toward histone H3 and is responsible for the bulk of histone H4 acetylation in vivo. Through chromatin acetylation it may function in DNA replication. May inhibit tumor progression by modulating the transcriptional output of signaling pathways which regulate cell proliferation. Can suppress brain tumor angiogenesis through transcriptional repression of RELA/NFKB3 target genes when complexed with RELA. May also specifically suppress loss of contact inhibition elicited by activated oncogenes such as MYC. Represses hypoxia inducible factor's (HIF) activity by interacting with HIF prolyl hydroxylase 2 (EGLN1).[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
The protein ING4 binds to histone H3 trimethylated at Lys4 (H3K4me3) through its C-terminal PlantHomeoDomain (PHD), thus recruiting the HBO1 histone acetyltransferase complex to target promoters. The structure of the PHD finger bound to an H3K4me3 peptide has been described, as well as the disorder and flexibility in the ING4 central region. We report the crystal structure of the ING4 N-terminal domain, which shows an antiparallel coiled-coil homodimer with each protomer folded into a helix-loop-helix structure. This arrangement suggests that ING4 can bind simultaneously two histone tails, on the same or different nucleosomes. Dimerization has a direct impact on ING4 tumor suppressor activity since monomeric mutants lose the ability of inducing apoptosis after genotoxic stress. Homology modeling based on the ING4 structure suggests that other ING dimers may also exist.
The crystal structure of the inhibitor of growth 4 (ING4) dimerization domain reveals the functional organization of the ING family of chromatin binding proteins.,Culurgioni S, Munoz IG, Moreno A, Palacios A, Villate M, Palmero I, Montoya G, Blanco FJ J Biol Chem. 2012 Feb 9. PMID:22334692[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shiseki M, Nagashima M, Pedeux RM, Kitahama-Shiseki M, Miura K, Okamura S, Onogi H, Higashimoto Y, Appella E, Yokota J, Harris CC. p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. Cancer Res. 2003 May 15;63(10):2373-8. PMID:12750254
- ↑ Zhang X, Xu LS, Wang ZQ, Wang KS, Li N, Cheng ZH, Huang SZ, Wei DZ, Han ZG. ING4 induces G2/M cell cycle arrest and enhances the chemosensitivity to DNA-damage agents in HepG2 cells. FEBS Lett. 2004 Jul 16;570(1-3):7-12. PMID:15251430 doi:https://dx.doi.org/10.1016/j.febslet.2004.06.010
- ↑ Garkavtsev I, Kozin SV, Chernova O, Xu L, Winkler F, Brown E, Barnett GH, Jain RK. The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature. 2004 Mar 18;428(6980):328-32. PMID:15029197 doi:https://dx.doi.org/10.1038/nature02329
- ↑ Kim S, Chin K, Gray JW, Bishop JM. A screen for genes that suppress loss of contact inhibition: identification of ING4 as a candidate tumor suppressor gene in human cancer. Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16251-6. Epub 2004 Nov 4. PMID:15528276 doi:https://dx.doi.org/10.1073/pnas.0407158101
- ↑ Ozer A, Wu LC, Bruick RK. The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci U S A. 2005 May 24;102(21):7481-6. Epub 2005 May 16. PMID:15897452 doi:0502716102
- ↑ Doyon Y, Cayrou C, Ullah M, Landry AJ, Cote V, Selleck W, Lane WS, Tan S, Yang XJ, Cote J. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell. 2006 Jan 6;21(1):51-64. PMID:16387653 doi:10.1016/j.molcel.2005.12.007
- ↑ Culurgioni S, Munoz IG, Moreno A, Palacios A, Villate M, Palmero I, Montoya G, Blanco FJ. The crystal structure of the inhibitor of growth 4 (ING4) dimerization domain reveals the functional organization of the ING family of chromatin binding proteins. J Biol Chem. 2012 Feb 9. PMID:22334692 doi:10.1074/jbc.M111.330001
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