Disease relevance of ING4

• Ectopic expression of ING4 attenuated the growth of T47D human breast cancer cells in soft agar [1].
• The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF) [2].
• Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas [3].
• In conclusion, frequent deletion and decreased mRNA expression of ING4 suggested it as a class two tumor suppressor gene and may play an important role in head and neck cancer [3].
• Expression of ING4 is significantly reduced in gliomas as compared with normal human brain tissue, and the extent of reduction correlates with the progression from lower to higher grades of tumours [4].

High impact information on ING4

• ING4 directly associates with the HIF prolyl hydroxylase, an Fe(II)-dependent oxygenase previously shown to mediate HIF stability as a function of oxygen availability [2].
• These data support a model in which, in addition to regulating HIF stability, HIF prolyl hydroxylases can modulate HIF function through the recruitment of ING4, a likely component of a chromatin-remodeling complex [2].
• Ectopic expression of ING4 suppressed the loss of contact inhibition elicited by either MYCN or MYC but had no direct effect on cellular proliferation [1].
• One of these genes was ING4, a potential tumor suppressor gene that maps to human chromosome 12p13 [1].
• A screen for genes that suppress loss of contact inhibition: identification of ING4 as a candidate tumor suppressor gene in human cancer [1].

Chemical compound and disease context of ING4

• In addition to its nuclear functions, cytoplasmic ING4 interacts with liprin alpha1 to regulate cell migration and, with its known antiangiogenic function, may prevent invasion and metastasis [5].

Biological context of ING4

• Interestingly, the overexpression of ING4 negatively regulated the cell growth with significant G2/M arrest of cell cycle, and moreover, enhanced the cell apoptosis triggered by serum starvation in HepG2 cells [6].
• ING4 induces G2/M cell cycle arrest and enhances the chemosensitivity to DNA-damage agents in HepG2 cells [6].
• We conclude that ING4 is a strong candidate as a tumor suppressor gene [1].
• In addition, we used comparative genomic hybridization to detect deletion of the ING4 locus in 10-20% of human breast cancer cell lines and primary breast tumors [1].
• ING4 is localized to chromosome 12p13.31 region and harbors the PHD domain highly homologous among ING family proteins [3].

Anatomical context of ING4

• ING4 and liprin alpha1 colocalized at lamellipodia in the vicinity of vinculin [5].
• Here, we identified liprin alpha1/PPFIA1, a cytoplasmic protein necessary for focal adhesion formation and axon guidance, as a novel interacting protein with ING4 [5].

Associations of ING4 with chemical compounds

• Moreover, HepG2 cells with exogenous ING4 could significantly increase cell death, as exposed to some DNA-damage agents, such as etoposide and doxorubicin, implying that ING4 could enhance chemosensitivity to certain DNA-damage agents in HepG2 cells [6].
• ING4 also suppressed cell motility that was enhanced by liprin alpha1 [5].
• In contrast to ING2, ING4 is not a phosphoinositide receptor and binds with similar affinity to the different methylation states of histone-3 at lysine 4 [7].

Physical interactions of ING4

• However, which region of ING4 could have contributed to the binding to p53 remains largely unclear [8].

Regulatory relationships of ING4

• However, ING4 did not further suppress cell motility when liprin alpha1 was suppressed with RNA interference, suggesting a functional and mechanistic interdependence between these proteins [5].

Other interactions of ING4

• Furthermore, the interaction of ING4 to p53 was abrogated in vitro and in vivo when certain mutations or the entire deletion of the NLS domain occurred [8].
• The potential tumor suppressor ING4 was recently shown to be a critical regulator of NF-kappaB-mediated IL-8 transcription and subsequent angiogenesis in gliomas [9].
• These results indicate that p29ING4 and p28ING5 may be significant modulators of p53 function [10].
• These data provide evidence for the role of ING4 in mediating the effect of low K intake on ROMK channel activity by stimulation of p38 and ERK MAPK [11].

Analytical, diagnostic and therapeutic context of ING4

• Quantitative real-time RT-PCR analysis demonstrated decreased expression of ING4 mRNA in 76% of primary tumors as compared with that of matched normal samples [3].
• In mice, xenografts of human glioblastoma U87MG, which has decreased expression of ING4, grow significantly faster and have higher vascular volume fractions than control tumours [4].
• Using the ING4 wobble isoforms as an example, we demonstrated that capillary electrophoresis can precisely separate DNA fragments with a small difference in size (<3 nt) and can be used to quantify the expression ratio, which thus measures the distribution of each splicing-junction wobble isoform in tissues [12].

References