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Shim, Hyeseok

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Shim, Hyeseok

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    Biology of Type 2 Phosphatidylinositol-5-Phosphate 4-Kinase
    (2015-09-22) Shim, Hyeseok; Cichowski, Karen; Toker, Alex; Blenis, John
    Type 2 phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) converts phosphatidylinositol-5-phosphate to phosphatidylinositol-4,5-bisphosphate. Mammals have three genes, PIP4K2A, PIP4K2B and PIP4K2C that encode the enzymes PI5P4Kα, PI5P4Kβ and PI5P4Kγ respectively. Studies in mice showed that PI5P4Kβ is a negative regulator of insulin signaling (Lamia et al., 2004) and that co-deletion of Pip4k2b and Trp53 resulted in synthetic embryonic lethality (Emerling et al., 2013). Also, deletion of two alleles of Pip4k2a and one allele of Pip4k2b suppressed the appearance of tumors in Trp53-/- mice. These studies suggest that drugs targeting PI5P4Kα and β could be effective therapies for treating insulin resistance, type 2 diabetes and TP53 mutant cancers. While less is known about PI5P4Kγ, several genome-wide association studies have revealed a SNP in front of the PIP4K2C at an autoimmunity susceptibility loci (Raychaudhuri et al., 2008). To evaluate the role of PI5P4Kγ, I generated Pip4k2c-/- mice and found an inflammatory phenotype with increased tissue immune infiltrates and pro-inflammatory cytokines, correlating with increased helper T cells and decreased regulatory T cells. Also, Pip4k2c-/- mice exhibited upregulated mammalian target of rapamycin complex 1 (mTORC1) signaling in tissues and rapamycin treatment reduced the inflammation of these mice. These studies support the concept that the SNP identified at the PIP4K2C locus in human patients with autoimmunity contributes to disease by reducing expression of PI5P4Kγ and indicates that inhibition of mTORC1 would be beneficial to these patients. Finally, in collaboration with Dr. Nathanael Gray’s laboratory we identified small molecules that covalently react with PI5P4Ks and thereby cause irreversible inhibition. These compounds, PIP4Kin1 and PIP4Kin2 mimicked the effect of shRNA mediated knockdown or knockout of PI5P4Kα and PI5P4Kβ, and impaired the growth of several TP53 mutant cancer cell lines, with little effect on most TP53 wild type cell lines. Utilizing the xenograft tumor model with BT474 (TP53 mutant) and MCF7 (TP53 wild type) cells, we showed that daily treatment of the mice with PIP4Kin2 inhibited the growth of the BT474 tumors but not the MCF7 tumors, without causing any obvious toxicity. These results further validate PI5P4Kα and PI5P4Kβ as targets for treating TP53 mutant cancers.