Stabilized Phosphatidylinositol-5-Phosphate Analogues as Ligands for the Nuclear Protein ING2:  Chemistry, Biology, and Molecular Modeling

Huang, Wei; Zhang, Honglu; Davrazou, Foteini; Kutateladze, Tatiana G.; Shi, Xiaobing; Gozani, Or; Prestwich, Glenn D.

doi:10.1021/ja070195b

Cited by 37 publications

(34 citation statements)

References 46 publications

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“…Given the fact that high levels of PtdIns-4,5-P 2 , which is the substrate of type I 4-phosphatase, are widely distributed in both cytoplasm and the nucleus, it is possible that this dephosphorylating process may be the predominate synthetic pathway for PtdIns-5-P. Several PHD fingers containing nuclear proteins are PtdIns-5-P-binding ligands (6,14,15). It has been shown that ING2 is a nuclear receptor for PtdIns-5-P in response to stress, and this interaction and its consequences have been studied extensively (6,8,16). The only known regulator of PtdIns-5-P in apoptotic events identified previously is PIPKII␤ (8).…”

Section: Discussionmentioning

confidence: 99%

Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis

Zou

Marjanovic

Kisseleva

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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A recently discovered phosphatidylinositol monophosphate, phosphatidylinositol 5-phosphate (PtdIns-5-P), plays an important role in nuclear signaling by influencing p53-dependent apoptosis. It interacts with a plant homeodomain finger of inhibitor of growth protein-2, causing an increase in the acetylation and stability of p53. Here we show that type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase (type I 4-phosphatase), an enzyme that dephosphorylates phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P2), forming PtdIns-5-P in vitro, can increase the cellular levels of PtdIns-5-P. When HeLa cells were treated with the DNAdamaging agents etoposide or doxorubicin, type I 4-phosphatase translocated to the nucleus and nuclear levels of PtdIns-5-P increased. This action resulted in increased p53 acetylation, which stabilized p53, leading to increased apoptosis. Overexpression of type I 4-phosphatase increased apoptosis, whereas RNAi of the enzyme diminished it. The half-life of p53 was shortened from 7 h to 1.8 h upon RNAi of type I 4-phosphatase. This enzyme therefore controls nuclear levels of PtdIns-5-P and thereby p53-dependent apoptosis.acetylated p53 ͉ inositol signaling ͉ nuclear translocation I nositol lipids participate in a variety of intracellular signaling pathways including cytoskeletal dynamics, intracellular membrane trafficking, cell proliferation, and apoptosis (1, 2). In response to agonists, the phosphoinositide profile is modulated by phospholipases, lipid kinases, and lipid phosphatases. The lipid messengers transduce signals through binding to proteins with binding domains specific for different phosphoinositides.The most recently discovered of the seven known phosphoinositides is phosphatidylinositol 5-phosphate (PtdIns-5-P), and its function is the least understood (3). The origin of PtdIns-5-P in cells was until recently unknown. A study of changes in the cellular levels of PtdIns-5-P suggested that PtdIns-5-P arises from the action of a phosphatase rather than a kinase (4). Our discovery of two phosphatases that convert PtdIns-4,5-P 2 to PtdIns-5-P provides a route for synthesis of this lipid (5). Recently, it was suggested that PtdIns-5-P specifically interacts with a plant homeodomain (PHD) finger of inhibitor of growth protein-2 (ING2) protein, and that this interaction is required for ING2-dependent activation of p53, which leads to increased apoptosis (6). This suggestion was based on the finding that RNAi of ING2 or overexpression of the phosphatidylinositol phosphate kinase (PIPK) type II␤, an enzyme that converts PtdIns-5-P to PtdIns-4,5-P 2 , decreases apoptosis. Thus, it was presumed that both ING2 and PtdIns-5-P were required for acetylation of p53, although cellular PtdIns-5-P was not measured in that study (6).The ING2 is a member of the inhibitor of growth family and acts as a cofactor on the histone acetyltransferase complex that functions in chromatin remodeling and p53 acetylation and activation (7). Mutation of the PHD finger that renders PtdIns-5-P-binding defective...

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Section: Discussionmentioning

confidence: 99%

Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis

Zou

Marjanovic

Kisseleva

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Although the biological functions of this region are not well understood, it has been reported that PtdIns5P bind to the PHD motif of ING2 [33,111]. Later, it was found that PtdIns3P and PtdIns4P can bind to the PBR [112].…”

Section: The Polybasic Regionmentioning

confidence: 99%

The ING family tumor suppressors: from structure to function

Aguissa-Touré

Wong

2010

Cell. Mol. Life Sci.

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The Inhibitor of Growth (ING) proteins belong to a well-conserved family which presents in diverse organisms with several structural and functional domains for each protein. The ING family members are found in association with many cellular processes. Thus, the ING family proteins are involved in regulation of gene transcription, DNA repair, tumorigenesis, apoptosis, cellular senescence and cell cycle arrest. The ING proteins have multiple domains that are potentially capable of binding to many partners. It is conceivable, therefore, that such proteins could function similarly within protein complexes. In this case, within this family, each function could be attributed to a specific domain. However, the role of ING domains is not definitively clear. In this review, we summarize recent advances in structure-function relationships in ING proteins. For each domain, we describe the known biological functions and the approaches utilized to identify the functions associated with ING proteins.

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“…Phosphonates are widely distributed compounds in living organisms, performing a variety of functions. Introduction of phosphonate, as bioisosteric group to phosphate, has been used in the development of drugs or searching for new therapeutic substances regarding their stability in the conditions of the enzymatic hydrolysis [5,6]. Moreover, among phosphonates, one can find active substances such as antiviral, antibacterial, antitumor, and drugs used in the treatment of osteoporosis [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Betulin Phosphonates; Synthesis, Structure, and Cytotoxic Activity

et al. 2016

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Abstract:Betulin derivatives are a widely studied group of compounds of natural origin due to their wide spectrum of biological activities. This paper describes new betulin derivatives, containing a phosphonate group. The allyl-vinyl isomerization and synthesis of acetylenic derivatives have been reported. Structural identification of products as E and Z isomers has been carried out using 1 H-, 13 C-, 31 P-NMR, and crystallographic analysis. The crystal structure in the orthorhombic space group and analysis of crystal packing contacts for 29-diethoxyphosphoryl-28-cyclopropylpropynoyloxy-lup-20E(29)-en-3β-ol 8a are reported. All new compounds were tested in vitro for their antiproliferative activity against human T47D (breast cancer), , and C32 (melanoma) cell lines.

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Stabilized Phosphatidylinositol-5-Phosphate Analogues as Ligands for the Nuclear Protein ING2: Chemistry, Biology, and Molecular Modeling

Cited by 37 publications

References 46 publications

Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis

Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis

The ING family tumor suppressors: from structure to function

Betulin Phosphonates; Synthesis, Structure, and Cytotoxic Activity

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