PIP4K and the role of nuclear phosphoinositides in tumour suppression.
Phosphatidylinositol-5-phosphate (PtdIns5P)-4-kinases (PIP4Ks) are stress-regulated lipid kinases that phosphorylate PtdIns5P to generate PtdIns(4,5)P₂. There are three isoforms of PIP4Ks: PIP4K2A, 2B and 2C, which localise to different subcellular compartments with the PIP4K2B isoform being localised predominantly in the nucleus. Suppression of PIP4K expression selectively prevents tumour cell growth in vitro and prevents tumour development in mice that have lost the tumour suppressor p53. p53 is lost or mutated in over 70% of all human tumours. These studies suggest that inhibition of PIP4K signalling constitutes a novel anti-cancer therapeutic target. In this review we will discuss the role of PIP4K in tumour suppression and speculate on how PIP4K modulates nuclear phosphoinositides (PPIns) and how this might impact on nuclear functions to regulate cell growth. This article is part of a Special Issue entitled Phosphoinositides.
Cellular Signalling Laboratory, DIBINEM, University of Bologna, Bologna, Italy. Electronic address: roberta.fiume@unibo.it.
Roberta
R
Fiume
Inositide Laboratory, Centre for Biological Sciences, Faculty of Natural & Environmental Sciences, Life Sciences Building 85, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK.
Yvette
Y
Stijf-Bultsma
Inositide Laboratory, Centre for Biological Sciences, Faculty of Natural & Environmental Sciences, Life Sciences Building 85, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK.
Zahid H
ZH
Shah
The Netherlands Cancer Institute, Amsterdam 1066CX, The Netherlands.
Willem Jan
WJ
Keune
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TF, UK.
David R
DR
Jones
IMP - Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
Julian Georg
JG
Jude
Inositide Laboratory, Centre for Biological Sciences, Faculty of Natural & Environmental Sciences, Life Sciences Building 85, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK. Electronic address: N.Divecha@soton.ac.uk.
Nullin
N
Divecha
D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002467:Cell Nucleus / Q000201:enzymology*; D003593:Cytoplasm / Q000201:enzymology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
D000970:Antineoplastic Agents; D007527:Isoenzymes; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C113567:phosphatidylinositol 5-phosphate; D019870:1-Phosphatidylinositol 4-Kinase
PIP4K