Publications
98 results found
Mak LH, Georgiades SN, Rosivatz E, et al., 2011, A Small Molecule Mimicking a Phosphatidylinositol (4,5)-Bisphosphate Binding Pleckstrin Homology Domain, ACS Chemical Biology, ISSN: 1554-8929
Georgiades S, Mak L, Angurell I, et al., 2011, Identification of a potent activator of Akt phosphorylation from a novel series of phenolic, picolinic, pyridino, and hydroxamic zinc(II) complexes, Journal of Biological Inorganic Chemistry, Vol: 16, Pages: 195-208, ISSN: 0949-8257
Rosivatz E, Woscholski R, 2011, Removal or masking of phosphatidylinositol(4,5)bisphosphate from the outer mitochondrial membrane causes mitochondrial fragmentation, Cell Signal., Vol: 23, Pages: 478-486
Mitochondria are central players in programmed cell death and autophagy. While phosphoinositides are well established regulators of membrane traffic, cellular signalling and the destiny of certain organelles, their presence and role for mitochondria remain elusive. In this study we show that removal of PtdIns(4,5)P(2) by phosphatases or masking the lipid with PH domains leads to fission of mitochondria and increased autophagy. Induction of general autophagy by amino acid starvation also coincides with the loss of mitochondrial PtdIns(4,5)P(2), suggesting an important role for this lipid in the processes that govern mitophagy. Our findings reveal that PKCalpha can rescue the removal or masking of PtdIns(4,5)P(2), indicating that the inositol lipid is upstream of PKC
Mak L, Vilar R, Woscholski R, 2010, Characterisation of the PTEN inhibitor VO-OHpic, Journal of Chemical Biology, Vol: 3, Pages: 157-163, ISSN: 1864-6158
Smith MEB, Gunn RM, Rosivatz E, et al., 2010, Development of chemical probes: Toward the mode of action of a methylene-linked di(aryl acetate) E1, Bioorganic & Medicinal Chemistry, Vol: 18, Pages: 4917-4927, ISSN: 0968-0896
Alimonti A, Nardella C, Pavese I, et al., 2010, PTEN and MDM2 inhibitors; Toward a novel pro-senescence therapy approach for patients with cancer., JOURNAL OF CLINICAL ONCOLOGY, Vol: 28, ISSN: 0732-183X
Alimonti A, Nardella C, Chen Z, et al., 2010, A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis, J.Clin.Invest, Vol: 120, Pages: 681-693
Irreversible cell growth arrest, a process termed cellular senescence, is emerging as an intrinsic tumor suppressive mechanism. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment. We previously demonstrated in a mouse model of prostate cancer that inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (Pten) elicits a senescence response that opposes tumorigenesis. Here, we show that Pten-loss-induced cellular senescence (PICS) represents a senescence response that is distinct from oncogene-induced senescence and can be targeted for cancer therapy. Using mouse embryonic fibroblasts, we determined that PICS occurs rapidly after Pten inactivation, in the absence of cellular proliferation and DDR. Further, we found that PICS is associated with enhanced p53 translation. Consistent with these data, we showed that in mice p53-stabilizing drugs potentiated PICS and its tumor suppressive potential. Importantly, we demonstrated that pharmacological inhibition of PTEN drives senescence and inhibits tumorigenesis in vivo in a human xenograft model of prostate cancer. Taken together, our data identify a type of cellular senescence that can be triggered in nonproliferating cells in the absence of DNA damage, which we believe will be useful for developing a "pro-senescence" approach for cancer prevention and therapy
Woscholski R, Hailes HC, Numbere MG, et al., 2009, Compounds
H or esters or amides thereof where n is 1-5; and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for use in modulating PKB activity.
Ho KK, Rosivatz E, Gunn RM, et al., 2009, The novel molecule 2-[5-(2-chloroethyl)-2-acetoxy-benzyl]-4-(2-chloroethyl)-phenyl acetate inhibits phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signalling through JNK activation in cancer cells, FEBS J., Vol: 276, Pages: 4037-4050
Screening a compound library of compound 48/80 analogues, we identified 2-[5-(2-chloroethyl)-2-acetoxy-benzyl]-4-(2-chloroethyl)-phenyl acetate (E1) as a novel inhibitor of the phosphoinositide 3-kinase/Akt pathway. In order to determine the mechanism of action of E1, we analysed the effect of E1 on components of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. E1 demonstrated dose-dependent and time-dependent repression of Akt and mTOR activity in prostate and breast cancer cell lines, PC-3 and MCF-7, respectively. Inhibition of Akt and mTOR activity by E1 also coincided with increased c-Jun NH2-terminal kinase (JNK) phosphorylation. However, the mode of action of E1 is different from that of the mTOR inhibitor rapamycin. Proliferation and cell cycle analysis revealed that E1 induced cell cycle arrest and cell death in PC-3 and MCF-7 cells. Moreover, pretreatment of cancer cells with the JNK inhibitor SP600125 abolished the repression of Akt and mTOR activity by E1, indicating that the inhibition of Akt and mTOR by E1 is mediated through JNK activation. Consistently, E1 repressed Akt and mTOR activity in wild-type and p38-null mouse embryonic fibroblasts (MEFs), but not in MEFs lacking JNK1/2, and JNK-null MEFs were less sensitive to the antiproliferative effects of E1. We further showed that E1 can function cooperatively with suboptimal concentrations of paclitaxel to induce cell death in PC-3 and MCF-7 cells. Taken together, these data suggest that E1 induces cancer cell death through the JNK-dependent repression of Akt and mTOR activity and may provide a valuable compound for further development and research
Garnier-Lhomme M, Byrne RD, Hobday TMC, et al., 2009, Nuclear envelope remnants: fluid membranes enriched in STEROLS and polyphosphoinositides, PLoS ONE, Vol: 4, ISSN: 1932-6203
BackgroundThe cytoplasm of eukaryotic cells is a highly dynamic compartment where membranes readily undergo fission and fusion to reorganize the cytoplasmic architecture, and to import, export and transport various cargos within the cell. The double membrane of the nuclear envelope that surrounds the nucleus, segregates the chromosomes from cytoplasm and regulates nucleocytoplasmic transport through pores. Many details of its formation are still unclear. At fertilization the sperm devoid of nuclear envelope pores enters the egg. Although most of the sperm nuclear envelope disassembles, remnants of the envelope at the acrosomal and centriolar fossae do not and are subsequently incorporated into the newly forming male pronuclear envelope. Remnants are conserved from annelid to mammalian sperm.Methodology/Principal FindingsUsing lipid mass spectrometry and a new application of deuterium solid-state NMR spectroscopy we have characterized the lipid composition and membrane dynamics of the sperm nuclear envelope remnants in isolated sperm nuclei.Conclusions/SignificanceWe report nuclear envelope remnants are relatively fluid membranes rich in sterols, devoid of sphingomyelin, and highly enriched in polyphosphoinositides and polyunsaturated phospholipids. The localization of the polybasic effector domain of MARCKS illustrates the non-nuclear aspect of the polyphosphoinositides. Based on their atypical biophysical characteristics and phospholipid composition, we suggest a possible role for nuclear envelope remnants in membrane fusion leading to nuclear envelope assembly.
Mulet X, Rosivatz E, Ho KK, et al., 2009, Spatial localization of PtdInsP2 in phase-separated giant unilamellar vesicles with a fluorescent PLC-delta 1 PH domain, Methods Mol.Biol., Vol: 462, Pages: 135-144
This chapter describes a method for the preparation of giant unilamellar vesicles containing phosphatidylinositol 4,5-bisphosphate that are larger than 20 microm in size. The phospholipids composition of the vesicular membrane is such that fluid lamellar and liquid-ordered or gel phases are formed and separate within the confines of one vesicle. It outlines the preparation of a protein fluorescent label, pleckstrin homology domain from phospholipase C-delta 1, that binds specifically to phosphatidylinositol 4,5-bisphosphate. Using fluorescence microscopy, the presence and spatial position of this phosphorylated phosphatidylinositol lipid on the lipid membrane have been located with the pleckstrin homology domain. We show that phosphatidylinositol 4,5-bisphosphate and the phospholipase C-delta 1 pleckstrin homology domain are located to the fluid phase of the vesicle membrane. This approach can therefore show how membrane physical properties can affect enzyme binding to phosphatidylinositol 4,5-bisphosphate and thus further the understanding of important membrane processes such as endocytosis
Rosivatz E, Woscholski R, 2009, Measurement of PTEN activity in vivo by imaging phosphorylated Akt, Methods Mol.Biol., Vol: 462, Pages: 213-222
This chapter describes an indirect approach to measure PTEN's lipid phosphatase activity in vivo. PTEN counteracts phosphatidylinositol 3-kinase action in dephosphorylating 3-phosphorylated phosphoinositides. Therefore, PtdIns(3,4,5)P3-dependent activation and phosphorylation of the survival kinase Akt can be used as readout for cellular PTEN activity. Here we have outlined a detailed procedure employing a phosphoserine-specific anti-Akt antibody to examine the content of phosphorylated Akt by immunofluorescence and its dependence on PTEN activity
Larijani B, Woscholski R, Rosser CA, 2009, Lipid signaling protocols, Publisher: Springer Verlag, ISBN: 9781588297273
Divided into two convenient sections, the volume begins by summarizing the physicalproperties of hydrophobic metabolites as well as the physical methodologies ...
Woscholski R, Larijani B, 2008, Not just another journal., J Chem Biol, Vol: 1, Pages: 1-2, ISSN: 1864-6158
Mulet X, Templer RH, Woscholski R, et al., 2008, Evidence that phosphatidylinositol promotes curved membrane interfaces, LANGMUIR, Vol: 24, Pages: 8443-8447, ISSN: 0743-7463
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- Citations: 31
Busch GK, Tate EW, Gaffney PR, et al., 2008, Specific N-terminal protein labelling: use of FMDV 3C pro protease and native chemical ligation, Chem.Commun.(Camb.), Pages: 3369-3371
We report an effective strategy for generating N-terminal cysteinyl proteins by proteolytic cleavage using the enzyme 3C pro, suitable for a wide range of applications via native chemical ligation
Ho KK, Anderson AA, Rosivatz E, et al., 2008, Identification of cyclin A2 as the downstream effector of the nuclear phosphatidylinositol 4,5-bisphosphate signaling network, J.Biol.Chem., Vol: 283, Pages: 5477-5485
In addition to the well characterized phosphoinositide second messengers derived from the plasma membrane, increasing evidence supports the existence of a nuclear phosphoinositide signaling network. The aim of this investigation was to dissect the role played by nuclear phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) in cell cycle progression and to determine the cell cycle regulatory component(s) that are involved. A number of cytosolic/nuclear PtdIns(4,5)P2-deficient Swiss 3T3 cell lines were established, and their G 0/G 1/S cell cycle phase transitions induced by defined mitogens were examined. Our results demonstrate that nuclear PtdIns(4,5)P2 down-regulation caused a delay in phorbol ester-induced S phase entry and that this was at least in part channeled through cyclin A2 at the transcriptional level. In summary, these data identify cyclin A2 as a downstream effector of the nuclear PtdIns(4,5)P2 signaling network and highlight the importance of nuclear PtdIns(4,5)P2 in the regulation of mammalian mitogenesis
Woscholski R, Hailes HC, Numbere MG, 2008, ProfileCalixarenes as Inhibitors of Protein Kinase B
The present invention provides compounds useful in inhibiting protein kinase B (PKB/Akt). Compositions comprising such compounds and their use are also provided.
Woscholski R, Rosivatz E, Vilar R, 2007, Vanadium compounds as inhibitors of phosphatases, 7,692,012
Novel Vanadium compounds are described as well as their use as inhibitors of phosphatases, particularly inositol phosphatases, The use of the compound in the treatment of nerodegenerative diseases is also described.
Barter LMC, Klug DR, Woscholski R, 2007, Does history repeat itself? The emergence of a new discipline (vol 1, pg 737, 2006), ACS CHEMICAL BIOLOGY, Vol: 2, Pages: 271-271, ISSN: 1554-8929
Byrne RD, Rosivatz E, Parsons M, et al., 2007, Differential activation of the PI 3-kinase effectors AKT/PKB and p70 S6 kinase by compound 48/80 is mediated by PKCalpha, Cell Signal., Vol: 19, Pages: 321-329
The secretagogue compound 48/80 (c48/80) is a well known activator of calcium mediated processes and PKCs, and is a potent inducer of mast cell degranulation. As the latter process is a phosphoinositide 3-kinase (PI 3-kinase) mediated event, we wished to address whether or not c48/80 was an activator of PI 3-kinases. The data presented here reveal that c48/80 is an effective activator of PI 3-kinases as judged by the increased phosphorylation of PKB and p70(S6K) in fibroblasts in a PI 3-kinase dependent fashion. Compound 48/80 effectively translocates PKB to the plasma membrane and induces phosphorylation at serine 473 (S473), detected by fluorescence imaging of fixed cells. At higher concentrations the secretagogue is inhibitory towards PKB phosphorylation on S473. Conversely, p70(S6K) phosphorylation on T389 is unaffected at high doses. We provide evidence that the differential effect on the two PI 3-kinase effectors is due to activation of PKCalpha by c48/80, itself a PI 3-kinase dependent process. We conclude that compound 48/80 is an effective activator of PI 3-kinase dependent pathways, leading to the activation of effectors including PKB/Akt, p70(S6K) and PKCalpha. The latter is only activated by higher doses of c48/80 resulting in an inhibition of the c48/80 induced PKB phosphorylation, thus explaining the observed biphasic activation profile for PKB in response to this secretagogue
Rosivatz E, Matthews JG, McDonald NQ, et al., 2006, A small molecule inhibitor for phosphatase and tensin homologue deleted on chromosome 10 (PTEN), ACS Chem.Biol., Vol: 1, Pages: 780-790
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphoinositide 3-phosphatase, is an important regulator of insulin-dependent signaling. The loss or impairment of PTEN results in an antidiabetic impact, which led to the suggestion that PTEN could be an important target for drugs against type II diabetes. Here we report the design and validation of a small- molecule inhibitor of PTEN. Compared with other cysteine-based phosphatases, PTEN has a much wider active site cleft enabling it to bind the PtdIns(3,4,5)P3 substrate. We have exploited this feature in the design of vanadate scaffolds complexed to a range of different organic ligands, some of which show potent inhibitory activity. A vanadyl complexed to hydroxypicolinic acid was found to be a highly potent and specific inhibitor of PTEN that increases cellular PtdIns(3,4,5)P3 levels, phosphorylation of Akt, and glucose uptake in adipocytes at nanomolar concentrations. The findings presented here demonstrate the applicability of a novel and specific chemical inhibitor against PTEN in research and drug development
Fili N, Calleja V, Woscholski R, et al., 2006, Compartmental signal modulation: Endosomal phosphatidylinositol 3-phosphate controls endosome morphology and selective cargo sorting, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 103, Pages: 15473-15478, ISSN: 0027-8424
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- Citations: 80
Larijani B, Rosser CA, Woscholski R, 2006, Chemical biology, Publisher: Wiley, ISBN: 9780470090640
Introduction. 1.1 Chemical biology - the present. 1.2 Chemical biology - the past. 1.3 Chemical biology - the future. 1.4 Chemical biology - mind the ...
Barter LMC, Klug DR, Woscholski R, 2006, Does history repeat itself? The emergence of a new discipline, ACS CHEMICAL BIOLOGY, Vol: 1, Pages: 737-740, ISSN: 1554-8929
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- Citations: 1
Rosivatz E, Vilar R, Woscholski R, 2005, Imaging of PKB phosphorylation as an <i>in vivo</i> readout for PTEN inhibition studies, IUBMB 50th Anniversary Symposium, Publisher: BLACKWELL PUBLISHING, Pages: 313-313, ISSN: 1742-464X
Numbere MG, Hailes HC, Rosivatz E, et al., 2005, Synthetic approach to compound 48/80 and its analogues., 229th National Meeting of the American-Chemical-Society, Publisher: AMER CHEMICAL SOC, Pages: U129-U130, ISSN: 0065-7727
Schmid AC, Wise HM, Mitchell CA, et al., 2004, Type II phosphoinositide 5-phosphatases have unique sensitivities towards fatty acid composition and head group phosphorylation, FEBS LETTERS, Vol: 576, Pages: 9-13, ISSN: 0014-5793
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- Citations: 109
Schmid AC, Byrne RD, Vilar R, et al., 2004, Bisperoxovanadium compounds are potent PTEN inhibitors, FEBS LETTERS, Vol: 566, Pages: 35-38, ISSN: 1873-3468
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- Citations: 188
Schmid AC, Woscholski R, 2004, Phosphatases as small-molecule targets: inhibiting the endogenous inhibitors of kinases, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 32, Pages: 348-349, ISSN: 0300-5127
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- Citations: 8
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