Reactive Lipid Species from Cyclooxygenase-2 Inactivate Tumor Suppressor LKB1/STK11

LKB1, a unique serine/threonine kinase tumor suppressor, modulates anabolic and catabolic homeostasis, cell proliferation, and organ polarity. Chemically reactive lipids, e.g. cyclopentenone prostaglandins, formed a covalent adduct with LKB1 in MCF-7 and RKO cells. Site-directed mutagenesis implicated Cys210 in the LKB1 activation loop as the residue modified. Notably, ERK, JNK, and AKT serine/threonine kinases with leucine or methionine, instead of cysteine, in their activation loop did not form a covalent lipid adduct. 4-Hydroxy-2-nonenal, 4-oxo-2-nonenal, and cyclopentenone prostaglandin A and J, which all contain α,β-unsaturated carbonyls, inhibited the AMP-kinase kinase activity of cellular LKB1. In turn, this attenuated signals throughout the LKB1 → AMP kinase pathway and disrupted its restraint of ribosomal S6 kinases. The electrophilic β-carbon in these lipids appears to be critical for inhibition because unreactive lipids, e.g. PGB1, PGE2, PGF2α, and TxB2, did not inhibit LKB1 activity (p > 0.05). Ectopic expression of cyclooxygenase-2 and endogenous biosynthesis of eicosanoids also inhibited LKB1 activity in MCF-7 cells. Our results suggested a molecular mechanism whereby chronic inflammation or oxidative stress may confer risk for hypertrophic or neoplastic diseases. Moreover, chemical inactivation of LKB1 may interfere with its physiological antagonism of signals from growth factors, insulin, and oncogenes. LKB1, a unique serine/threonine kinase tumor suppressor, modulates anabolic and catabolic homeostasis, cell proliferation, and organ polarity. Chemically reactive lipids, e.g. cyclopentenone prostaglandins, formed a covalent adduct with LKB1 in MCF-7 and RKO cells. Site-directed mutagenesis implicated Cys210 in the LKB1 activation loop as the residue modified. Notably, ERK, JNK, and AKT serine/threonine kinases with leucine or methionine, instead of cysteine, in their activation loop did not form a covalent lipid adduct. 4-Hydroxy-2-nonenal, 4-oxo-2-nonenal, and cyclopentenone prostaglandin A and J, which all contain α,β-unsaturated carbonyls, inhibited the AMP-kinase kinase activity of cellular LKB1. In turn, this attenuated signals throughout the LKB1 → AMP kinase pathway and disrupted its restraint of ribosomal S6 kinases. The electrophilic β-carbon in these lipids appears to be critical for inhibition because unreactive lipids, e.g. PGB1, PGE2, PGF2α, and TxB2, did not inhibit LKB1 activity (p > 0.05). Ectopic expression of cyclooxygenase-2 and endogenous biosynthesis of eicosanoids also inhibited LKB1 activity in MCF-7 cells. Our results suggested a molecular mechanism whereby chronic inflammation or oxidative stress may confer risk for hypertrophic or neoplastic diseases. Moreover, chemical inactivation of LKB1 may interfere with its physiological antagonism of signals from growth factors, insulin, and oncogenes. The classic model of tumor suppressors as recessive genes stipulates that biallelic inactivation is necessary for tumorigenesis (1Knudson A.G. Am. J. Med. Genet. 2002; 111: 96-102Crossref PubMed Scopus (147) Google Scholar, 2Hansen M.F. Cavenee W.K. Cell. 1988; 53: 173-174Abstract Full Text PDF PubMed Scopus (68) Google Scholar, 3Knudson A.G. Proc. Natl. Acad. Sci. U. S. A. 1971; 68: 820-823Crossref PubMed Scopus (5519) Google Scholar). This model fits Rb1, adenomatous polyposis coli, and p53 in many familial and sporadic cancers (1Knudson A.G. Am. J. Med. Genet. 2002; 111: 96-102Crossref PubMed Scopus (147) Google Scholar, 4Vogelstein B. Kinzler K.W. Nat. Med. 2004; 10: 789-799Crossref PubMed Scopus (3302) Google Scholar). Paradoxically, tumors often retain one functional allele of some tumor suppressor genes, e.g. 27Kip1 (5Fero M.L. Randel E. Gurley K.E. Roberts J.M. Kemp C.J. Nature. 1998; 396: 177-180Crossref PubMed Scopus (681) Google Scholar), phosphatase tensin homolog (6Kwabi-Addo B. Giri D. Schmidt K. Podsypanina K. Parsons R. Greenberg N. Ittmann M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 11563-11568Crossref PubMed Scopus (273) Google Scholar), LKB1 (7Avizienyte E. Loukola A. Roth S. Hemminki A. Tarkkanen M. Salovaara R. Arola J. Butzow R. Husgafvel-Pursiainen K. Kokkola A. Jarvinen H. Aaltonen L.A. Am. J. Pathol. 1999; 154: 677-681Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 8Esteller M. Avizienyte E. Corn P.G. Lothe R.A. Baylin S.B. Aaltonen L.A. Herman J.G. Oncogene. 2000; 19: 164-168Crossref PubMed Scopus (161) Google Scholar), and even p53 (9Venkatachalam S. Shi Y.P. Jones S.N. Vogel H. Bradley A. Pinkel D. Donehower L.A. EMBO J. 1988; 17: 4657-4667Crossref Scopus (373) Google Scholar). Such haploinsufficiency deviates from Knudson's model (10Santarosa M. Ashworth A. Biochim. Biophys. Acta. 2004; 1654: 105-122Crossref PubMed Scopus (165) Google Scholar, 11Paige A.J. Cell. Mol. Life Sci. 2003; 60: 2147-2163Crossref PubMed Scopus (43) Google Scholar, 12Cook W.D McCaw B.J. Oncogene. 2000; 19: 3434-3438Crossref PubMed Scopus (81) Google Scholar), suggesting that these particular tumor suppressors may succumb to inactivation processes that are distinct from genetic or epigenetic lesions (13Jones P.A. Laird P.W. Nat. Genet. 1999; 21: 163-167Crossref PubMed Scopus (2049) Google Scholar). Recently, we discovered that biologically relevant, chemically reactive lipids inactivated the p53 protein, with functional consequences equivalent to the loss of one allele of the p53 gene (14Moos P.J. Edes K. Fitzpatrick F.A. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 9215-9220Crossref PubMed Scopus (65) Google Scholar, 15Moos P.J. Edes K. Cassidy P. Massuda E. Fitzpatrick F.A. J. Biol. Chem. 2003; 278: 745-750Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). That observation, along with the reported exceptions to Knudson's hypothesis (7Avizienyte E. Loukola A. Roth S. Hemminki A. Tarkkanen M. Salovaara R. Arola J. Butzow R. Husgafvel-Pursiainen K. Kokkola A. Jarvinen H. Aaltonen L.A. Am. J. Pathol. 1999; 154: 677-681Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 8Esteller M. Avizienyte E. Corn P.G. Lothe R.A. Baylin S.B. Aaltonen L.A. Herman J.G. Oncogene. 2000; 19: 164-168Crossref PubMed Scopus (161) Google Scholar) and the precedent of lipids inactivating IκB kinase (16Rossi A. Kapahi P. Natoli G. Takahashi T. Chen Y. Karin M. Santoro M.G. Nature. 2000; 403: 103-108Crossref PubMed Scopus (1200) Google Scholar, 17Ji C. Kozak K.R. Marnett L.J. J. Biol. Chem. 2001; 276: 18223-18228Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar), directed our attention to LKB1, a recently discovered tumor suppressor associated with Peutz-Jeghers hamartoma syndrome (18Jenne D.E. Reimann H. Nezu J. Friedel W. Loff S. Jeschke R. Muller O. Back W. Zimmer M. Nat. Genet. 1998; 18: 38-43Crossref PubMed Scopus (974) Google Scholar, 19Hemminki A. Markie D. Tomlinson I. Avizienyte E. Roth S. Loukola A. Bignell G. Warren W. Aminoff M. Hoglund P. Jarvinen H. Kristo P. Pelin K. Ridanpaa M. Salovaara R. Toro T. Bodmer W. Olschwang S. Olsen A.S. Stratton M.R. de la Chapelle A. Aaltonen L.A. Nature. 1998; 391: 184-187Crossref PubMed Scopus (1335) Google Scholar). LKB1 is a novel serine/threonine kinase (STK11) at the apex of a signaling cascade that senses cellular energy homeostasis and adjusts anabolic and catabolic processes (Fig. 1). LKB1, an AMP-kinase kinase and tumor suppressor, is a unique link between metabolic and proliferation/polarity signaling (20Woods A. Johnstone S.R. Dickerson K. Leiper F.C. Fryer L.G. Neumann D. Schlattner U. Wallimann T. Carlson M. Carling D. Curr. Biol. 2003; 13: 2004-2008Abstract Full Text Full Text PDF PubMed Scopus (1323) Google Scholar, 21Shaw R.J. Kosmatka M. Bardeesy N. Hurley R.L. Witters L.A. DePinho R.A. Cantley L.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 3329-3335Crossref PubMed Scopus (1418) Google Scholar, 22Lizcano J.M. Goransson O. Toth R. Deak M. Morrice N.A. Boudeau J. Hawley S.A. Udd L. Makela T.P. Hardie D.G. Alessi D.R. EMBO J. 2004; 23: 833-843Crossref PubMed Scopus (1047) Google Scholar, 23Hardie D.G. J. Cell Sci. 2004; 117: 5479-5487Crossref PubMed Scopus (957) Google Scholar, 24Kyriakis J.M. J. Biol. 2003. 2003; : 2/26Google Scholar). We report that reactive lipid species covalently modify LKB1 at a nucleophilic Cys210 residue in its activation loop, thereby inhibiting both the phosphorylation of AMPKα 3The abbreviations used are: AMPKα, AMP-activated kinase α; ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; APB, amidopentyl biotin; 4-HNE, 4-hydroxy-2-nonenal; IKK, IκB kinase; NFκB, nuclear factor κB; 4-ONE, 4-oxo-2-nonenal; PG, prostaglandin; S6K, S6 kinase; Tx, thromboxane; mTOR, mammalian target of rapamycin; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; PVDF, polyvinylidene difluoride; FCS, fetal calf serum; HA, hemagglutinin; IP, immunoprecipitation; NA, neutravidin. 3The abbreviations used are: AMPKα, AMP-activated kinase α; ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; APB, amidopentyl biotin; 4-HNE, 4-hydroxy-2-nonenal; IKK, IκB kinase; NFκB, nuclear factor κB; 4-ONE, 4-oxo-2-nonenal; PG, prostaglandin; S6K, S6 kinase; Tx, thromboxane; mTOR, mammalian target of rapamycin; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; PVDF, polyvinylidene difluoride; FCS, fetal calf serum; HA, hemagglutinin; IP, immunoprecipitation; NA, neutravidin. and the downstream propagation of signals through the LKB1-AMPKα-TSC1/2-mTOR-S6K cascade. Disruption of anabolic and catabolic homeostasis and the failure to restrain inappropriate protein translation could contribute to hamartoma formation and the heightened cancer risk in Peutz-Jeghers syndrome. Chemical inactivation of tumor suppressor proteins, like LKB1 and p53, could be an etiological factor in dysplasia and hyperplasia associated with overexpression of COX-2 or chronic inflammation that can expose cells to reactive lipid species (25Thun M.J. Henley S.J. Gansler T. Novartis Found. Symp. 2004; 256: 6-21Crossref PubMed Google Scholar, 26Fitzpatrick F.A. Int. Immunopharmacol. 2001; 1: 1651-1667Crossref PubMed Scopus (135) Google Scholar). Materials—Supplies used were Dulbecco's modified Eagle's medium and supplements (Invitrogen); bovine insulin and gentamicin (Invitrogen); PG (Cayman Chemicals); 4-HNE and 4-ONE (Cayman Chemicals); 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) (Toronto Research Chemicals Inc); Complete™ protease inhibitor mixture and FuGENE 6 transfection reagent (Roche Applied Science); polyclonal antibodies directed against LKB1, phospho-Thr172-AMPKα, AMPKα, phospho-Ser79-ACC, ACC, phospho-Thr389-S6K, S6K, ERK, JNK, AKT, IKKα, IKKγ and COX-2 (Cell Signaling Technologies); rapamycin (Cell Signaling Technologies); horseradish peroxidase-conjugated secondary antibodies (Santa Cruz Biotechnology); PVDF membranes and Western Lighting™ chemiluminescence reagents (PerkinElmer Life Sciences); neutravidin-conjugated beads (Pierce); hemagglutinin epitope-tagged constructs for LKB1 (gift from Dr. Tomi Makela, University of Helsinki, Finland); and a QuikChange™ site-directed mutagenesis kit (Stratagene). Cell Culture—MCF-7 breast cancer cells (ATCC) were maintained in minimal essential medium at 37 °C in a humidified incubator with 5% CO2. The medium was supplemented with 2 mm l-glutamine, 1.5 g/liter sodium bicarbonate, 0.1 mm nonessential amino acids, 1 mm sodium pyruvate, bovine insulin, and fetal bovine RKO cancer cells were maintained in minimal essential medium supplemented with 1.5 g/liter sodium bicarbonate, 0.1 mm nonessential amino acids, mm sodium pyruvate, and fetal bovine In cells were in medium fetal bovine for 6 to of and RKO cells were with or for The cells were in mm mm mm 1 mm Complete™ protease 2 mm sodium and 2 mm sodium The were for 1 at at for of protein from cell were with of beads in 1 of with for at The were at for to The beads were with 1 of The were in of and at °C for were and to PVDF were with 5% in for at °C with antibodies directed against LKB1 IKKγ and AKT horseradish secondary were with Western Lighting™ or LKB1 was RKO cells 1 for the COX-2 was MCF-7 cells 1 for the was of COX-2 protein in cell were and as and membranes were for at °C with antibodies directed against COX-2 Site-directed LKB1 was a QuikChange™ site-directed mutagenesis kit the was from a to a a to a The of the was AMPKα, ACC, and Western cells were with of the Tx, 4-HNE, or 4-ONE for this 2 mm J.M. J.G. Hawley S.A. Hardie D.G. J. PubMed Scopus Google Scholar), an AMP was to cells for In cells were with PG for and rapamycin for 2 to The cells were as of protein was and were to PVDF The membranes were with antibodies directed against AMPKα and horseradish secondary were with Western The were a and the was to a of the were and the and were to and COX-2 was MCF-7 cells 1 of for the were with COX-2 inhibitor (Cayman or for 1 with of for kit and (Cayman were used the from cell was and at were and results the was of with or for of LKB1 PG and 4-HNE covalently with (16Rossi A. Kapahi P. Natoli G. Takahashi T. Chen Y. Karin M. Santoro M.G. Nature. 2000; 403: 103-108Crossref PubMed Scopus (1200) Google Scholar, 17Ji C. Kozak K.R. Marnett L.J. J. Biol. Chem. 2001; 276: 18223-18228Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). these lipids may modify serine/threonine kinases with to the residue in LKB1, a unique serine/threonine kinase tumor suppressor, a nucleophilic Cys210 that with the residue in the activation loop of and In ERK, JNK, and AKT kinases or in the (Fig. electrophilic could with LKB1 and we used This PG the α,β-unsaturated of a instead of a that with contain a which to thereby their and P.J. Edes K. Cassidy P. Massuda E. Fitzpatrick F.A. J. Biol. Chem. 2003; 278: 745-750Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). covalently with cellular LKB1 and not with AKT, or IKKγ (Fig. kinases the residue to in or Cys210 in LKB1. these kinases at cellular serine/threonine kinases not with these We results for not Site-directed mutagenesis that Cys210 in the activation loop of LKB1 is for lipid adduct RKO cells of we with LKB1 or the formed a covalent adduct with LKB1 protein not with the protein (Fig. formation with LKB1 was not overexpression of the LKB1 formed with LKB1 in MCF-7 cells (Fig. adduct formation is not unique to as both and formed with LKB1 in cells (Fig. of LKB1 AMP-kinase kinase activity of LKB1 can be the cellular of AMPKα of were in MCF-7 cells in (Fig. 1). in cells with the AMP (Fig. and in cells in for 6 (Fig. inhibited the formation of these (Fig. and reactive lipid species that electrophilic 4-HNE, 4-ONE, and inhibited the AMP-kinase kinase activity of LKB1 in MCF-7 cells with (Fig. was (Fig. with of 4-HNE and 4-ONE The electrophilic β-carbon to be critical for because unreactive lipids, cyclopentenone PGB1, PGE2, PGF2α, and at of did not inhibit LKB1 activity (Fig. of the Signaling of LKB1 reactive lipids and in its signaling pathway downstream from and 4-HNE inhibited the phosphorylation of ACC, a for phospho-Thr172-AMPKα, did not (Fig. signaling through the S6 kinase pathway was The of kinase was in MCF-7 which be in insulin (Fig. and 1). of the cellular pathway with 2 mm the of phospho-Thr389-S6K, the form of (Fig. and activity in MCF-7 cells (Fig. and 2 1). the of cellular LKB1 activity and the of to the (Fig. and and 1). which with mTOR, the inactivation of LKB1 and phosphorylation of (Fig. and and inactivating cellular LKB1 at the apex of the AMPKα the formation of phospho-Thr389-S6K, with the in of LKB1 Ectopic of expression and activity are in inflammation and in tumors (25Thun M.J. Henley S.J. Gansler T. Novartis Found. Symp. 2004; 256: 6-21Crossref PubMed Google Scholar, 26Fitzpatrick F.A. Int. Immunopharmacol. 2001; 1: 1651-1667Crossref PubMed Scopus (135) Google Scholar). This cells to and reactive lipid our we or not transfection of cells with a COX-2 inhibit LKB1 kinase activity biosynthesis of endogenous Ectopic expression of COX-2 in the of its inhibited the kinase activity of LKB1. LKB1 as was in MCF-7 cells with 2 mm (Fig. LKB1 activity with in MCF-7 cells with COX-2 and with 2 mm The (p in MCF-7 cells with COX-2 and supplemented with (Fig. In MCF-7 cells with the were from the (p > (Fig. a inhibitor of the kinase activity of LKB1 (Fig. are with the inhibition of LKB1 reactive lipid We that MCF-7 cells with COX-2 and cells with 1). a COX-2 and formation cells with COX-2 not cells. MCF-7 cells Google Scholar), which for and biosynthesis formation MCF-7 transfection transfection in a Recently, LKB1 was as the gene for Peutz-Jeghers syndrome (18Jenne D.E. Reimann H. Nezu J. Friedel W. Loff S. Jeschke R. Muller O. Back W. Zimmer M. Nat. Genet. 1998; 18: 38-43Crossref PubMed Scopus (974) Google Scholar, 19Hemminki A. Markie D. Tomlinson I. Avizienyte E. Roth S. Loukola A. Bignell G. Warren W. Aminoff M. Hoglund P. Jarvinen H. Kristo P. Pelin K. Ridanpaa M. Salovaara R. Toro T. Bodmer W. Olschwang S. Olsen A.S. Stratton M.R. de la Chapelle A. Aaltonen L.A. Nature. 1998; 391: 184-187Crossref PubMed Scopus (1335) Google Scholar), which to tumors of the and in Peutz-Jeghers syndrome is in the S.B. S.R. A.J. N. J. Med. PubMed Scopus Google Scholar), and is the familial cancer syndrome to in a serine/threonine The cellular and of LKB1 were discovered that and as a unique AMP-kinase kinase (20Woods A. Johnstone S.R. Dickerson K. Leiper F.C. Fryer L.G. Neumann D. Schlattner U. Wallimann T. Carlson M. Carling D. Curr. Biol. 2003; 13: 2004-2008Abstract Full Text Full Text PDF PubMed Scopus (1323) Google Scholar, 21Shaw R.J. Kosmatka M. Bardeesy N. Hurley R.L. Witters L.A. DePinho R.A. Cantley L.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 3329-3335Crossref PubMed Scopus (1418) Google Scholar, 22Lizcano J.M. Goransson O. Toth R. Deak M. Morrice N.A. Boudeau J. Hawley S.A. Udd L. Makela T.P. Hardie D.G. Alessi D.R. EMBO J. 2004; 23: 833-843Crossref PubMed Scopus (1047) Google Scholar, 23Hardie D.G. J. Cell Sci. 2004; 117: 5479-5487Crossref PubMed Scopus (957) Google Scholar, 24Kyriakis J.M. J. Biol. 2003. 2003; : 2/26Google Scholar). LKB1 cellular as tumor suppressor and of LKB1 its the pathway (Fig. 1). their LKB1 and AKT signals that the of the of mTOR, and ribosomal in turn, anabolic and catabolic processes in to cellular energy homeostasis D.G. J. Cell Sci. 2004; 117: 5479-5487Crossref PubMed Scopus (957) Google Scholar). Our that electrophilic lipids, as as endogenous cellular can inhibit LKB1 activity and the in the pathway phosphorylation and activation of ribosomal this cells to translation of proteins, tumor of protein translation is in cancers S.J. C.J. J. 2002; PubMed Scopus Google Scholar, J. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Cell Biol. PubMed Scopus Google Scholar). expression of LKB1 in breast tumors is associated with and 2002; Google Scholar) and with the from to tumor growth in cancer H. M. M. D. 2003; Google Scholar). that COX-2 C. A. M. L. M.L. J. 2003; PubMed Scopus Google Scholar, H. S.B. 2003; Google Scholar), and its expression tumorigenesis a I. P. T. C. I. Tomlinson I. J. Pathol. 1999; PubMed Scopus Google Scholar, M.L. de J. Pathol. 2001; PubMed Scopus Google Scholar). at this our results that inhibition of LKB1 because of its chemical inactivation reactive lipid species or overexpression of as in may consequences to loss of expression of LKB1 or LKB1 is a tumor suppressor that often one from Knudson's This that LKB1 is a for inactivating processes that are distinct from genetic or epigenetic we that LKB1 be covalently modified and inactivated cyclopentenone PG and 4-HNE as and inhibit some serine/threonine kinases not inhibit not or (16Rossi A. Kapahi P. Natoli G. Takahashi T. Chen Y. Karin M. Santoro M.G. Nature. 2000; 403: 103-108Crossref PubMed Scopus (1200) Google Scholar, S. A. L. J. 2000; PubMed Scopus Google Scholar). site-directed mutagenesis and with and reactive (16Rossi A. Kapahi P. Natoli G. Takahashi T. Chen Y. Karin M. Santoro M.G. Nature. 2000; 403: 103-108Crossref PubMed Scopus (1200) Google Scholar) a at the residue in the activation loop as the molecular for inhibition of and LKB1 is a of a tumor suppressor, which as a serine/threonine kinase (18Jenne D.E. Reimann H. Nezu J. Friedel W. Loff S. Jeschke R. Muller O. Back W. Zimmer M. Nat. Genet. 1998; 18: 38-43Crossref PubMed Scopus (974) Google Scholar, 19Hemminki A. Markie D. Tomlinson I. Avizienyte E. Roth S. Loukola A. Bignell G. Warren W. Aminoff M. Hoglund P. Jarvinen H. Kristo P. Pelin K. Ridanpaa M. Salovaara R. Toro T. Bodmer W. Olschwang S. Olsen A.S. Stratton M.R. de la Chapelle A. Aaltonen L.A. Nature. 1998; 391: 184-187Crossref PubMed Scopus (1335) Google Scholar), we the amino of LKB1 its activation loop with for IKK, ERK, JNK, AKT, and This a Cys210 residue in LKB1 that to the residue in are distinct to LKB1, IKKα, and not ERK, JNK, and which or in (Fig. Our results that cyclopentenone of the and covalently modify LKB1 and not AKT, or an LKB1 with Cys210 these cellular serine/threonine kinases not with our The results in 2 and are with the the (16Rossi A. Kapahi P. Natoli G. Takahashi T. Chen Y. Karin M. Santoro M.G. Nature. 2000; 403: 103-108Crossref PubMed Scopus (1200) Google Scholar, S. A. L. J. 2000; PubMed Scopus Google the chemical between and α,β-unsaturated and the of amino of the and the chemical of between and amino the and nucleophilic of its all lipids to cellular some lipids with an α,β-unsaturated this with to their electrophilic β-carbon a nucleophilic that is for in (16Rossi A. Kapahi P. Natoli G. Takahashi T. Chen Y. Karin M. Santoro M.G. Nature. 2000; 403: 103-108Crossref PubMed Scopus (1200) Google Scholar), Cys210 in LKB1, in the of G. M. M. G. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus Google Scholar), in the of E. E. D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), in J. M. K. Sci. 2002; PubMed Scopus Google Scholar), and in T. T. T. S. H. H. J. K. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar), and results in a covalent lipid adduct. and of and which particular cellular can form with or P.J. Edes K. Cassidy P. Massuda E. Fitzpatrick F.A. J. Biol. Chem. 2003; 278: 745-750Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, A. Kapahi P. Natoli G. Takahashi T. Chen Y. Karin M. Santoro M.G. Nature. 2000; 403: 103-108Crossref PubMed Scopus (1200) Google Scholar, G. M. M. G. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus Google Scholar, E. E. D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, T. T. T. S. H. H. J. K. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, A. A. G. J. 2004; PubMed Scopus Google Scholar) or 4-HNE P.J. Edes K. Cassidy P. Massuda E. Fitzpatrick F.A. J. Biol. Chem. 2003; 278: 745-750Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 17Ji C. Kozak K.R. Marnett L.J. J. Biol. Chem. 2001; 276: 18223-18228Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, J. M. K. Sci. 2002; PubMed Scopus Google Scholar, C. 2003; PubMed Scopus Google Scholar). The of nucleophilic against α,β-unsaturated as a covalent with protein these reactive lipids with lipids with α,β-unsaturated can with a particular protein, e.g. P.J. Edes K. Cassidy P. Massuda E. Fitzpatrick F.A. J. Biol. Chem. 2003; 278: 745-750Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar), (16Rossi A. Kapahi P. Natoli G. Takahashi T. Chen Y. Karin M. Santoro M.G. Nature. 2000; 403: 103-108Crossref PubMed Scopus (1200) Google Scholar), and LKB1. a particular electrophilic e.g. 4-HNE, can with one protein P.J. Edes K. Cassidy P. Massuda E. Fitzpatrick F.A. J. Biol. Chem. 2003; 278: 745-750Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 17Ji C. Kozak K.R. Marnett L.J. J. Biol. Chem. 2001; 276: 18223-18228Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, J. M. K. Sci. 2002; PubMed Scopus Google Scholar, C. 2003; PubMed Scopus Google Scholar). oxidative or overexpression of the may contain electrophilic species with an α,β-unsaturated to 4-HNE, cyclopentenone and in cellular at of inflammation Y. Roberts L.J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (141) Google Scholar, Y. Roberts L.J. Biochim. Biophys. Acta. 1999; PubMed Scopus Google Scholar, T. M. T. N. M. K. J. Biol. Chem. 2000; Full Text Full Text PDF Scopus Google Scholar, H. P. A. PubMed Scopus Google Scholar). even that these reactive lipid species inflammation covalently IκB kinases and (16Rossi A. Kapahi P. Natoli G. Takahashi T. Chen Y. Karin M. Santoro M.G. Nature. 2000; 403: 103-108Crossref PubMed Scopus (1200) Google Scholar, T. Nat. 2002; PubMed Scopus Google Scholar). Such an mechanism of for inflammation may confer as the of and tumors Disruption of tumor suppressors to cancers associated with chronic inflammation or overexpression of and (25Thun M.J. Henley S.J. Gansler T. Novartis Found. Symp. 2004; 256: 6-21Crossref PubMed Google Scholar, 26Fitzpatrick F.A. Int. Immunopharmacol. 2001; 1: 1651-1667Crossref PubMed Scopus (135) Google Scholar). We Dr. Tomi Makela for the LKB1.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.