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PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP

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PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP
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  ORIGINAL PAPERS PKB/Akt induces transcription of enzymes involved in cholesterol and fattyacid biosynthesis via activation of SREBP Thomas Porstmann 1,4 , Beatrice Griffiths 1,4 , Yuen-Li Chung 2 , Oona Delpuech 1 , John R Griffiths 2 ,Julian Downward 3 and Almut Schulze* ,1 1 Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A3PX, UK;  2 Cancer Research UK Biomedical Magnetic Resonance Research Group, Department of Basic Medical Science, StGeorge’s Hospital Medical School, London, UK;  3 Signal Transduction Laboratory, Cancer Research UK, London Research Institute,44 Lincoln’s Inn Fields, London WC2A 3PX, UK  Protein kinase B (PKB/Akt) has been shown to play a rolein protection from apoptosis, cell proliferation and cellgrowth. It is also involved in mediating the effects of insulin, such as lipogenesis, glucose uptake and conversionof glucose into fatty acids and cholesterol. Sterol-regulatory element binding proteins (SREBPs) are themajor transcription factors that regulate genes involved infatty acid and cholesterol synthesis. It has been postulatedthat constitutive activation of the phosphatidylinositol 3kinase/Akt pathway may be involved in fatty acid andcholesterol accumulation that has been described inseveral tumour types. In this study, we have analysedchanges in gene expression in response to Akt activationusing DNA microarrays. We identified several enzymesinvolved in fatty acid and cholesterol synthesis as targetsfor Akt-regulated transcription. Expression of theseenzymes has previously been shown to be regulated bythe SREBP family of transcription factors. Activation of Akt induces synthesis of full-length SREBP-1 andSREBP-2 proteins as well as expression of fatty acidsynthase (FAS), the key regulatory enzyme in lipidbiosynthesis. We also show that Akt leads to theaccumulation of nuclear SREBP-1 but not SREBP-2,and that activation of SREBP is required for Akt-inducedactivation of the FAS promoter. Finally, activation of Aktinduces an increase in the concentration of cellular fattyacids as well as phosphoglycerides, the components of cellular membranes. Our data indicate that activationof SREBP by Akt leads to the induction of key enzymesof the cholesterol and fatty acid biosynthesis pathways,and thus membrane lipid biosynthesis. Oncogene  (2005)  24,  6465–6481. doi:10.1038/sj.onc.1208802;published online 27 June 2005 Keywords:  PKB/Akt; SREBP; cholesterol and fatty acidbiosynthesis; transcription; microarray Introduction The serine threonine kinase Akt (PKB/Akt) is a down-stream effector of phosphatidylinositol 3 kinase (PI3-kinase) and has been found to be involved in promotingcell survival in the presence of different apoptotic stimuli(Vivanco and Sawyers, 2002; Brazil  et al  ., 2004).Although some of the substrates of Akt, such as Bad,are directly involved in the regulation of apoptosis, ithas been recognized that regulation of transcription byAkt may contribute to its prosurvival function (Brunet et al  ., 2001). Akt is also an important mediator of themetabolic effects of insulin in several importantphysiological target tissues. Akt stimulates glucoseuptake, glycogen synthesis, protein synthesis andlipogenesis in muscle and adipose tissue, resulting inthe reduction of circulating glucose levels (Whiteman et al  ., 2002). Akt is also involved in mediating insulin-induced inhibition of glucogenolysis in the liver,possibly by regulating expression of the genes forglucose-6-phosphatase (Nakae  et al  ., 2001) and phospho-enolpyruvate carboxykinase (Barthel  et al  ., 2001). Akthas been implicated in promoting cell cycle progressionby regulating cyclin D1 stability (Diehl  et al  ., 1998) andmodulating expression and subcellular localization of thecdk inhibitors p27KIP1 (Kops  et al  ., 2002; Shin  et al  .,2002) and p21WAF1 (Zhou  et al  ., 2001). In addition, thePI3-kinase/Akt pathway has been implicated in theregulation of cell size and it was recently shown thatAkt phosphorylates and inhibits TSC2 leading to theactivation of p70S6-kinase, which results in increasedprotein synthesis (Potter  et al  ., 2002).Akt has been shown to regulate the activity of anumber of transcription factors, most notably the FoxOfamily of transcriptional regulators (Burgering andKops, 2002), which are directly phosphorylated by Aktresulting in inactivation of the transcription factors bycytoplasmic retention (del Peso  et al  ., 1999; Kops  et al  .,1999; Takaishi  et al  ., 1999). Other transcription factorsthat are regulated by Akt are CREB and NF- k B. Aktphosphorylation of CREB increases binding to CBP andenhances CREB transcriptional activity (Pugazhenthi et al  ., 1999). The regulation of NF- k B by Akt issomewhat less clear but may involve phosphorylation of  Received 24 August 2004; revised 12 April 2005; accepted 28 April 2005;published online 27 June 2005 *Correspondence: A Schulze; E-mail: almut.schulze@cancer.org.uk 4 These authors contributed equally to this work Oncogene (2005) 24 , 6465–6481 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc  IKK, resulting in the dissociation of the inhibitoryfactor I k B and nuclear translocation of transcriptionallyactive NF- k B (Romashkova and Makarov, 1999).NF- k B induces expression of several prosurvival genes,such as Bfl-1 and IAP1/2, which may contribute to theantiapoptotic effect of Akt activation (Wang  et al  ., 1998;Zong  et al  ., 1999).Sterol-regulatory element binding proteins (SREBPs)consist of three closely related transcription factors,SREBP-1a, SREBP-1c and SREBP-2 (Eberle  et al  .,2004). They have been identified as mediators of theeffect of sterols on expression of enzymes involved inlipid and cholesterol homoeostasis (Yokoyama  et al  .,1993). SREBP-1c (also termed ADD1) has beendescribed independently as a factor involved in adipo-cyte differentiation (Tontonoz  et al  ., 1993). SREBPsbelong to the family of basic helix–loop–helix–leucinezipper (bHLH-Zip) transcription factors and consist of an N-terminal transactivation domain, the bHLH-ZipDNA-binding domain and two hydrophobic transmem-brane domains (Yokoyama  et al  ., 1993). They aresynthesized as inactive precursors bound to the en-doplasmic reticulum (ER) (Sato  et al  ., 1994; Brown andGoldstein, 1999). In order to be transcriptionally active,the N-terminal part of the SREBP protein has to becleaved by a mechanism termed regulated intramem-brane processing (Wang  et al  ., 1994; Rawson, 2003).When intracellular sterol concentrations are low,SREBPs are bound to the SREBP cleavage-activatingprotein (SCAP) and escorted to the Golgi apparatuswhere two proteolytic steps are required to release thetranscriptionally active N-terminal part of the protein,which then translocates to the nucleus (Brown  et al  .,2002; Yang  et al  ., 2002). When sterol concentrations arehigh, another protein, termed INSIG, binds to SCAPand prevents translocation of the SREBP/SCAP com-plex resulting in the inhibition of SREBP-dependenttranscription (Yang  et al  ., 2002).SREBPs bind to DNA sequences that contain adirect repeat of 5 0 -PyCAPy-3 0 , designated the sterol-regulatory element (SRE). SREs are found in thepromoter regions of a number of genes involved incholesterol and fatty acid biosynthesis. Studies inknockout and transgenic mice have shown thatSREBP-1c preferentially regulates genes involved infatty acid biosynthesis, while SREBP-2 mainly regulatesgenes of the cholesterol pathway (Horton  et al  ., 2003).SREBP-1a also shows a preference for genes involved infatty acid biosynthesis albeit less pronounced than thatof SREBP-1c (Amemiya-Kudo  et al  ., 2002). Morerecently, selective binding of different SREBP isoformsto target promoters was analysed using chromatin IP(Bennett  et al  ., 2004). This study showed that SREBP-1abut not SREBP-1c can bind to SREs in the HMG-CoA-reductase and fatty acid synthase (FAS) promoters,resulting in the recruitment of histone acetylase.SREBP-1a and SREBP-1c also differ in their bindingto transcriptional coactivators, such as CBP andmammalian mediator complex, which may explain thelow transcriptional activity of SREBP-1c (Toth  et al  .,2004).A number of studies have addressed the regulation of SREBP gene expression  in vivo  and  in vitro . SREBP-1ais expressed at low constitutive levels  in vivo , but appearsto be the predominant form in cultured cells (Shimo-mura  et al  ., 1997). The expression of SREBP-1c andSREBP-2 seems to be subject to distinct regulation  invivo . Both genes contain SREs in their promoter region(Sato  et al  ., 1996; Amemiya-Kudo  et al  ., 2000) andregulation through a feed-forward loop has beendescribed in transgenic animals overexpressing thedifferent SREBP proteins (Horton  et al  ., 2003). Tran-scription from the SREBP-1c promoter is modulated byinsulin (Shimomura  et al  ., 1999; Fleischmann andIynedjian, 2000). In addition, sterols have been shownto activate SREBP-1c expression by inducing binding of liver X-activated receptors (LXR) to binding sites on thepromoter (Repa  et al  ., 2000; Deng  et al  ., 2002; Bobard et al  ., 2005).Although aberrant cholesterol and fatty acid bio-synthesis have been mainly linked to metabolic abnorm-alities like diabetes and obesity, it has been postulatedthat deregulation of SREBP controlled gene expressioncould contribute to cell transformation and tumourdevelopment (Swinnen  et al  ., 2004). The accumulationof fatty acids and cholesterol has been described for anumber of solid tumours (Alo  et al  ., 1996; Rashid  et al  .,1997; Pizer  et al  ., 1998) and FAS has been discussed as ametabolic oncogene in prostate cancer (Baron  et al  .,2004). Cholesterol is a component of membrane lipidrafts that are involved in signalling processes (Simonsand Toomre, 2000) and aberrant regulation of choles-terol synthesis may contribute to cell survival in tumourcells (Freeman and Solomon, 2004). The use of drugsthat inhibit cholesterol synthesis for cancer treatmenthas been discussed (Brower, 2003).In this study, we describe activation of SREBP-dependent transcription by the Akt kinase, which itself is frequently activated in human tumours either byoverexpression, as a result of oncogenic activation of theRas pathway, or through inactivation of the PTENtumour suppressor gene. Results PKB/c-Akt induced changes in gene expression In order to identify changes in gene expression that arethe result of activation of Akt, we have used aninducible version of the kinase in which a constitutivelyactive form of Akt (myrAkt) is fused to the hormonebinding domain of the oestrogen receptor (myrAkt-ER)(Kohn  et al  ., 1998). Human retinoic pigment epithelial(RPE) cells expressing myrAkt-ER were treated with4-hydroxytamoxifen (4-OHT), resulting in activationof the fusion protein detected by phosphorylation onSer473 as well as phosphorylation of the Akt substratesGSK3 a / b  (Figure 1a). Akt has been shown to protectepithelial cells from detachment induced apoptosis, andattachment of cells to components of the extracellularmatrix induces endogenous Akt activation (Khwaja Induction of SREBP by Akt T Porstmann  et al 6466 Oncogene  et al  ., 1997). Figure 1a shows activation of myrAkt-ERin adherent and suspension cells resulting in phosphor-ylation of Akt substrates under both conditions.Activation of myrAkt-ER also leads to protection fromdetachment-induced apoptosis in these cells (Figure 1b).We analysed changes in gene expression in responseto activation of the myrAkt-ER fusion protein in RPEcells by performing comparative hybridization of RNAprepared from 4-OHT-treated cells and ethanol-treatedcontrols to cDNA microarrays. Since detachment frommatrix leads to repression of the activity of endogenousAkt protein (data not shown), we activated myrAkt-ERin these cells under adherent and suspension conditions.To eliminate 4-OHT-induced effects, the same experi-ment was performed with parental cells (data notshown). Among the 10000 cDNA clones representedon the array, we found 160 that showed reproducibleregulation in response to 4-OHT treatment in myrAkt-ER, but not in parental cells in either adherent orsuspension cells in four replicate experiments. In all, 145of these could be mapped to genes or EST sequences,and intensity ratios for these clones are shown inTable 1. Functional classification of genes found to beup- or downregulated in response to Akt activationrevealed that a large number of upregulated genes (24cDNA clones) code for enzymes that are involved insterol or fatty acid biosynthesis (Figure 2a). Expressionprofiles of these 24 clones (mapping to 15 distinct genes)are represented in the panel in Figure 2b. A number of these genes (marked by asterisks) have been previouslyreported to be regulated by the SREBP family of transcription factors (Horton  et al  ., 2003). Althoughmany probes are also regulated by Akt activation inadherent cells, the magnitude of modulation is morepronounced in suspension cells, indicating that repres-sion of endogenous Akt activity by loss of matrixattachment results in the inhibition of expression of those genes. Akt induces expression of genes involved in sterol and fatty acid biosynthesis We first investigated whether the observed changes ingene expression in response to Akt activation can bereproduced by an independent method. Figure 3a showsthe results of a Northern blot analysis for FAS, malicenzyme, ATP-citrate pro-S-lyase and lysosomal acidlipase, all of which show similar changes in mRNAabundance as measured in the microarray experiment.In addition, a probe detecting both transcripts of theSREBP-1 gene (SREBP-1a and SREBP-1c) shows anincrease in mRNA after Akt activation in adherent andsuspension cells (Figure 3a). Semiquantitative PCRusing isoform-specific primers shows an increase inSREBP-1a and SREBP-1c transcripts after Akt activa-tion in adherent and suspension cells, while transcriptsfor SREBP-2 are only marginally modulated (Figure 3b,upper panel). In addition, Akt activation induced accu-mulation of transcripts of the FAS, HMG-CoA-reduc-tase and HMG-CoA-synthase (SYN) genes (Figure 3b,lower panel).In a parallel experiment, whole-cell lysates wereanalysed for SCAP and FAS as well as for full-lengthSREBP-1 and SREBP-2 protein (Figure 3c). It shouldbe noted that the antibody against SREBP-1 detectsboth isoforms (SREBP-1a and SREBP-1c). While FAS,SREBP-1a, SREBP-1c and SREBP-2 protein levels areincreased in response to 24 or 48h of Akt activation inadherent and suspension cells, SCAP expression remainsunchanged.The FAS gene has been shown to be regulated bySREBP transcription factors through SRE sequences inits promoter. A sterol-responsive element at position  54 to   71 consisting of two direct repeat SREs andone E-Box in the rat FAS promoter has been identifiedto mediate SREBP-induced transcription in cultured Figure 1  Activation of myrAkt-ER protects RPE cells fromdetachment-induced apoptosis. ( a ) RPE myrAkt-ER cells wereplated on normal (A) or poly-HEMA-coated dishes (S) in mediumcontaining 1% FCS and treated with 100n M  4-OHT ( þ ) orsolvent (  ) for 24h. Activation of myrAkt-ER and phosphoryla-tion of Akt substrates GSK3 a  and GSK3 b  was detected usingphosphospecific antibodies. ( b ) Detection of cell death (apoptosis)in RPE myrAkt-ER cells after 24 and 48h culture on normal (A) orpoly-HEMA-coated plates (S) in medium containing 3% FCS inthe presence of 100n M  4-OHT ( þ ) or solvent (  ). The experimentrepresents the means and standard variation of two experimentsperformed in duplicates Induction of SREBP by Akt T Porstmann  et al 6467 Oncogene  Table 1  Differential gene expression induced by Akt activation in RPE cells under adherent and suspension culture conditions Identifier A+/A   s.d. S   /A   s.d. S+/S   s.d. Name RefSeq Description Ensembl gene IDSterol and fatty acid biosynthesis 123474_A 1.14 0.21 0.94 0.63 3.23 1.10 SCD NM_005063 Stearoyl-CoA desaturase ENSG00000099194124486_A 1.39 0.09 0.81 0.27 2.78 1.53 SC4MOL NM_006745 C-4 methyl sterol oxidase ENSG00000052802366192_A 1.56 0.35 0.54 0.11 2.48 0.83 FASN NM_004104 Fatty acid synthase ENSG0000016971043848_A 1.04 0.23 0.60 0.06 2.37 0.39 DHCR7 NM_001360 7-Dehydrocholesterol reductase ENSG0000017289336393_A 1.09 0.14 0.53 0.13 2.35 1.04 ACAT2 NM_005891 Acetyl-coenzyme A acetyltransferase 2 ENSG00000120437770355_A 1.02 0.31 0.60 0.20 2.28 0.60 LSS NM_002340 Lanosterol synthase ENSG0000016028538798_A 1.13 0.19 0.86 0.13 2.12 0.72 HMGCR NM_000859 3-Hydroxy-3-methylglutaryl-coenzyme A reductase ENSG00000113161361378_A 1.28 0.26 0.72 0.25 2.11 0.79 DHCR7 NM_001360 7-Dehydrocholesterol reductase ENSG0000017289335936_A 0.94 0.16 0.78 0.20 2.05 0.47 LSS NM_002340 Lanosterol synthase ENSG00000160285306925_B 1.12 0.40 0.91 0.52 2.01 1.02 LSS NM_002340 Lanosterol synthase ENSG00000160285309255_A 1.36 0.27 1.03 0.19 1.99 0.62 HMGCR NM_000859 3-Hydroxy-3-methylglutaryl-coenzyme A reductase ENSG00000113161111974_B 0.89 0.14 0.92 0.17 1.95 0.36 HMGCS1 NM_002130 HMG-CoA synthase ENSG0000011297243555_B 1.16 0.43 1.10 0.18 1.94 0.71 ME1 NM_002395 Malic enzyme ENSG0000006583340847_A 1.15 0.11 0.74 0.20 1.82 0.51 ACLY NM_001096 ATP-citrate lyase ENSG00000131473298691_B 1.36 0.13 0.78 0.19 1.77 0.48 HMGCR NM_000859 HMG-CoA reductase ENSG0000011316137690_A 1.45 0.34 0.95 0.26 1.72 0.43 ACLY NM_001096 ATP-citrate lyase ENSG00000131473214923_A 1.37 0.16 1.61 0.34 1.71 0.24 FABP5 NM_001444 Fatty acid-binding protein ENSG00000166899728114_A 1.79 0.26 2.06 0.14 1.63 0.25 FABP5 NM_001444 Fatty acid-binding protein ENSG0000016689949584_A 0.96 0.13 1.14 0.09 1.58 0.23 LIPA NM_000235 Lysosomal acid lipase ENSG0000010779838809_A 1.01 0.38 1.06 0.15 1.56 0.24 SREBF2 NM_004599 SREBP-2 ENSG00000100152138518_A 1.10 0.08 0.84 0.07 1.51 0.23 ELOVL5 NM_021814 Long-chain polyunsaturated fatty acid elongation enzyme 2 ENSG00000012660293270_A 1.45 0.20 7.82 2.35 1.51 0.72 AKR1C2 NM_001354 Aldo-keto reductase C2 ENSG00000151632244990_A 1.23 0.11 1.01 0.20 1.48 0.25 LIPA NM_000235 Lysosomal acid lipase ENSG0000010779833477_A 0.87 0.15 0.59 0.12 1.44 0.26 EBP NM_006579 3-Beta-hydroxysteroid-delta(8),delta(7)-isomerase ENSG00000147155 Other metabolism 1979334_A 1.37 0.48 2.97 1.15 2.79 1.34 AKR1B10 NM_020299 Aldo-keto reductase family 1 member B10 ENSG000001065801028770_A 1.29 0.32 2.49 1.49 2.31 1.21 AKR1B10 NM_020299 Aldo-keto reductase family 1 member B10 ENSG00000106580772905_A 1.19 0.16 0.79 0.06 2.03 0.23 P4HA1 NM_000917 Prolyl 4-hydroxylase alpha-1 subunit precursor ENSG0000012288442910_A 1.24 0.38 1.21 0.65 2.01 0.76 ME1 NM_002395 NADP-dependent malic enzyme ENSG0000006583325108_A 1.03 0.30 1.04 0.27 1.70 0.40 GALNAC4S NM_015892  N  -acetylgalactosamine 4-sulphate 6- o -sulphotransferase ENSG00000171838359475_A 1.11 0.33 0.89 0.12 1.52 0.26 GYS1 NM_002103 Glycogen synthase ENSG00000104812772283_A 1.54 0.31 1.10 0.19 1.43 0.29 ATP6V0B NM_004047 Vacuolar ATP synthase 21kDa proteolipid subunit ENSG0000011741024642_C 1.19 0.34 1.30 0.31 1.42 0.29 ENPP2 NM_006209 Ectonucleotide pyrophosphatase/phosphodiesterase 2 ENSG00000136960342410_A 1.26 0.32 1.00 0.20 1.39 0.24 P4HA2 NM_004199 Prolyl 4-hydroxylase alpha-2 subunit precursor ENSG00000072682429592_A 1.55 0.27 1.42 0.18 1.30 0.24 BPGM NM_001724 Bisphosphoglycerate mutase ENSG00000172331726576_A 1.60 0.19 1.18 0.29 1.28 0.32 ATP6V0B NM_004047 Vacuolar ATP synthase 21kDa proteolipid subunit ENSG00000117410stSG89160 1.70 0.47 1.24 0.17 1.05 0.30 HMOX1 NM_002133 Haeme oxygenase 1 ENSG00000100292788143_A 1.77 0.38 7.25 2.67 0.77 0.25 SAT NM_002970 Diamine acetyltransferase ENSG00000130066199945_A 0.76 0.20 1.03 0.07 0.80 0.27 TGM2 NM_004613 Protein-glutamine gamma-glutamyltransferase ENSG0000010141848256_A 0.70 0.20 1.53 0.71 0.62 0.23 TGM2 NM_004613 Protein-glutamine gamma-glutamyltransferase ENSG00000101418 Regulation of transcription 2107471_A 1.14 0.13 0.87 0.26 2.10 0.92 CREM NM_001881 cAMP-responsive element modulator, alpha isoforms ENSG00000095794813467_A 1.13 0.14 0.85 0.06 1.75 0.46 ZFP36L2 NM_006887 Butyrate response factor 2 (TIS11D, EGF-response factor 2) ENSG00000152518469768_A 1.26 0.27 0.87 0.32 1.63 0.50 ZFP36L2 NM_006887 Butyrate response factor 2 (TIS11D, EGF-response factor 2) ENSG00000152518262914_A 1.11 0.16 1.05 0.23 1.43 0.28 TIEG NM_005655 TGFB-inducible early growth response protein 1 ENSG00000155090301777_A 1.65 0.16 1.26 0.12 1.38 0.23 ZFP36L1 NM_004926 Butyrate response factor 1 (TIS11B, EGF-response factor 1) ENSG00000100597321704_A 1.74 0.31 1.31 0.08 1.32 0.28 ZFP36L1 NM_004926 Butyrate response factor 1 (TIS11B, EGF-response factor 1) ENSG00000100597 I    n  d   u c  t    i      o n  o f     S  R E  B P   b    y A  k    t     T  P   o r   s  t   m a n n   e  t      a l        6   4  6   8    On c  o  g en e  Table 1 ( continued  ) Identifier A+/A   s.d. S   /A   s.d. S+/S   s.d. Name RefSeq Description Ensembl gene ID 207794_A 0.98 0.30 1.30 0.53 1.25 0.38 NFE2 NM_006163 Transcription factor NF-E2 45kDa subunit ENSG00000123405269815_A 1.52 0.12 0.82 0.32 1.17 0.26 NR4A3 NM_006981 Nuclear hormone receptor NOR-1 ENSG0000011950828995_A 1.02 0.40 1.65 0.34 0.82 0.52 HDAC5 NM_005474 Histone deacetylase 5 ENSG0000010884048653_A 0.89 0.09 1.32 0.55 0.81 0.42 ETV1 NM_004956 ETS translocation variant 1 ENSG0000000646834386_A 0.96 0.12 1.51 0.57 0.77 0.25 ETV1 NM_004956 ETS translocation variant 1 ENSG000000064681666837_A 0.71 0.06 1.34 0.32 0.69 0.26 ELK3 NM_005230 ETS-domain protein ELK-3 ENSG00000111145730806_A 0.77 0.18 1.46 0.39 0.68 0.24 HBP1 NM_012257 HMG-box containing protein 1 ENSG00000105856264165_A 0.83 0.15 1.53 0.48 0.67 0.27 CREBL1 NM_004381 Cyclic-AMP-dependent transcription factor ATF-6 beta ENSG00000168468139984_A 0.87 0.20 2.20 0.54 0.57 0.24 HDAC5 NM_005474 Histone deacetylase 5 ENSG00000108840267145_A 0.86 0.19 0.45 0.20 0.54 0.23 HMG2 NM_002129 High-mobility group protein 2 ENSG00000164104124257_A 0.74 0.12 0.45 0.14 0.53 0.28 HMG2 NM_002129 High-mobility group protein 2 ENSG00000164104 Signalling 43113_A 1.01 0.16 1.64 0.76 3.26 1.89 GUCY1A3 NM_000856 Guanylate cyclase soluble, alpha-1 chain ENSG00000164116376637_A 0.96 0.21 1.22 0.44 2.59 1.21 GUCY1A3 NM_000856 Guanylate cyclase soluble, alpha-1 chain ENSG00000164116241855_A 1.35 0.35 1.51 0.27 1.99 0.25 ACVR1 NM_001105 Activin receptor type I precursor ENSG0000011517035647_A 1.44 0.28 1.62 0.25 1.69 0.43 ACVR1 NM_001105 Activin receptor type I precursor ENSG00000115170141815_A 2.71 0.48 1.12 0.37 1.56 0.65 JAG1 NM_000214 Jagged 1 precursor ENSG00000101384768370_A 1.13 0.42 1.10 0.41 1.43 0.47 ARHB NM_004040 Transforming protein RhoB ENSG00000143878151523_A 1.40 0.30 1.16 0.23 1.39 0.40 WNT5A NM_003392 Wnt-5a protein precursor ENSG00000114251324655_B 2.50 1.24 1.74 0.93 1.19 0.45 IL1B NM_000576 Interleukin-1 beta precursor ENSG00000125538323783_B 1.80 0.32 2.39 0.71 1.08 0.22 VEGF NM_003376 Vascular endothelial growth factor a precursor ENSG00000112715297980_A 0.67 0.21 0.48 0.13 1.40 0.36 IGFBP5 NM_000599 Insulin-like growth factor binding protein 5 precursor ENSG00000115461192725_A 0.63 0.25 1.39 0.88 0.93 0.39 AKT1 NM_005163 Rac-alpha serine/threonine kinase ENSG00000142208302434_A 1.42 0.36 1.04 0.47 0.92 0.29 DTR NM_001945 Heparin-binding EGF-like growth factor precursor ENSG0000011307021531_A 0.89 0.24 0.91 0.47 0.79 0.28 RGS2 NM_002923 Regulator of G-protein signalling 2 ENSG00000116741357373_A 0.74 0.07 0.41 0.07 0.71 0.26 DLG7 NM_014750 Drosophila disk-large tumour suppressor like ENSG00000126787259596_A 0.93 0.04 0.51 0.15 0.69 0.24 DLG7 NM_014750 Drosophila disk-large tumour suppressor like ENSG00000126787161878_A 0.72 0.16 0.92 0.16 0.60 0.26 AKAP12 NM_005100 A-kinase anchor protein 12 ENSG0000013101623697_A 0.82 0.06 0.62 0.18 0.55 0.24 STMN1 NM_005563 Stathmin ENSG00000117632 Cell adhesion/extracellular matrix 357031_A 1.15 0.40 1.04 0.32 2.21 0.52 TNFAIP6 NM_007115 Tumour necrosis factor-inducible protein TSG-6 precursor ENSG00000123610786098_A 1.50 0.48 0.87 0.16 1.93 0.61 TNFAIP6 NM_007115 Tumour necrosis factor-inducible protein TSG-6 precursor ENSG00000123610236380_B 1.15 0.23 1.14 0.32 1.64 0.36 PCDH7 NM_002589NM_032456NM_032457Protocadherin 7 precursor ENSG00000169851156520_A 1.04 0.18 0.87 0.04 1.64 0.33 TNFAIP6 NM_007115 Tumour necrosis factor-inducible protein TSG-6 precursor ENSG00000123610195273_A 1.52 0.73 1.90 1.50 1.23 0.23 COL2A1 NM_033150NM_001844Collagen alpha 1(II) chain precursor ENSG00000139219360874_B 1.47 0.61 1.38 0.53 1.07 0.25 TFPI2 NM_006528 Tissue factor pathway inhibitor 2 precursor ENSG00000105825362494_A 0.63 0.22 1.40 0.50 0.90 0.35 SDC3 NM_014654 Syndecan-3 ENSG0000016251243286_A 0.59 0.16 1.20 0.13 0.75 0.24 SDC3 NM_014654 Syndecan-3 ENSG00000162512811740_A 1.14 0.20 1.81 0.99 0.60 0.23 ITGA2 NM_002203 Integrin alpha-2 precursor ENSG00000164171 Apoptosis 740369_A 1.70 0.21 0.91 0.09 1.79 0.23 TSSC3 NM_003311 Tumour suppressing subtransferable candidate 3 ENSG00000161329249092_A 1.86 0.35 1.85 0.36 1.11 0.23 IER3 NM_052815NM_003897Radiation-inducible immediate-early gene IEX-1 ENSG00000137331295208_A 0.81 0.17 0.60 0.15 0.58 0.26 BTK NM_000061 Tyrosine-protein kinase BTK ENSG00000010671 I    n  d   u c  t    i      o n  o f     S  R E  B P   b    y A  k    t     T  P   o r   s  t   m a n n   e  t      a l        6   4  6   9    On c  o  g en e
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