DOCSLIB.ORG

Review Research

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Review Research Published OnlineFirst May 3, 2013; DOI: 10.1158/0008-5472.CAN-12-3876 Cancer Review Research AMPK: A Contextual Oncogene or Tumor Suppressor? Jiyong Liang and Gordon B. Mills Abstract The AMP-activated protein kinase (AMPK) functions to monitor and maintain energy homeostasis at the cellular and organism level. AMPK was perceived historically primarily as a component of the LKB1/STK11 tumor suppressor (LKB1 mutations cause the Peutz-Jegher cancer predisposition syndrome) cascade upstream of the TSC1/2/mTOR pathway and thus likely to be a tumor suppressor. However, AMPK has recently been shown to promote cancer cell survival in the face of extrinsic and intrinsic stressors including bioenergetic, growth factor, and oncogene stress compatible with studies showing that AMPK is required for oncogenic transformation. Thus, whether AMPK acts as a bona fide tumor suppressor or a contextual oncogene and, of particular importance, whether AMPK should be targeted for activation or inhibition during cancer therapy, is controversial and requires clarification. We aim to initiate discussions of these critical questions by reviewing the role of AMPK with an emphasis on cancer cell adaptation to microenvironment stress and therapeutic intervention. Cancer Res; 73(10); 1–7. Ó2013 AACR. AMPK Regulation increasing number of drugs and xenobiotics, such as paclitaxel, The AMPK holoenzymes metformin, and resveratrol. However, it is important to make a Kinase-competent AMP-activated protein kinase (AMPK) clear distinction between the effects of energy stress and AMPK complexes exist in mammalian cells as heterotrimers com- activation per se before any cellular outcome can be appro- posed of one a catalytic and 2 b and g regulatory subunits priately attributed to AMPK (3). As an example, metformin, encoded by the PRKAA1, PRKAA2, PRKAB1, PRKAB2, PRKAG1, which has been proposed to be an AMPK "agonist," has no PRKAG2, and PRKAG3 genes. To add to the complexity, mul- direct effect on either AMPK or its upstream kinase LKB1 (4). tiple potentially functional splice variants have been identified. Instead, metformin inhibits the mitochondrial electron trans- As a result, multiple AMPK isoenzyme complexes are likely port chain complex I disrupting energy homeostasis (5) and present in any cell depending on the tissue and cell specificity also alters mTOR function independently of AMPK and TSC2 of individual subunit expression. (6). Allosteric versus "agonistic" activation T-loop phosphorylation AMPK is unique as a kinase in terms of functioning as a AMPK activation requires phosphorylation at the conserved sensor of cellular energy levels. Mammalian AMPKg has 3 CBS threonine residue (Thr172 in case of human and murine adenosine phosphate binding sites; ATP, ADP, and AMP AMPKa2) within the activation loop (i.e., the T-loop) of the compete for CBS1 and CBS3, whereas CBS4 is constitutively catalytic subunit. LKB1 is the primary kinase phosphorylating occupied by AMP independent of adenyl nucleotide concen- this site; however, depending on cellular and activation con- trations. AMP/ADP binding promotes T-loop phosphorylation text, other kinases, including CaMKKb and TAK1, can activate and allosteric activation of a subunits, whereas ATP binding AMPK. AMPK activation can also be affected by Thr172 inhibits the kinase complex (1). Thus, AMPK activation is dephosphorylation, although the responsible phosphatase(s) fi regulated by adenylate energy charge rather than solely by awaits identi cation (1, 2). The relative contribution of Thr172 relative levels of AMP and ATP as thought previously. Other phosphorylation/dephosphorylation and allosteric activation metabolic intermediates including glycogen and NADH can of AMPK by nucleotide binding remains controversial. bind AMPK complexes, but whether they alter AMPK activity remains undefined (2). In theory, any stimulus that alters AMPK and Cancer cellular energy levels alters AMPK activation, including an AMPK and "stress management" in cancer cells AMPK functions physiologically to allow cells to cope with stress, including metabolic, growth factor deprivation, and Authors' Affiliation: Systems Biology, The University of Texas MD Ander- son Cancer Center, Houston, Texas oncogenic stress (Fig. 1). AMPK activates catabolic and inhibits anabolic metabolism, a scenario that is not compatible with Corresponding Authors: Jiyong Liang, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. cell proliferation and is consistent with a tumor suppressor Phone: 713-834-6161; Fax: 713-563-4235; E-mail:[email protected]; role. However, although AMPK, when highly activated, can and Gordon B. Mills, E-mail: [email protected] potently inhibit cell proliferation and tumor growth, loss of doi: 10.1158/0008-5472.CAN-12-3876 AMPK is not sufficient to confer cell proliferation in the Ó2013 American Association for Cancer Research. absence of adequate nutrients and growth factors, which is www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst May 3, 2013; DOI: 10.1158/0008-5472.CAN-12-3876 Liang and Mills AMPK TBC1D1 PFKFB3 PGC1A GLUT1 ACC1 TSC2 Figure 1. AMPK promotes cell ACC2 ULK1 survival. Under conditions where growth factors, nutrients, Glycolysis oxygen, adhesion, and pH IRS1 Glutamine Glucose p27 are unfavorable for cell metabolism uptake proliferation, as well as under oncogenic stress induced by deregulated Ras and Myc NADPH mTOR oncogenes, AMPK can activate multiple pathways that maintain bioenergetic homeostasis to support cell survival. Which β- HIF1 downstream processes oxidation Autophagy manifest under basal conditions and in response to particular stress conditions as well as the functional outcomes Energy Cyclin are dependent on the cellular AKT TBC1D4 Nutrients homeostasis Cdks context and the duration and magnitude of the stress. GSK3β Survival under stress © 2013 American Association for Cancer Research distinct from defects in genome surveillance genes that lead to inherited condition characterized primarily by benign intesti- cell division despite unrepaired DNA errors. Instead, loss of nal hamartomatous polyps and mucocutaneous pigmentation bioenergetic homeostasis leads to programmed cell death in associated with increased risk of developing malignant cells lacking either LKB1 or AMPK but not normal cells tumors of multiple lineages (13–16). Somatic LKB1 mutations identically stressed (7–10). Further, cells lacking AMPK are are found in lung and cervical cancer; epigenetic inactivation of resistant to oncogenic transformation (11). We posit that LKB1, although rare, has been reported in sporadic papillary þ À AMPK may act as a conditional tumor suppressor or oncogene breast cancer. LKB1 haploinsufficiency (LKB1 / ) in mice depending on the degree of AMPK activation, the particular gives rise to phenotypes similar to human PJS with the for- AMPK isoforms present, and other processes activated in the mation of polyps in the gastrointestinal tract and increased cell (12). It is possible that modest activation of AMPK engages frequency of liver, bone, and endometrial cancer (13). Thus, cell protective mechanisms resulting in oncogene-like activi- LKB1 is a validated tumor suppressor gene. ties, whereas increased magnitude or duration of stress could In contrast with LKB1, AMPK a, b, and g subunits are rarely induce growth arrest or cell death exhibiting a tumor sup- (<3% for any subunit) somatically mutated in human cancers pressor function. and indeed are amplified more frequently than mutated (cancergenome.nih.gov/), and there is no evidence for a germ- AMPK-related kinases other than AMPK may mediate line cancer predisposition syndrome involving AMPK subunits. some of the tumor suppressor functions of LKB1 Complete loss of AMPK function is embryonically lethal in Germline mutations in LKB1 are the cause of Peutz-Jegher mice. Conditional AMPK knockout models have been created cancer predisposition syndrome (PJS), a rare and dominantly (17); however, the role of AMPK in tumorigenesis has not been OF2 Cancer Res; 73(10) May 15, 2013 Cancer Research Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst May 3, 2013; DOI: 10.1158/0008-5472.CAN-12-3876 AMPK Regulates Cancer Metabolism extensively studied in these models. Similar to LKB1 deletion and mTORC1 (37). Thus, AMPK-related kinases rather than (14, 18), murine fibroblasts lacking both catalytic isoforms of AMPK may mediate the tumor suppressor role of LKB1 (38, 39), AMPK are resistant to oncogenic transformation (11), which is although NuAK1 (also known as ARK5), NuAK2, SIK1, SIK2, consistent with AMPK and an intact energy-sensing mecha- and SIK3 have been linked to tumor formation, invasion, and nism being required during oncogenesis. Although loss of metastasis (40–44). AMPK on its own is insufficient to provoke tumor formation in mice, inactivation of AMPKa1, the sole catalytic subunit in AMPK and the p53 tumor suppressor murine B-cell lineages, can accelerate Myc-driven lymphoma- AMPK regulates p53 acetylation and phosphorylation (45, genesis (19). In contrast, deletion of the a2 but not the a1 46), again leading to the perception that AMPK functions as a subunit of AMPK increases susceptibility to H-RasV12– tumor suppressor. However, AMPK-dependent p53 activation induced transformation in murine fibroblasts (20), raising an promotes
Load more

Recommended publications
  • Supplemental Information to Mammadova-Bach Et Al., “Laminin Α1 Orchestrates VEGFA Functions in the Ecosystem of Colorectal Carcinogenesis”
    Supplemental information to Mammadova-Bach et al., “Laminin α1 orchestrates VEGFA functions in the ecosystem of colorectal carcinogenesis” Supplemental material and methods Cloning of the villin-LMα1 vector The plasmid pBS-villin-promoter containing the 3.5 Kb of the murine villin promoter, the first non coding exon, 5.5 kb of the first intron and 15 nucleotides of the second villin exon, was generated by S. Robine (Institut Curie, Paris, France). The EcoRI site in the multi cloning site was destroyed by fill in ligation with T4 polymerase according to the manufacturer`s instructions (New England Biolabs, Ozyme, Saint Quentin en Yvelines, France). Site directed mutagenesis (GeneEditor in vitro Site-Directed Mutagenesis system, Promega, Charbonnières-les-Bains, France) was then used to introduce a BsiWI site before the start codon of the villin coding sequence using the 5’ phosphorylated primer: 5’CCTTCTCCTCTAGGCTCGCGTACGATGACGTCGGACTTGCGG3’. A double strand annealed oligonucleotide, 5’GGCCGGACGCGTGAATTCGTCGACGC3’ and 5’GGCCGCGTCGACGAATTCACGC GTCC3’ containing restriction site for MluI, EcoRI and SalI were inserted in the NotI site (present in the multi cloning site), generating the plasmid pBS-villin-promoter-MES. The SV40 polyA region of the pEGFP plasmid (Clontech, Ozyme, Saint Quentin Yvelines, France) was amplified by PCR using primers 5’GGCGCCTCTAGATCATAATCAGCCATA3’ and 5’GGCGCCCTTAAGATACATTGATGAGTT3’ before subcloning into the pGEMTeasy vector (Promega, Charbonnières-les-Bains, France). After EcoRI digestion, the SV40 polyA fragment was purified with the NucleoSpin Extract II kit (Machery-Nagel, Hoerdt, France) and then subcloned into the EcoRI site of the plasmid pBS-villin-promoter-MES. Site directed mutagenesis was used to introduce a BsiWI site (5’ phosphorylated AGCGCAGGGAGCGGCGGCCGTACGATGCGCGGCAGCGGCACG3’) before the initiation codon and a MluI site (5’ phosphorylated 1 CCCGGGCCTGAGCCCTAAACGCGTGCCAGCCTCTGCCCTTGG3’) after the stop codon in the full length cDNA coding for the mouse LMα1 in the pCIS vector (kindly provided by P.
    [Show full text]
  • Brief Genetics Report Haplotype Structures and Large
    Brief Genetics Report Haplotype Structures and Large-Scale Association Testing of the 5؅ AMP-Activated Protein Kinase Genes PRKAA2, PRKAB1, and PRKAB2 With Type 2 Diabetes Maria W. Sun,1,2 Jennifer Y. Lee,1,2 Paul I.W. de Bakker,1,2,3 Noe¨l P. Burtt,2 Peter Almgren,4 Lennart Råstam,5 Tiinamaija Tuomi,6 Daniel Gaudet,7 Mark J. Daly,2,8 Joel N. Hirschhorn,2,3,9 David Altshuler,1,2,3,8,10 Leif Groop,4,6 and Jose C. Florez1,2,8,10 AMP-activated protein kinase (AMPK) is a key molecular plasma glucose, or insulin sensitivity. Several nominal asso- regulator of cellular metabolism, and its activity is induced ciations of variants in PRKAA2 and PRKAB1 with BMI appear by both metformin and thiazolidinedione antidiabetic med- to be consistent with statistical noise. Diabetes 55:849–855, ications. It has therefore been proposed both as a putative 2006 agent in the pathophysiology of type 2 diabetes and as a valid target for therapeutic intervention. Thus, the genes that encode the various AMPK subunits are intriguing ype 2 diabetes arises from the complex interplay candidates for the inherited basis of type 2 diabetes. We therefore set out to test for the association of common of various pathophysiologic mechanisms involv- variants in the genes that encode three selected AMPK ing peripheral insulin resistance and relative subunits with type 2 diabetes and related phenotypes. Of Tinsulin insufficiency. The final expression of the the seven genes that encode AMPK isoforms, we initially diabetic phenotype is strongly influenced by inheritance; chose PRKAA2, PRKAB1, and PRKAB2 because of their however, with the exception of rare monogenic forms of higher prior probability of association with type 2 diabetes, diabetes, common type 2 diabetes is thought to have a based on previous reports of genetic linkage, functional polygenic architecture (1).
    [Show full text]
  • A New Computational Approach to Evaluating Systemic Gene–Gene Interactions in a Pathway Affected by Drug LY294002
    processes Article A New Computational Approach to Evaluating Systemic Gene–Gene Interactions in a Pathway Affected by Drug LY294002 Shinuk Kim College of Kyedang General Education, Sangmyung University, Cheonan 31066, Korea; [email protected]; Tel.: +82-(41)-550-5452; Fax: +82-(41)-550-5439 Received: 14 August 2020; Accepted: 23 September 2020; Published: 1 October 2020 Abstract: In this study, we investigate how drugs systemically affect genes via pathways by integrating information from interactions between chemical compounds and molecular expression datasets, and from pathway information such as gene sets using mathematical models. First, we adopt drug-induced gene expression datasets; then, employ gene set enrichment analysis tools for selecting candidate enrichment pathways; and lastly, implement the inverse algorithm package for identifying gene–gene regulatory networks in a pathway. We tested LY294002-induced datasets of the MCF7 breast cancer cell lines, and found a CELL CYCLE pathway with 101 genes, ERBB signaling pathway consisting of 82 genes, and MTOR pathway consisting of 45 genes. We consider two interactions: quantity strength depending on number of interactions, and quality strength depending on weight of interaction as positive (+) and negative ( ) interactions. Our methods revealed ANAPC1-CDK6 ( 0.412) and − − ORC2L- CHEK1(0.951) for the CELL CYCLE pathway; INS-RPS6 ( 3.125) and PRKAA2-PRKAA2 − (+1.319) for the MTOR pathway; and CBLB-RPS6KB1 ( 0.141), RPS6KB1-CBLC (+0.238) for the ERBB − signaling pathway to be top quality interactions. Top quantity interactions discovered include 12; the CDC ( ,+) gene family for the CELL CYCLE pathway, 20; PIK3 ( ), 23; PIK3CG (+) for the MTOR − − pathway, 11; PAK ( ), 10; PIK3 (+) for the ERBB signaling pathway.
    [Show full text]
  • Association Study of AMP-Activated Protein Kinase Subunit Genes In
    European Journal of Endocrinology (2009) 161 405–409 ISSN 0804-4643 CLINICAL STUDY Association study of AMP-activated protein kinase subunit genes in polycystic ovary syndrome Kari Sproul1,2, Michelle R Jones3, Ricardo Azziz1,2,4 and Mark O Goodarzi1,3,4,5 1Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA, 2Department of Obstetrics and Gynecology, the David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA, 3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room B-131, Los Angeles, California 90048, USA, 4Department of Medicine, the David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA and 5Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA (Correspondence should be addressed to M O Goodarzi at Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center; Email: [email protected]) Abstract Objective: To examine the genes for AMP-activated protein kinase (AMPK) subunits a2(PRKAA2) and g3(PRKAG3) as candidates for polycystic ovary syndrome (PCOS) and its component traits. Design and methods: A total of 287 white PCOS women were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham and 187 white control subjects were recruited from the surrounding community. Seven PRKAA2 single nucleotide polymorphisms (SNPs) and four PRKAG3 SNPs were genotyped in PCOS cases and controls. Genotyping and association analysis were performed at Cedars-Sinai Medical Center. Results: Nominal associations of PRKAA2 variants with insulin-related traits and the PRKAG3 Pro71Ala variant with PCOS were not statistically significant after multiple testing correction.
    [Show full text]
  • NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development Via CDK Activation
    Published OnlineFirst April 1, 2015; DOI: 10.1158/0008-5472.CAN-13-3209 Cancer Therapeutics, Targets, and Chemical Biology Research NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development via CDK Activation Takeshi Namiki1,2,3, Tomonori Yaguchi2, Kenta Nakamura2,4, Julio C. Valencia1, Sergio G. Coelho1, Lanlan Yin1, Masakazu Kawaguchi1, Wilfred D. Vieira1, Yasuhiko Kaneko5, Atsushi Tanemura6, Ichiro Katayama6, Hiroo Yokozeki3, Yutaka Kawakami2, and Vincent J. Hearing1 Abstract The AMPK-related kinase NUAK2 has been implicated in number of cells in S phase. NUAK2 silencing and inactivation of melanoma growth and survival outcomes, but its therapeutic the PI3K pathway efficiently controlled CDK2 expression, where- utility has yet to be confirmed. In this study, we show how as CDK2 inactivation specifically abrogated the growth of its genetic amplification in PTEN-deficient melanomas may NUAK2-amplified and PTEN-deficient melanoma cells. Immu- rationalize the use of CDK2 inhibitors as a therapeutic strategy. nohistochemical analyses confirmed an association of CDK2 Analysis of array-CGH data revealed that PTEN deficiency is expression with NUAK2 amplification and p-Akt expression in coupled tightly with genomic amplification encompassing the melanomas. Finally, pharmacologic inhibition of CDK2 was NUAK2 locus, a finding strengthened by immunohistochemical sufficient to suppress the growth of NUAK2-amplified and evidence that phospho-Akt overexpression was correlated with PTEN-deficient melanoma cells in vitro and in vivo. Overall, our NUAK2 expression in clinical specimens of acral melanoma. results show how CDK2 blockade may offer a promising therapy Functional studies in melanoma cells showed that inactivation for genetically defined melanomas, where NUAK2 is amplified of the PI3K pathway upregulated p21 expression and reduced the and PTEN is deleted.
    [Show full text]
  • Ahn Supp. Fig. 1 AB 1.5 ARRDC4 1.5 ARRDC4 * * * 1.0 1.0
    Ahn_Supp. Fig. 1 AB 1.5 ARRDC4 1.5 ARRDC4 * * * 1.0 1.0 * * 0.5 * 0.5 * * * Relative mRNA levels mRNA Relative Relative mRNA levels mRNA Relative 0.0 0.0 1.5 MLXIP (MondoA) 1.5 MLXIP (MondoA) 1.0 1.0 0.5 0.5 Relative mRNA levels mRNA Relative Relative mRNA levels mRNA Relative 0.0 0.0 MondoA MondoA 0124824 Starvation (6h) -++++++ Glucose Starvation (h) Refeeding (h) --0.51248 C 1.5 ARRDC4 1.5 MLXIP (MondoA) † Con # KD 1.0 1.0 0.5 0.5 * * * * Relative mRNA levels mRNA Relative Relative mRNA levels mRNA Relative * * 0.0 0.0 BasalStarvation Refeeding BasalStarvation Refeeding MondoA Con + + - - + + - - + + - - KD - - + + - - + + - - + + BasalStarvation Refeeding Supplemental Figure 1. Glucose-mediated regulation of ARRDC4 is dependent on MondoA in human skeletal myotubes. (A) (top) ARRDC4 and MLXIP (MondoA) mRNA levels were determined by qRT-PCR in human skeletal myotubes following deprivation of glucose at the indicated time (n=4). (bottom) Representative Western blot analysis of MondoA demonstrating the effect of glucose deprivation. *p<0.05 vs. 0h. (B) (top) ARRDC4 and MLXIP (MondoA) expression in human myotubes following a 6h glucose removal and refeeding at the times indicated (n=4). (bottom) Corresponding Western blot analysis. *p<0.05 vs Starvation 6h. (C) (top) Expression of ARRDC4 and MLXIP in human myotubes following deprivation and refeeding of glucose in the absence or presence of siRNA-mediated MondoA KD (n=4). (bottom) Corresponding Western blot analysis. *p<0.05 vs siControl. # p<0.05. § p<0.05. The data represents mean ± SD. All statistical significance determined by one-way ANOVA with Tukey multiple comparison post-hoc test.
    [Show full text]
  • The Study of Copy Number Variations in the Regions of PRKAB2 and PPM1K Among Congenital Heart Defects Patients
    The study of copy number variations in the regions of PRKAB2 and PPM1K among congenital heart defects patients Han-Quan Dong1 Yue-Xin Du2 1. Department of Pneumology, Tianjin Children’s Hospital, Tianjin, 300074–China 2. Department of Child Healthcare, Tianjin Municipal Women and Children health care center, Tianjin, 300070, China http://dx.doi.org/10.1590/1806-9282.65.6.786 SUMMARY OBJECTIVE: This study was to assess the genetic association of copy number variations in two genes (PRKAB2 and PPM1K) located in two regions (tetralogy of Fallot and ventricular septal defect) in a Chinese Han population. METHODS: A total of 200 congenital heart disease patients (100 tetralogy of Fallot patients and 100 ventricular septal defect patients) and 100 congenital heart defect-free controls were recruited, and quantitative real-time PCR analysis was used to replicate the asso- ciation of two copy number variations with congenital heart defects in a Chinese Han population. RESULTS: One deletion at PRKAB2 and one duplication at PPM1K were found in two of the tetralogy of Fallot patients, respectively; while all these regions were duplicated in both ventricular septal defect patients and in the 100 congenital heart defects-free controls. CONCLUSIONS: We replicated the copy number variations at the disease-candidate genes of PRKAB2 and PPM1K with tetralogy of Fallot in a Chinese Han population, and in patients with ventricular septal defect mutations in these two genes were not found. These results indicate the same molecular population genetics exist in these two genes with different ethnicity. This shows that these two genes are possibly specific pf tetralogy of Fallot candidates.
    [Show full text]
  • Table S1. Complete Gene List. Genbank Refseq and Description of Each Gene Were Provided By
    Document downloaded from http://www.elsevier.es, day 24/09/2021. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Table S1. Complete gene list. GenBank RefSeq and description of each gene were provided by the array supplier. Unigene GeneBank Symbol Description Gene Name/s Rn.11422 NM_033230 Akt1 V-akt murine thymoma viral oncogene homolog 1 Akt Rn.2104 NM_019288 App Amyloid beta (A4) precursor protein - Rn.23323 NM_001034933 Arsa Arylsulfatase A MGC125207 Rn.94004 NM_033443 Arsb Arylsulfatase B - Rn.6224 NM_001038495 Atg12 ATG12 autophagy related 12 Apg12l, MGC125080 Rn.101734NM_001108809 Atg16l1 ATG16 autophagy related 16-like 1 Apg16l, Wdr30 Rn.104199NM_001191560 Atg16l2 ATG16 autophagy related 16-like 2 RGD1311400 Rn.3084 NM_134394 Atg3 ATG3 autophagy related 3 Apg3l, PIG-1, Pig1 Rn.163086NM_001025711 Atg4b ATG4 autophagy related 4 homolog B Apg4b, MGC112887 Rn.23378 NM_001107948 Atg4c ATG4 autophagy related 4 homolog C - Rn.98385 NM_001014250 Atg5 ATG5 autophagy related 5 - Rn.162765NM_001012097 Atg7 ATG7 autophagy related 7 Apg7l Rn.35248 NM_001014218 Atg9a ATG9 autophagy related 9 homolog A MGC105908, RGD1310450 Rn.36696 NM_022698 Bad BCL2-associated agonist of cell death MGC72439 Rn.14598 NM_053812 Bak1 BCL2-antagonist/killer 1 MGC108627 Rn.10668 NM_017059 Bax Bcl2-associated X protein - Rn.9996 NM_016993 Bcl2 B-cell CLL/lymphoma 2 Bcl-2 Rn.10323 NM_031535 Bcl2l1 Bcl2-like 1 Bcl-xl, Bcl2l, Bclx, bcl-X Rn.2776 NM_053739 Becn1 Beclin 1, autophagy related - Rn.31142 NM_022684
    [Show full text]
  • (AMP)-Activated Protein Kinase: a New Target for Nutraceutical Compounds
    International Journal of Molecular Sciences Review Adenosine Monophosphate (AMP)-Activated Protein Kinase: A New Target for Nutraceutical Compounds Fabiola Marín-Aguilar 1, Luis E. Pavillard 1, Francesca Giampieri 2, Pedro Bullón 1 and Mario D. Cordero 1,* 1 Research Laboratory, Oral Medicine Department, University of Sevilla, Sevilla 41009, Spain; [email protected] (F.M.-A.); [email protected] (L.E.P.); [email protected] (P.B.) 2 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche—Sez. Biochimica, Università Politecnica delle Marche, Ancona 60100, Italy; [email protected] * Correspondence: [email protected]; Tel.: +34-954-481-120; Fax: +34-954-486-784 Academic Editor: Rosa M. Lamuela-Raventós Received: 17 November 2016; Accepted: 23 January 2017; Published: 29 January 2017 Abstract: Adenosine monophosphate-activated protein kinase (AMPK) is an important energy sensor which is activated by increases in adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio and/or adenosine diphosphate (ADP)/ATP ratio, and increases different metabolic pathways such as fatty acid oxidation, glucose transport and mitochondrial biogenesis. In this sense, AMPK maintains cellular energy homeostasis by induction of catabolism and inhibition of ATP-consuming biosynthetic pathways to preserve ATP levels. Several studies indicate a reduction of AMPK sensitivity to cellular stress during aging and this could impair the downstream signaling and the maintenance of the cellular energy balance and the stress resistance. However, several diseases have been related with an AMPK dysfunction. Alterations in AMPK signaling decrease mitochondrial biogenesis, increase cellular stress and induce inflammation, which are typical events of the aging process and have been associated to several pathological processes.
    [Show full text]
  • PRKAA2 (Human) Recombinant Protein (Q01)
    PRKAA2 (Human) Recombinant that monitors cellular energy status. In response to Protein (Q01) cellular metabolic stresses, AMPK is activated, and thus phosphorylates and inactivates acetyl-CoA carboxylase Catalog Number: H00005563-Q01 (ACC) and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating Regulation Status: For research use only (RUO) de novo biosynthesis of fatty acid and cholesterol. Studies of the mouse counterpart suggest that this Product Description: Human PRKAA2 partial ORF ( catalytic subunit may control whole-body insulin NP_006243, 453 a.a. - 552 a.a.) recombinant protein sensitivity and is necessary for maintaining myocardial with GST-tag at N-terminal. energy homeostasis during ischemia. [provided by RefSeq] Sequence: MSLQLYLVDNRSYLLDFKSIDDEVVEQRSGSSTPQRS CSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLS SVSPRLGSHTMDFFEMCASLITTLAR Host: Wheat Germ (in vitro) Theoretical MW (kDa): 36.74 Applications: AP, Array, ELISA, WB-Re (See our web site product page for detailed applications information) Protocols: See our web site at http://www.abnova.com/support/protocols.asp or product page for detailed protocols Preparation Method: in vitro wheat germ expression system Purification: Glutathione Sepharose 4 Fast Flow Storage Buffer: 50 mM Tris-HCI, 10 mM reduced Glutathione, pH=8.0 in the elution buffer. Storage Instruction: Store at -80°C. Aliquot to avoid repeated freezing and thawing. Entrez GeneID: 5563 Gene Symbol: PRKAA2 Gene Alias: AMPK, AMPK2, PRKAA Gene Summary: The protein encoded by this gene is a catalytic subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting of an alpha catalytic subunit, and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme Page 1/1 Powered by TCPDF (www.tcpdf.org).
    [Show full text]
  • NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development Via CDK Activation
    Published OnlineFirst April 1, 2015; DOI: 10.1158/0008-5472.CAN-13-3209 Cancer Therapeutics, Targets, and Chemical Biology Research NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development via CDK Activation Takeshi Namiki1,2,3, Tomonori Yaguchi2, Kenta Nakamura2,4, Julio C. Valencia1, Sergio G. Coelho1, Lanlan Yin1, Masakazu Kawaguchi1, Wilfred D. Vieira1, Yasuhiko Kaneko5, Atsushi Tanemura6, Ichiro Katayama6, Hiroo Yokozeki3, Yutaka Kawakami2, and Vincent J. Hearing1 Abstract The AMPK-related kinase NUAK2 has been implicated in number of cells in S phase. NUAK2 silencing and inactivation of melanoma growth and survival outcomes, but its therapeutic the PI3K pathway efficiently controlled CDK2 expression, where- utility has yet to be confirmed. In this study, we show how as CDK2 inactivation specifically abrogated the growth of its genetic amplification in PTEN-deficient melanomas may NUAK2-amplified and PTEN-deficient melanoma cells. Immu- rationalize the use of CDK2 inhibitors as a therapeutic strategy. nohistochemical analyses confirmed an association of CDK2 Analysis of array-CGH data revealed that PTEN deficiency is expression with NUAK2 amplification and p-Akt expression in coupled tightly with genomic amplification encompassing the melanomas. Finally, pharmacologic inhibition of CDK2 was NUAK2 locus, a finding strengthened by immunohistochemical sufficient to suppress the growth of NUAK2-amplified and evidence that phospho-Akt overexpression was correlated with PTEN-deficient melanoma cells in vitro and in vivo. Overall, our NUAK2 expression in clinical specimens of acral melanoma. results show how CDK2 blockade may offer a promising therapy Functional studies in melanoma cells showed that inactivation for genetically defined melanomas, where NUAK2 is amplified of the PI3K pathway upregulated p21 expression and reduced the and PTEN is deleted.
    [Show full text]
  • Supplemental File
    SUPPLEMENTARY MATERIALS AND METHODS ### reorder as minimun to maximum relative induction. allks2=cbind(allks,apply(allks,1,sum)) For the different analyses, the macros are as following: allks3=allks2[order(allks2[,length(colnames(allks2))]),] allks5=allks3[,-length(colnames(allks2))] -Heatmap and correlation analyses # check allks5 source("http://bioconductor.org/biocLite.R") biocLite() -Heatmap install.packages("gplots") library("gplots") #Set a color scale "zero centered" #Set Graph title (do one by one) breaks=c(seq(-(max(allks5)), max(allks5) , by = 0.05)) titre = "allkinases SASP " mycol <- colorpanel(n=length(breaks)- titre = "allkinases SASP + p16" 1,low="green",mid="black",high="red") titre = "allkinases SASP + p16 + NFkB" #Load Normalized RT-QPCR table (do one by one) # Heatmap, "symkey = T" allks<-read.table("allkS.txt", header = TRUE, sep = "\t", dec = ",", fill = TRUE, , row.names=1 ) dev.off() allks<-read.table("allkSp16.txt", header = TRUE, sep = heatmap.2(allks5, scale = "none", col = mycol, "\t", dec = ",", fill = TRUE, , row.names=1 ) breaks=breaks, symkey = F, allks<-read.table("allkSp16NFkB.txt", header = TRUE, trace = 'none', cexRow=0.8, cexCol = 1.6, srtCol sep = "\t", dec = ",", fill = TRUE, , row.names=1 ) = 0, keysize = 1.3, -Log2 relative fold changes induction calculation key.title = "", margins = c(8, 10), # matrix of minimun values main = paste("relative FC"," ", titre), min=apply(allks, 2, min ) Rowv=F mat<-matrix(min, length(row.names(allks)),length(colnames(allks)), -corrgram byrow=TRUE) # check mat install.packages("corrgram")
    [Show full text]