期刊论文详细信息
Cell & Bioscience
The regulation of cellular metabolism by tumor suppressor p53
Zhaohui Feng1  Juan Liu1  Yingjian Liang1 
[1] The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA
关键词: Antioxidant defense;    Glutaminolysis;    Lipid metabolism;    Oxidative phosphorylation;    Glycolysis;    The Warburg effect;    Cancer metabolism;    Tumor suppressor;    p53;   
Others  :  792956
DOI  :  10.1186/2045-3701-3-9
 received in 2012-08-20, accepted in 2012-12-06,  发布年份 2013
PDF
【 摘 要 】

As a hallmark of tumor cells, metabolic alterations play a critical role in tumor development and could be targeted for tumor therapy. Tumor suppressor p53 plays a central role in tumor prevention. As a transcription factor, p53 mainly exerts its function in tumor suppression through its transcriptional regulation of its target genes to initiate various cellular responses. Cell cycle arrest, apoptosis and senescence are most well-understood functions of p53, and are traditionally accepted as the major mechanisms for p53 in tumor suppression. Recent studies have revealed a novel function of p53 in regulation of cellular metabolism. p53 regulates mitochondrial oxidative phosphorylation, glycolysis, glutamine metabolism, lipid metabolism, and antioxidant defense. Through the regulation of these metabolic processes, p53 maintains the homeostasis of cellular metabolism and redox balance in cells, which contributes significantly to the role of p53 as a tumor suppressor. Further understanding of the role and molecular mechanism of p53 in cellular metabolism could lead to the identification of novel targets and development of novel strategies for tumor therapy.

【 授权许可】

   
2013 Liang et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20140705041918642.pdf 555KB PDF download
Figure 3. 39KB Image download
Figure 2. 38KB Image download
Figure 1. 61KB Image download
【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】
  • [1]Levine AJ, Hu W, Feng Z: The P53 pathway: what questions remain to be explored? Cell Death Differ 2006, 13(6):1027-1036.
  • [2]Vousden KH, Prives C: Blinded by the Light: The Growing Complexity of p53. Cell 2009, 137(3):413-431.
  • [3]Levine AJ, Oren M: The first 30 years of p53: growing ever more complex. Nat Rev Cancer 2009, 9(10):749-758.
  • [4]Vogelstein B, Lane D, Levine AJ: Surfing the p53 network. Nature 2000, 408(6810):307-310.
  • [5]Olivier M, Hussain SP, Caron De Fromentel C, Hainaut P, Harris CC: TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci Publ 2004, 157:247-270.
  • [6]Wade M, Wahl GM: Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Mol Cancer Res 2009, 7(1):1-11.
  • [7]Lu X: Tied up in loops: positive and negative autoregulation of p53. Cold Spring Harb Perspect Biol 2010, 2(5):a000984.
  • [8]Harris SL, Levine AJ: The p53 pathway: positive and negative feedback loops. Oncogene 2005, 24(17):2899-2908.
  • [9]Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM: The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990, 63(6):1129-1136.
  • [10]Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A: Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 1992, 356(6366):215-221.
  • [11]Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT, Weinberg RA: Tumor spectrum analysis in p53-mutant mice. Curr Biol 1994, 4(1):1-7.
  • [12]Strong LC: General keynote: hereditary cancer: lessons from Li-Fraumeni syndrome. Gynecol Oncol 2003, 88(1 Pt 2):S4-S7. discussion S11-13
  • [13]Riley T, Sontag E, Chen P, Levine A: Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 2008, 9(5):402-412.
  • [14]Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM: p53 regulates mitochondrial respiration. Science 2006, 312(5780):1650-1653.
  • [15]Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH: TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006, 126(1):107-120.
  • [16]Vousden KH, Ryan KM: p53 and metabolism. Nat Rev Cancer 2009, 9(10):691-700.
  • [17]Feng Z, Levine AJ: The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol 2010, 20(7):427-434.
  • [18]Budanov AV, Sablina AA, Feinstein E, Koonin EV, Chumakov PM: Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 2004, 304(5670):596-600.
  • [19]Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM: The antioxidant function of the p53 tumor suppressor. Nat Med 2005, 11(12):1306-1313.
  • [20]Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y, Baer R, Gu W: Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence. Cell 2012, 149(6):1269-1283.
  • [21]Warburg O: On the origin of cancer cells. Science 1956, 123(3191):309-314.
  • [22]Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011, 144(5):646-674.
  • [23]Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009, 324(5930):1029-1033.
  • [24]Cairns RA, Harris IS, Mak TW: Regulation of cancer cell metabolism. Nat Rev Cancer 2011, 11(2):85-95.
  • [25]Hsu PP, Sabatini DM: Cancer cell metabolism: Warburg and beyond. Cell 2008, 134(5):703-707.
  • [26]Fantin VR, St-Pierre J, Leder P: Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 2006, 9(6):425-434.
  • [27]Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC: The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 2008, 452(7184):230-233.
  • [28]Dang CV: Glutaminolysis: supplying carbon or nitrogen or both for cancer cells? Cell Cycle 2010, 9(19):3884-3886.
  • [29]Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, et al.: Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 2010, 18(3):207-219.
  • [30]Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, et al.: Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 2008, 105(48):18782-18787.
  • [31]Santos CR, Schulze A: Lipid metabolism in cancer. FEBS J 2012, 279(15):2610-2623.
  • [32]Biswas S, Lunec J, Bartlett K: Non-glucose metabolism in cancer cells-is it all in the fat? Cancer Metastasis Rev 2012, 31(3-4):689-698.
  • [33]Medes G, Thomas A, Weinhouse S: Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res 1953, 13(1):27-29.
  • [34]Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR: Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA 1994, 91(14):6379-6383.
  • [35]Levine AJ, Puzio-Kuter AM: The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 2010, 330(6009):1340-1344.
  • [36]Dang CV, Kim JW, Gao P, Yustein J: The interplay between MYC and HIF in cancer. Nat Rev Cancer 2008, 8(1):51-56.
  • [37]Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, et al.: c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009, 458(7239):762-765.
  • [38]Denko NC: Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 2008, 8(9):705-713.
  • [39]Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC: HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006, 3(3):187-197.
  • [40]Kim JW, Tchernyshyov I, Semenza GL, Dang CV: HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006, 3(3):177-185.
  • [41]Zwerschke W, Mazurek S, Massimi P, Banks L, Eigenbrodt E, Jansen-Durr P: Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein. Proc Natl Acad Sci USA 1999, 96(4):1291-1296.
  • [42]Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC: Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 2008, 452(7184):181-186.
  • [43]Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR: Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp 70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol 1994, 14(7):4902-4911.
  • [44]Inoki K, Li Y, Zhu T, Wu J, Guan KL: TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002, 4(9):648-657.
  • [45]Inoki K, Corradetti MN, Guan KL: Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 2005, 37(1):19-24.
  • [46]Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, Wang Y, Jing Y, Yang H, Chen R, et al.: Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA 2011, 108(10):4129-4134.
  • [47]Garcia-Cao I, Song MS, Hobbs RM, Laurent G, Giorgi C, de Boer VC, Anastasiou D, Ito K, Sasaki AT, Rameh L, et al.: Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell 2012, 149(1):49-62.
  • [48]Shaw R, Kosmatka M, Bardeesy N, Hurley R, Witters L, DePinho R, Cantley L: The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 2004, 101:3329-3335.
  • [49]Vahsen N, Cande C, Briere JJ, Benit P, Joza N, Larochette N, Mastroberardino PG, Pequignot MO, Casares N, Lazar V, et al.: AIF deficiency compromises oxidative phosphorylation. EMBO J 2004, 23(23):4679-4689.
  • [50]Stambolsky P, Weisz L, Shats I, Klein Y, Goldfinger N, Oren M, Rotter V: Regulation of AIF expression by p53. Cell Death Differ 2006, 13(12):2140-2149.
  • [51]Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z: Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA 2010, 107(16):7455-7460.
  • [52]Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, et al.: Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci USA 2010, 107(16):7461-7466.
  • [53]Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, Hu W, Feng Z: Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci USA 2011, 108(39):16259-16264.
  • [54]Cesari R, Martin ES, Calin GA, Pentimalli F, Bichi R, McAdams H, Trapasso F, Drusco A, Shimizu M, Masciullo V, et al.: Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc Natl Acad Sci USA 2003, 100(10):5956-5961.
  • [55]Poulogiannis G, McIntyre RE, Dimitriadi M, Apps JR, Wilson CH, Ichimura K, Luo F, Cantley LC, Wyllie AH, Adams DJ, et al.: PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice. Proc Natl Acad Sci USA 2010, 107(34):15145-15150.
  • [56]Contractor T, Harris CR: p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res 2012, 72(2):560-567.
  • [57]Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, Chretien D, de Lonlay P, Paquis-Flucklinger V, Arakawa H, et al.: Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet 2007, 39(6):776-780.
  • [58]Kulawiec M, Ayyasamy V, Singh KK: p53 regulates mtDNA copy number and mitocheckpoint pathway. J Carcinog 2009, 8:8.
  • [59]Achanta G, Sasaki R, Feng L, Carew JS, Lu W, Pelicano H, Keating MJ, Huang P: Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol gamma. EMBO J 2005, 24(19):3482-3492.
  • [60]Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E: The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 2004, 64(7):2627-2633.
  • [61]Kawauchi K, Araki K, Tobiume K, Tanaka N: p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol 2008, 10(5):611-618.
  • [62]Kondoh H, Lleonart ME, Gil J, Wang J, Degan P, Peters G, Martinez D, Carnero A, Beach D: Glycolytic enzymes can modulate cellular life span. Cancer Res 2005, 65(1):177-185.
  • [63]Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, Yang X: p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 2011, 13(3):310-316.
  • [64]Engelman JA: Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009, 9(8):550-562.
  • [65]Cully M, You H, Levine AJ, Mak TW: Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006, 6(3):184-192.
  • [66]Feng Z: p53 Regulation of the IGF-1/AKT/mTOR Pathways and the Endosomal Compartment. Cold Spring Harb Perspect Biol 2010, 2(2):a001057.
  • [67]Levine AJ, Feng Z, Mak TW, You H, Jin S: Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 2006, 20(3):267-275.
  • [68]Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S, Mak TW: Regulation of PTEN transcription by p53. Mol Cell 2001, 8(2):317-325.
  • [69]Feng Z, Hu W, de Stanchina E, Teresky A, Jin S, Lowe S, Levine AJ: The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 2007, 67(7):3043-3053.
  • [70]Budanov AV, Karin M: p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 2008, 134(3):451-460.
  • [71]Feng Z, Zhang H, Levine AJ, Jin S: The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 2005, 102(23):8204-8209.
  • [72]Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, Oliner JD, McKeon F, Haber DA: REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol Cell 2002, 10(5):995-1005.
  • [73]Olalla L, Gutierrez A, Jimenez AJ, Lopez-Tellez JF, Khan ZU, Perez J, Alonso FJ, de la Rosa V, Campos-Sandoval JA, Segura JA, et al.: Expression of the scaffolding PDZ protein glutaminase-interacting protein in mammalian brain. J Neurosci Res 2008, 86(2):281-292.
  • [74]Ide T, Brown-Endres L, Chu K, Ongusaha PP, Ohtsuka T, El-Deiry WS, Aaronson SA, Lee SW: GAMT, a p53-inducible modulator of apoptosis, is critical for the adaptive response to nutrient stress. Mol Cell 2009, 36(3):379-392.
  • [75]Assaily W, Rubinger DA, Wheaton K, Lin Y, Ma W, Xuan W, Brown-Endres L, Tsuchihara K, Mak TW, Benchimol S: ROS-mediated p53 induction of Lpin1 regulates fatty acid oxidation in response to nutritional stress. Mol Cell 2011, 44(3):491-501.
  • [76]Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JC Jr, Kelly DP: Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab 2006, 4(3):199-210.
  • [77]Phan J, Reue K: Lipin, a lipodystrophy and obesity gene. Cell Metab 2005, 1(1):73-83.
  • [78]Tan M, Li S, Swaroop M, Guan K, Oberley LW, Sun Y: Transcriptional activation of the human glutathione peroxidase promoter by p53. J Biol Chem 1999, 274(17):12061-12066.
  • [79]Yoon KA, Nakamura Y, Arakawa H: Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J Hum Genet 2004, 49(3):134-140.
  • [80]Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, Zhang DD: Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol Cell 2009, 34(6):663-673.
  • [81]Liu G, Chen X: The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis. Oncogene 2002, 21(47):7195-7204.
  • [82]Martindale JL, Holbrook NJ: Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 2002, 192(1):1-15.
  • [83]Rivera A, Maxwell SA: The p53-induced gene-6 (proline oxidase) mediates apoptosis through a calcineurin-dependent pathway. J Biol Chem 2005, 280(32):29346-29354.
  • [84]Bensaad K, Vousden KH: p53: new roles in metabolism. Trends Cell Biol 2007, 17(6):286-291.
  • [85]Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD: Metformin and reduced risk of cancer in diabetic patients. BMJ 2005, 330(7503):1304-1305.
  • [86]Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB: Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007, 67(14):6745-6752.
  • [87]Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T: Restoration of p53 function leads to tumour regression in vivo. Nature 2007, 445(7128):661-665.
  • [88]Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW: Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007, 445(7128):656-660.
  • [89]Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, et al.: In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004, 303(5659):844-848.
  • [90]Vassilev LT: MDM2 inhibitors for cancer therapy. Trends Mol Med 2007, 13(1):23-31.
  文献评价指标  
  下载次数:17次 浏览次数:12次