Introduction to Genes, Oncogenes, and Anti-oncogenes

  • Undurti N. Das


Cancer is a major cause of significant morbidity and mortality in many countries across the globe though the type of cancers is different in different countries. The exact cause of majority of the cancers is not clear. Environmental agents (that include many mutagens and carcinogens) are considered to cause more than 50% of cancers. DNA damage leading to activation of oncogenes seems to be the underlying cause of cancer. In addition, suppression of the tumor suppressor genes is also at the center of the onset of cancer. Under normal physiological conditions, the immune system of the body recognizes tumor cells as foreign and mounts an attack to eliminate them. Cancer-specific antigens being weak antigens’ stimulation to the immune system is not adequate to mount a successful attack and eliminate them. As a result of DNA damage, there will be alterations in the activity and/or expression of p53, PTEN, ghrelin, leptin, Ras/Raf/ERK1/2, and PI3K/Akt and PIP3 that cause mitochondrial dysfunction, which results in changes in cell survival and function, growth, proliferation, migration, and cell size that ultimately leads to the development of cancer.


Cancer. Oncogenes Anti-oncogenes p53 PTEN 


  1. 1.
    Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad of Sci USA. 1971;68:820–3.CrossRefGoogle Scholar
  2. 2.
    Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science. 1990;249:912–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ. The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature. 1998;396:177–80.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Sherr CJ. Principles of tumor suppression. Cell. 2004;116:235–46.PubMedCrossRefGoogle Scholar
  5. 5.
    Stiegler P, De Luca A, Bagella L, Giordano A. The COOH-terminal region of pRb2/p130 binds to histone deacetylase 1 (HDAC1), enhancing transcriptional repression of the E2F-dependent cyclin a promoter. Cancer Res. 1998;58:5049–52.PubMedGoogle Scholar
  6. 6.
    Agoston AT, Argani P, De Marzo AM, Hicks JL, Nelson WG. Retinoblastoma pathway dysregulation causes DNA methyltransferase 1 overexpression in cancer via MAD2-mediated inhibition of the anaphase-promoting complex. Am J Pathol. 2007;170:1585–93.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Jung JK, Arora P, Pagano JS, Jang KL. Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclin D1-CDK 4/6-pRb-E2F1 pathway. Cancer Res. 2007;67:5771–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Münger K, Howley P. Human papillomavirus immortalization and transformation functions. Virus Res. 2002;89:213–28.PubMedCrossRefGoogle Scholar
  9. 9.
    Frolov M, Dyson N. Molecular mechanisms of E2F-dependent activation and RB-mediated repression. J Cell Sci. 2004;117(Pt 11):2173–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Goodrich D, Wang N, Qian Y, Lee E, Lee W. The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle. Cell. 1991;67:293–302.PubMedCrossRefGoogle Scholar
  11. 11.
    Wu C, Zukerberg L, Ngwu C, Harlow E, Lees J. In vivo association of E2F and DP family proteins. Mol Cell Biol. 1995;15:2536–46.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Vietri M, Bianchi M, Ludlow J, Mittnacht S, Villa-Moruzzi E. Direct interaction between the catalytic subunit of protein phosphatase 1 and pRb. Cancer Cell Int. 2006;6:3.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Parsam V, Kannabiran C, Honavar S, Vemuganti G, Ali M. A comprehensive, sensitive and economical approach for the detection of mutations in the RB1 gene in retinoblastoma. J Genet. 2009;88:517–27.PubMedCrossRefGoogle Scholar
  14. 14.
    Sage C, Huang M, Vollrath M, Brown M, Hinds P, Corey D, et al. Essential role of retinoblastoma protein in mammalian hair cell development and hearing. Proc Natl Acad Sci U S A. 2006;103:7345–50.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Weber T, Corbett M, Chow L, Valentine M, Baker S, Zuo J. Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells. Proc Natl Acad Sci U S A. 2008;105:781–5.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Lu N, Chen Y, Wang Z, Chen G, Lin Q, Chen Z, et al. Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein. Biochem Biophys Res Commun. 2013;430:700–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Christie K, Krishnan A, Martinez J, Purdy K, Singh B, Eaton S, et al. Enhancing adult nerve regeneration through the knockdown of retinoblastoma protein. Nat Commun. 2014;5:3670.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Bradley K, Scatizzi JC, Fiore S, Shamiyeh E, Koch AE, Firestein GS, Gorges LL, Kuntsman K, Pope RM, Moore TL, Han J, Perlman H. Retinoblastoma suppression of matrix metalloproteinase 1, but not interleukin-6, through a p38-dependent pathway in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2004;50:78–87.PubMedCrossRefGoogle Scholar
  19. 19.
    Nonomura Y, Nagasaka K, Hagiyama H, Sekine C, Nanki T, Tamamori-Adachi M, Miyasaka N, Kohsaka H. Direct modulation of rheumatoid inflammatory mediator expression in retinoblastoma protein-dependent and -independent pathways by cyclin-dependent kinase 4/6. Arthritis Rheum. 2006;54:2074–83.PubMedCrossRefGoogle Scholar
  20. 20.
    Féliers D, Frank MA, Riley DJ. Activation of cyclin D1-Cdk4 and Cdk4-directed phosphorylation of RB protein in diabetic mesangial hypertrophy. Diabetes. 2002;51:3290–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Matlashewski G, Lamb P, Pim D, Peacock J, Crawford L, Benchimol S. Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene. EMBO J. 1984;3:3257–62.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Isobe M, Emanuel B, Givol D, Oren M, Croce C. Localization of gene for human p53 tumour antigen to band 17p13. Nature. 1986;320:84–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Kern S, Kinzler K, Bruskin A, Jarosz D, Friedman P, Prives C, et al. Identification of p53 as a sequence-specific DNA-binding protein. Science. 1991;252:1708–11.PubMedCrossRefGoogle Scholar
  24. 24.
    McBride O, Merry D, Givol D. The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proc Natl Acad Sci U S A. 1986;83:130–4.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    May P, May E. Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene. 1999;18:7621–36.PubMedCrossRefGoogle Scholar
  26. 26.
    Venot C, Maratrat M, Dureuil C, Conseiller E, Bracco L, Debussche L. The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression. EMBO J. 1998;17:4668–79.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Larsen S, Yokochi T, Isogai E, Nakamura Y, Ozaki T, Nakagawara A. LMO3 interacts with p53 and inhibits its transcriptional activity. Biochem Biophys Res Commun. 2010;392:252–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Harms K, Chen X. The C terminus of p53 family proteins is a cell fate determinant. Mol Cell Biol. 2005;25:2014–30.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Mraz M, Malinova K, Kotaskova J, Pavlova S, Tichy B, Malcikova J, et al. MiR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities. Leukemia. 2009;23:1159–63.PubMedCrossRefGoogle Scholar
  30. 30.
    Dolezalova D, Mraz M, Barta T, et al. MicroRNAs regulate p21Waf1/Cip1 protein expression and the DNA damage response in human embryonic stem cells. Stem Cells. 2012;7:1362–72.CrossRefGoogle Scholar
  31. 31.
    Bates S, Phillips A, Clark P, Stott F, Peters G, Ludwig R, et al. p14ARF links the tumour suppressors RB and p53. Nature. 1998;395:124–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Naqshe Zahra S, Khattak NA, Mir A. Comparative modeling and docking studies of p16ink4/cyclin D1/Rb pathway genes in lung cancer revealed functionally interactive residue of RB1 and its functional partner E2F1. Theor Biol Med Model 2013; 10: 1.CrossRefGoogle Scholar
  33. 33.
    Treanor L, Bellamy C, Harrison DJ, Prost S. Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells. Int J Oncol. 2010;37:31–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Yap DB, Hsieh JK, Chan FS, Lu X. mdm2: a bridge over the two tumour suppressors, p53 and Rb. Oncogene. 1999;18:7681–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Hsieh JK, Chan FS, O’Connor DJ, Mittnacht S, Zhong S, Lu X. RB regulates the stability and the apoptotic function of p53 via MDM2. Mol Cell. 1999;3:181–93.PubMedCrossRefGoogle Scholar
  36. 36.
    Hu W, Feng Z, Teresky A, Levine A. p53 regulates maternal reproduction through LIF. Nature. 2007;450:721–4.PubMedCrossRefGoogle Scholar
  37. 37.
    Cui R, Widlund H, Feige E, Lin J, Wilensky D, Igras V, et al. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell. 2007;128:853–64.PubMedCrossRefGoogle Scholar
  38. 38.
    Murase D, Hachiya A, Amano Y, Ohuchi A, Kitahara T, Takema Y. The essential role of p53 in hyperpigmentation of the skin via regulation of paracrine melanogenic cytokine receptor signaling. J Biol Chem. 2009;284:4343–53.PubMedCrossRefGoogle Scholar
  39. 39.
    Hock A, Vigneron A, Carter S, Ludwig R. Vousden K (2011). Regulation of p53 stability and function by the deubiquitinating enzyme USP42. EMBO J. 2011;30:4921–30.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, et al. A genomic and functional inventory of deubiquitinating enzymes. Cell. 2005;123:773–86.PubMedCrossRefGoogle Scholar
  41. 41.
    Yuan J, Luo K, Zhang L, Cheville JC, Lou Z. USP10 regulates p53 localization and stability by deubiquitinating p53. Cell. 2010;140:384–96.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Liu J, Chung HJ, Vogt M, Jin Y, Malide D, et al. JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress. EMBO J. 2011;30:846–58.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, et al. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 2007;26:976–86.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Hock AK, Vigneron AM, Carter S, Ludwig RL, Vousden KH. Regulation of p53 stability and function by the deubiquitinating enzyme USP42. EMBO J. 2011;30:4921–30.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Luo J, Lu Z, Lu X, Chen L, Cao J, Zhang S, Ling Y, Zhou X. OTUD5 regulates p53 stability by deubiquitinating p53. PLoS One. 2013;8:e77682.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res. 2008;102:703–10.PubMedCrossRefGoogle Scholar
  47. 47.
    Hollstein M, Sidransky D, Vogelstein B, Harris C. p53 mutations in human cancers. Science. 1991;253:49–53.PubMedCrossRefGoogle Scholar
  48. 48.
    Yang L, Zhou Y, Li Y, Zhou J, Wu Y, Cui Y, Yang G, Hong Y. Mutations of p53 and KRAS activate NF-κB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells. Cancer Lett. 2015;357:520–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Cooks T, Harris CC. p53 mutations and inflammation-associated cancer are linked through TNF signaling. Mol Cell. 2014;56:611–2.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Di Minin G, Bellazzo A, Dal Ferro M, Chiaruttini G, Nuzzo S, Bicciato S, Piazza S, Rami D, Bulla R, Sommaggio R, Rosato A, Del Sal G, Collavin L. Mutant p53 reprograms TNF signaling in cancer cells through interaction with the tumor suppressor DAB2IP. Mol Cell. 2014;56:617–29.PubMedCrossRefGoogle Scholar
  51. 51.
    Weissmueller S, Manchado E, Saborowski M, Morris JP 4th, Wagenblast E, Davis CA, Moon SH, Pfister NT, Tschaharganeh DF, Kitzing T, Aust D, Markert EK, Wu J, Grimmond SM, Pilarsky C, Prives C, Biankin AV, Lowe SW. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling. Cell. 2014;157:382–94.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Tyner S, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, et al. p53 mutant mice that display early ageing-associated phenotypes. Nature. 2002;415:45–53.PubMedCrossRefGoogle Scholar
  53. 53.
    Yang G, Zhao K, Ju Y, Mani S, Cao Q, Puukila S, Khaper N, Wu L, Wang R. Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2. Antioxid Redox Signal. 2013;18:1906–19.PubMedCrossRefGoogle Scholar
  54. 54.
    Zhang DY, Wang HJ, Tan YZ. Wnt/β-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway. PLoS One. 2011;6:e21397.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Ugalde AP, Ramsay AJ, de la Rosa J, Varela I, Mariño G, Cadiñanos J, Lu J, Freije JM, López-Otín C. Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53. EMBO J. 2011;30:2219–32.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Pearson S, Jia H, Kandachi K. China approves first gene therapy. Nat Biotechnol. 2004;22:3–4.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Angeletti P, Zhang L, Wood C. (2008). The viral etiology of AIDS-associated malignancies. Adv Pharmacol. 2008;56:509–57.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Jacobs M, Harrison S. Structure of an IkappaBalpha/NF-kappaB complex. Cell. 1998;95:749–58.CrossRefPubMedGoogle Scholar
  59. 59.
    Verma I, Stevenson J, Schwarz E, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev. 1995;9:2723–35.PubMedCrossRefGoogle Scholar
  60. 60.
    Cabannes E, Khan G, Aillet F, Jarrett R. Hay R (1999). Mutations in the IkBα gene in Hodgkin’s disease suggest a tumour suppressor role for IkappaBalpha. Oncogene. 1999;18:3063–70.PubMedCrossRefGoogle Scholar
  61. 61.
    Gilmore TD. Introduction to NF-κB: players, pathways, perspectives. Oncogene. 2006;25:6680–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Brasier AR. The NF-κB regulatory network. Cardiovasc Toxicol. 2006;6:111–30.PubMedCrossRefGoogle Scholar
  63. 63.
    Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function. Nat Rev Mol Cell Biol. 2007;8:49–62.PubMedCrossRefGoogle Scholar
  64. 64.
    Albensi BC, Mattson MP. Evidence for the involvement of TNF and NF-κB in hippocampal synaptic plasticity. Synapse. 2000;35:151–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L, Prüllage M, Pfeiffer J, Lindecke A, Staiger V, Israël A, Kaltschmidt C, Mémet S. NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase a/CREB signaling. Mol Cell Biol. 2006;26:2936–46.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Wang J, Fu XQ, Lei WL, Wang T, Sheng AL, Luo ZG. Nuclear factor kappaB controls acetylcholine receptor clustering at the neuromuscular junction. J Neurosci. 2010;30:11104–13.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Boersma MC, Dresselhaus EC, De Biase LM, Mihalas AB, Bergles DE, Meffert MK. A requirement for nuclear factor-{kappa}B in developmental and plasticity-associated synaptogenesis. J Neurosci. 2011;31:5414–25.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Gutierrez H, Hale VA, Dolcet X, Davies A. NF-kappaB signalling regulates the growth of neural processes in the developing PNS and CNS. Development. 2005;132:1713–26.PubMedCrossRefGoogle Scholar
  69. 69.
    Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-α. Nature. 2006;440:1054–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Beattie EC, David Stellwagen D, Morishita W, Jacqueline C, Bresnahan JC, Ha BK, Zastrow MV, Beattie MS, Malenka RC. Control of synaptic strength by glial TNFα. Science. 2002;295:2282–5.PubMedCrossRefGoogle Scholar
  71. 71.
    Yang L, Xie M, Yang M, Yu Y, Zhu S, Hou W, Kang R, Lotze MT, Billiar TR, Wang H, Cao L, Tang D. PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun. 2014;5:4436.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Yanai H, Matsuda A, An J, Koshiba R, Nishio J, Negishi H, Ikushima H, Onoe T, Ohdan H, Yoshida N, Taniguchi T. Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection. Proc Natl Acad Sci U S A. 2013;110:20699–704.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Yang M, Cao L, Xie M, Yu Y, Kang R, Yang L, Zhao M, Tang D. Chloroquine inhibits HMGB1 inflammatory signaling and protects mice from lethal sepsis. Biochem Pharmacol. 2013;86:410–8.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Liu Z, Chang Y, Zhang J, Huang X, Jiang J, Li S, Wang Z. Magnesium deficiency promotes secretion of high-mobility group box 1 protein from lipopolysaccharide-activated macrophages in vitro. J Surg Res. 2013;180:310–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, Al-Abed Y, Wang H, Metz C, Miller EJ, Tracey KJ, Ulloa L. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;10:1216–21.PubMedCrossRefGoogle Scholar
  76. 76.
    Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285:248–51.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Weisz L, Damalas A, Liontos M, Karakaidos P, Fontemaggi G, Maor-Aloni R, Kalis M, Levrero M, Strano S, Gorgoulis VG, Rotter V, Blandino G, Oren M. Mutant p53 enhances nuclear factor kappaB activation by tumor necrosis factor alpha in cancer cells. Cancer Res. 2007;67:2396–401.PubMedCrossRefGoogle Scholar
  78. 78.
    Firestein GS, Nguyen K, Aupperle KR, Yeo M, Boyle DL, Zvaifler NJ. Apoptosis in rheumatoid arthritis: p53 overexpression in rheumatoid arthritis synovium. Am J Pathol. 1996;149:2143–51.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Yao Q, Wang S, Glorioso JC, Evans CH, Robbins PD, Ghivizzani SC, Oligino TJ. Gene transfer of p53 to arthritic joints stimulates synovial apoptosis and inhibits inflammation. Mol Ther. 2001;3:901–10.PubMedCrossRefGoogle Scholar
  80. 80.
    Migita K, Tanaka F, Yamasaki S, Shibatomi K, Ida H, Kawakami A, Aoyagi T, Kawabe Y, Eguchi K. Regulation of rheumatoid synoviocyte proliferation by endogenous p53 induction. Clin Exp Immunol. 2001;126:334–8.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Yamanishi Y, Boyle DL, Pinkoski MJ, Mahboubi A, Lin T, Han Z, Zvaifler NJ, Green DR, Firestein GS. Regulation of joint destruction and inflammation by p53 in collagen-induced arthritis. Am J Pathol. 2002;160:123–30.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Leech M, Lacey D, Xue JR, Santos L, Hutchinson P, Wolvetang E, David JR, Bucala R, Morand EF. Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis. Arthritis Rheum. 2003;48:1881–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Simelyte E, Rosengren S, Boyle DL, Corr M, Green DR, Firestein GS. Regulation of arthritis by p53: critical role of adaptive immunity. Arthritis Rheum. 2005;52:1876–84.PubMedCrossRefGoogle Scholar
  84. 84.
    Leech M, Xue JR, Dacumos A, Hall P, Santos L, Yang Y, Li M, Kitching AR, Morand EF. The tumour suppressor gene p53 modulates the severity of antigen-induced arthritis and the systemic immune response. Clin Exp Immunol. 2008;152:345–53.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Lin J, Huo R, Xiao L, Zhu X, Xie J, Sun S, He Y, Zhang J, Sun Y, Zhou Z, Wu P, Shen B, Li D, Li N. A novel p53/microRNA-22/Cyr61 axis in synovial cells regulates inflammation in rheumatoid arthritis. Arthritis Rheumatol. 2014;66:49–59.PubMedCrossRefGoogle Scholar
  86. 86.
    Park JS, Lim MA, Cho ML, Ryu JG, Moon YM, Jhun JY, Byun JK, Kim EK, Hwang SY, Ju JH, Kwok SK, Kim HY. p53 controls autoimmune arthritis via STAT-mediated regulation of the Th17 cell/Treg cell balance in mice. Arthritis Rheum. 2013;65:949–59.PubMedCrossRefGoogle Scholar
  87. 87.
    Gu Z, Jiang J, Tan W, Xia Y, Cao H, Meng Y, Da Z, Liu H, Cheng C. p53/p21 pathway involved in mediating cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients. Clin Dev Immunol. 2013;2013:134243.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Gu Z, Tan W, Feng G, Meng Y, Shen B, Liu H, Cheng C. Wnt/β-catenin signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients through the p53/p21 pathway. Mol Cell Biochem. 2014;387:27–37.PubMedCrossRefGoogle Scholar
  89. 89.
    Allam R, Sayyed SG, Kulkarni OP, Lichtnekert J, Anders HJ. Mdm2 promotes systemic lupus erythematosus and lupus nephritis. J Am Soc Nephrol. 2011;22:2016–27.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Salvador JM, Hollander MC, Nguyen AT, Kopp JB, Barisoni L, Moore JK, Ashwell JD, Fornace AJ Jr. Mice lacking the p53-effector gene Gadd45a develop a lupus-like syndrome. Immunity. 2002;16:499–508.PubMedCrossRefGoogle Scholar
  91. 91.
    Herkel J, Mimran A, Erez N, Kam N, Lohse AW, Märker-Hermann E, Rotter V, Cohen IR. Autoimmunity to the p53 protein is a feature of systemic lupus erythematosus (SLE) related to anti-DNA antibodies. J Autoimmun. 2001;17:63–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Herkel J, Erez-Alon N, Mimran A, Wolkowicz R, Harmelin A, Ruiz P, Rotter V, Cohen IR. Systemic lupus erythematosus in mice, spontaneous and induced, is associated with autoimmunity to the C-terminal domain of p53 that recognizes damaged DNA. Eur J Immunol. 2000;30:977–84.PubMedCrossRefGoogle Scholar
  93. 93.
    Chu EC, Tarnawski AS. PTEN regulatory functions in tumor suppression and cell biology. Med Sci Monitor. 2004;10:RA 235–41.Google Scholar
  94. 94.
    Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436:725–30.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Rhei E, Kang L, Bogomolniy F, Federici MG, Borgen PI, Boyd J. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res. 1997;57:3657–9.PubMedGoogle Scholar
  96. 96.
    Cairns P, Evron E, Okami K, Halachmi N, Esteller M, Herman JG, Bose S, Wang SI, Parsons R, Sidransky D. Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Oncogene. 1998;16:3215–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A. 1999;96:1563–8.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG, Mariman EC, Padberg GW, Kremer H. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet. 1997;6:1383–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Tzortzatos G, Aravidis C, Lindblom A, Mints M, Tham E. Screening for germline phosphatase and tensin homolog-mutations in suspected Cowden syndrome and Cowden syndrome-like families among uterine cancer patients. Oncol Lett. 2015;9:1782–6.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genetics. 2004;41:323–6.CrossRefGoogle Scholar
  101. 101.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–7.PubMedCrossRefGoogle Scholar
  102. 102.
    Lynch ED, Ostermeyer EA, Lee MK, Arena JF, Ji H, Dann J, Swisshelm K, Suchard D, MacLeod PM, Kvinnsland S, Gjertsen BT, Heimdal K, Lubs H, Møller P, King MC. Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis. Am J Hum Genet. 1997;61:1254–60.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Sakai A, Thieblemont C, Wellmann A, Jaffe ES, Raffeld M. PTEN gene alterations in lymphoid neoplasms. Blood. 1998;92:3410–5.PubMedCrossRefGoogle Scholar
  104. 104.
    Minobe K, Bando K, Fukino K, Soma S, Kasumi F, Sakamoto G, Furukawa K, Higuchi K, Onda M, Nakamura Y, Emi M. Somatic mutation of the PTEN/MMAC1 gene in breast cancers with microsatellite instability. Cancer Lett. 1999;144:9–16.PubMedCrossRefGoogle Scholar
  105. 105.
    Liu J, Visser-Grieve S, Boudreau J, Yeung B, Lo S, Chamberlain G, Yu F, Sun T, Papanicolaou T, Lam A, Yang X, Chin-Sang I. Insulin activates the insulin receptor to downregulate the PTEN tumour suppressor. Oncogene. 2014;33:3878–85.PubMedCrossRefGoogle Scholar
  106. 106.
    Halachmi N, Halachmi S, Evron E, Cairns P, Okami K, Saji M, Westra WH, Zeiger MA, Jen J, Sidransky D. Somatic mutations of the PTEN tumor suppressor gene in sporadic follicular thyroid tumors. Genes Chromosomes Cancer. 1998;23:239–43.PubMedCrossRefGoogle Scholar
  107. 107.
    Duman BB, Kara OI, Uğuz A, Ates BT. Evaluation of PTEN, PI3K, MTOR, and KRAS expression and their clinical and prognostic relevance to differentiated thyroid carcinoma. Contemp Oncol (Pozn). 2014;18:234–40.Google Scholar
  108. 108.
    Charles RP, Silva J, Iezza G, Phillips WA, McMahon M. Activating BRAF and PIK3CA mutations cooperate to promote anaplastic thyroid carcinogenesis. Mol Cancer Res. 2014;12:979–86.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Kurose K, Bando K, Fukino K, Sugisaki Y, Araki T, Emi M. Somatic mutations of the PTEN/MMAC1 gene in fifteen Japanese endometrial cancers: evidence for inactivation of both alleles. Jpn J Cancer Res. 1998;89:842–8.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    El-Mansi MT, Williams AR. Evaluation of PTEN expression in cervical adenocarcinoma by tissue microarray. Int J Gynecol Cancer. 2006;16:1254–60.PubMedCrossRefGoogle Scholar
  111. 111.
    Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, et al. Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53. PLoS One. 2012;7:e42504.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Sperow M, Berry RB, Bayazitov IT, Zhu G, Baker SJ, Zakharenko SS. Phosphatase and tensin homologue (PTEN) regulates synaptic plasticity independently of its effect on neuronal morphology and migration. J Physiol. 2012;590(Pt 4):777–92.PubMedCrossRefGoogle Scholar
  113. 113.
    Takeuchi K, Gertner MJ, Zhou J, Parada LF, Bennett MV, Zukin RS. Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism. Proc Natl Acad Sci U S A. 2013;110:4738–43.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Blair PJ, Harvey J. PTEN: a new player controlling structural and functional synaptic plasticity. J Physiol. 2012;590(Pt 5):1017.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J, Tsao MS, Shannon P, Bolon B, Ivy GO, Mak TW. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet. 2001;29:396–403.PubMedCrossRefGoogle Scholar
  116. 116.
    Chalhoub N, Zhu G, Zhu X, Baker SJ. Cell type specificity of PI3K signaling in Pdk1- and Pten-deficient brains. Genes Dev. 2009;23:1619–24.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Moult PR, Cross A, Santos SD, Carvalho AL, Lindsay Y, Connolly CN, Irving AJ, Leslie NR, Harvey J. Leptin regulates AMPA receptor trafficking via PTEN inhibition. J Neurosci. 2010;30:4088–101.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Jurado S, Benoist M, Lario A, Knafo S, Petrok CN, Esteban JA. PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression. EMBO J. 2010;29:2827–40.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Harvey J. Leptin: a diverse regulator of neuronal function. J Neurochem. 2007;100:307–13.PubMedCrossRefGoogle Scholar
  120. 120.
    Shanley LJ, Irving AJ, Harvey J. Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. J Neurosci. 2001;21:RC186.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neurosci. 2002;113:607–15.CrossRefGoogle Scholar
  122. 122.
    Durakoglugil M, Irving AJ, Harvey J. Leptin induces a novel form of NMDA receptor-dependent long-term depression. J Neurochem. 2005;95:396–405.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Moult PR, Milojkovic B, Harvey J. Leptin reverses long-term potentiation at hippocampal CA1 synapses. J Neurochem. 2009;108:685–96.PubMedCrossRefGoogle Scholar
  124. 124.
    Collingridge GL, Isaac JT, Wang YT. Receptor trafficking and synaptic plasticity. Nat Rev Neurosci. 2004;5:952–62.PubMedCrossRefGoogle Scholar
  125. 125.
    Ashwood P, Kwong C, Hansen R, Hertz-Picciotto I, Croen L, Krakowiak P, Walker W, Pessah IN, Van de Water J. Brief report: plasma leptin levels are elevated in autism: association with early onset phenotype? J Autism Dev Disord. 2008;38:169–75.PubMedCrossRefGoogle Scholar
  126. 126.
    Blardi P, de Lalla A, Ceccatelli L, Vanessa G, Auteri A, Hayek J. Variations of plasma leptin and adiponectin levels in autistic patients. Neurosci Lett. 2010;479:54–7.PubMedCrossRefGoogle Scholar
  127. 127.
    Blardi P, de Lalla A, D’Ambrogio T, Vonella G, Ceccatelli L, Auteri A, Hayek J. Long-term plasma levels of leptin and adiponectin in Rett syndrome. Clin Endocrinol. 2009;70:706–9.CrossRefGoogle Scholar
  128. 128.
    Rodrigues DH, Rocha NP, Sousa LF, Barbosa IG, Kummer A, Teixeira AL. Changes in adipokine levels in autism spectrum disorders. Neuropsychobiology. 2014;69:6–10.PubMedCrossRefGoogle Scholar
  129. 129.
    Al-Zaid FS, Alhader AA, Al-Ayadhi LY. Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation. Sci Rep. 2014;4:6478.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M, Katsuura G, Makino S, Fujino MA, Kasuga M. A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology. 2001;74:143–7.PubMedCrossRefGoogle Scholar
  131. 131.
    Sato T, Fukue Y, Teranishi H, Yoshida Y, Kojima M. Molecular forms of hypothalamic ghrelin and its regulation by fasting and 2-deoxy-d-glucose administration. Endocrinology. 2005;146:2510–6.PubMedCrossRefGoogle Scholar
  132. 132.
    DeLong GR. Autism, amnesia, hippocampus, and learning. Neurosci Biobehav Rev. 1992;16:63–70.PubMedCrossRefGoogle Scholar
  133. 133.
    Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschöp MH, Horvath TL. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci. 2006;9:381–8.PubMedCrossRefGoogle Scholar
  134. 134.
    Bourgeron T. A synaptic trek to autism. Curr Opin Neurobiol. 2009;19:231–4.PubMedCrossRefGoogle Scholar
  135. 135.
    Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S, Barnhouse S, Lee W. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metab (Lond). 2011;8:34.PubMedCentralCrossRefGoogle Scholar
  136. 136.
    Shimmura C, Suda S, Tsuchiya KJ, Hashimoto K, Ohno K, Matsuzaki H, Iwata K, Matsumoto K, Wakuda T, Kameno Y, Suzuki K, Tsujii M, Nakamura K, Takei N, Mori N. Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS One. 2011;6:e25340.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Pfluger PT, Kirchner H, Günnel S, Schrott B, Perez-Tilve D, Fu S, Benoit SC, Horvath T, Joost HG, Wortley KE, Sleeman MW, Tschöp MH. Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure. Am J Physiol Gastrointest Liver Physiol. 2008;294:G610–8.PubMedCrossRefGoogle Scholar
  138. 138.
    Gail Williams P, Sears LL, Allard A. Sleep problems in children with autism. J Sleep Res. 2004;13:265–8.PubMedCrossRefGoogle Scholar
  139. 139.
    Hackler J. Treatment of compulsive eating disorders in an autistic girl by combining behavior therapy and pharmacotherapy. Case report Z Kinder Jugendpsychiatr. 1986;14:220–7.PubMedGoogle Scholar
  140. 140.
    Zhao Z, Sakata I, Okubo Y, Koike K, Kangawa K, Sakai T. Gastric leptin, but not estrogen and somatostatin, contributes to the elevation of ghrelin mRNA expression level in fasted rats. J Endocrinol. 2008;196:529–38.PubMedCrossRefGoogle Scholar
  141. 141.
    Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, Angelastro J, Omanska-Klusek A, Schoenfeld R, Giulivi C. Mitochondrial dysfunction in Pten Haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53. PLoS One. 2012;7:e42504.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Garcia-Cao I, Song MS, Hobbs RM, Laurent G, Giorgi C, et al. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell. 2012;149:49–62.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Araghi-Niknam M, Fatemi SH. Levels of Bcl-2 and P53 are altered in superior frontal and cerebellar cortices of autistic subjects. Cell Mol Neurobiol. 2003;23:945–52.PubMedCrossRefGoogle Scholar
  144. 144.
    Fatemi SH, Halt AR, Stary JM, Realmuto GM, Jalali-Mousavi M. Reduction in anti-apoptotic protein Bcl-2 in autistic cerebellum. Neuroreport. 2001;12:929–33.PubMedCrossRefGoogle Scholar
  145. 145.
    Fatemi SH, Stary JM, Halt AR, Realmuto GR. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord. 2001;31:529–35.PubMedCrossRefGoogle Scholar
  146. 146.
    Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68:820–3.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–7.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Di Cristofano A, De Acetis M, Koff A, CordonCardo C, Pandolfi PP. Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet. 2001;27:222–4.PubMedCrossRefGoogle Scholar
  149. 149.
    Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell. 2000;100:387–90.PubMedCrossRefGoogle Scholar
  150. 150.
    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;8:317–25.PubMedCrossRefGoogle Scholar
  151. 151.
    Mayo LD, Dixon JE, Durden DL, Tonks NK, Donner DB. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem. 2002;277:5484–9.PubMedCrossRefGoogle Scholar
  152. 152.
    Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol. 2001;3:973–82.PubMedCrossRefGoogle Scholar
  153. 153.
    Freeman DJ, Li AG, Wei G, Li H-H, Kertesz N, Lesche R, Whale AD, MartinezDiaz H, Rozengurt N, Cardiff RD, et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell. 2003;3:117–30.PubMedCrossRefGoogle Scholar
  154. 154.
    Trotman LC, Pandolfi PP. PTEN and p53: who will get the upper hand? Cancer Cell. 2003;3:97–9.PubMedCrossRefGoogle Scholar
  155. 155.
    Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet. 2002;32:355–7.PubMedCrossRefGoogle Scholar
  156. 156.
    Sheikh AM, Li X, Wen G, Tauqeer Z, Brown WT, Malik M. Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects. Neuroscience. 2010;165:363–70.PubMedCrossRefGoogle Scholar
  157. 157.
    Sheikh AM, Malik M, Wen G, Chauhan A, Chauhan V, Gong CX, Liu F, Brown WT, Li X. BDNF-Akt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects. J Neurosci Res. 2010;88:2641–7.PubMedGoogle Scholar
  158. 158.
    Yang K, Sheikh AM, Malik M, Wen G, Zou H, Brown WT, Li X. Upregulation of Ras/Raf/ERK1/2 signaling and ERK5 in the brain of autistic subjects. Genes Brain Behav. 2011;10:834–43.PubMedCrossRefGoogle Scholar
  159. 159.
    Zou H, Yu Y, Sheikh AM, Malik M, Yang K, Wen G, Chadman KK, Brown WT, Li X. Association of upregulated Ras/Raf/ERK1/2 signaling with autism. Genes Brain Behav. 2011;10:615–24.PubMedCrossRefGoogle Scholar
  160. 160.
    Yang K, Cao F, Sheikh AM, Malik M, Wen G, Wei H, Ted Brown W, Li X. Up-regulation of Ras/Raf/ERK1/2 signaling impairs cultured neuronal cell migration, neurogenesis, synapse formation, and dendritic spine development. Brain Struct Funct. 2013;218:669–82.PubMedCrossRefGoogle Scholar
  161. 161.
    Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci. 2010;13:1075–81.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Thottassery JV, Sun Y, Westbrook L, Rentz SS, Manuvakhova M, Qu Z, Samuel S, Upshaw R, Cunningham A, Kern FG. Prolonged extracellular signal-regulated kinase 1/2 activation during fibroblast growth factor 1- or heregulin beta1-induced antiestrogen-resistant growth of breast cancer cells is resistant to mitogen-activated protein/extracellular regulated kinase kinase inhibitors. Cancer Res. 2004;64:4637–47.PubMedCrossRefGoogle Scholar
  163. 163.
    Hao XK, Wu W, Wang CX, Xie GB, Li T, Wu HM, Huang LT, Zhou ML, Hang CH, Shi JX. Ghrelin alleviates early brain injury after subarachnoid hemorrhage via the PI3K/Akt signaling pathway. Brain Res. 2014;1587:15–22.PubMedCrossRefGoogle Scholar
  164. 164.
    Waseem T, Duxbury M, Ashley SW, Robinson MK. Ghrelin promotes intestinal epithelial cell proliferation through PI3K/Akt pathway and EGFR trans-activation both converging to ERK 1/2 phosphorylation. Peptides. 2014;52:113–21.PubMedCrossRefGoogle Scholar
  165. 165.
    Chen X, Chen Q, Wang L, Li G. Ghrelin induces cell migration through GHSR1a-mediated PI3K/Akt/eNOS/NO signaling pathway in endothelial progenitor cells. Metabolism. 2013;62:743–52.PubMedCrossRefGoogle Scholar
  166. 166.
    Wen R, Hu S, Xiao Q, Han C, Gan C, Gou H, Liu H, Li L, Xu H, He H, Wang J. Leptin exerts proliferative and anti-apoptotic effects on goose granulosa cells through the PI3K/Akt/mTOR signaling pathway. J Steroid Biochem Mol Biol. 2015;149:70–9.PubMedCrossRefGoogle Scholar
  167. 167.
    Ting CC, Hargrove ME. Activation of natural killer-derived cytotoxic T lymphocytes. I. Regulation by macrophage and prostaglandins. J Immunol. 1983;131:1734–41.PubMedGoogle Scholar
  168. 168.
    Parhar RS, Lala PK. Prostaglandin E2-mediated inactivation of various killer lineage cells by tumor-bearing host macrophages. J Leukoc Biol. 1988;44:474–84.PubMedCrossRefGoogle Scholar
  169. 169.
    Adamson GM, Carlson TJ, Billings RE. Phospholipase A2 activation in cultured mouse hepatocytes exposed to tumor necrosis factor-alpha. J Biochem Toxicol. 1994;9:181–90.PubMedCrossRefGoogle Scholar
  170. 170.
    Liu SJ, McHowat J. Stimulation of different phospholipase A2 isoforms by TNF-alpha and IL-1beta in adult rat ventricular myocytes. Am J Phys. 1998;275:H1462–72.Google Scholar
  171. 171.
    Mayer K, Schmidt R, Muhly-Reinholz M, Bögeholz T, Gokorsch S, Grimminger F, Seeger W. In vitro mimicry of essential fatty acid deficiency in human endothelial cells by TNF alpha impact of omega-3 versus omega-6 fatty acids. J Lipid Res. 2002;43:944–51.PubMedGoogle Scholar
  172. 172.
    Medeiros R, Figueiredo CP, Pandolfo P, Duarte FS, Prediger RD, Passos GF, Calixto JB. The role of TNF-alpha signaling pathway on COX-2 upregulation and cognitive decline induced by beta-amyloid peptide. Behav Brain Res. 2010;209:165–73.PubMedCrossRefGoogle Scholar
  173. 173.
    Vila-del Sol V, Fresno M. Involvement of TNF and NF-kappa B in the transcriptional control of cyclooxygenase-2 expression by IFN-gamma in macrophages. J Immunol. 2005;174:2825–33.PubMedCrossRefGoogle Scholar
  174. 174.
    Huang WC, Chen JJ, Inoue H, Chen CC. Tyrosine phosphorylation of I-kappa B kinase alpha/beta by protein kinase C-dependent c-Src activation is involved in TNF-alpha-induced cyclooxygenase-2 expression. J Immunol. 2003;170:4767–75.PubMedCrossRefGoogle Scholar
  175. 175.
    Chen CC, Sun YT, Chen JJ, Chiu KT. TNF-alpha-induced cyclooxygenase-2 expression in human lung epithelial cells: involvement of the phospholipase C-gamma 2, protein kinase C-alpha, tyrosine kinase, NF-kappa B-inducing kinase, and I-kappa B kinase 1/2 pathway. J Immunol. 2000;165:2719–28.PubMedCrossRefGoogle Scholar
  176. 176.
    Haliday EM, Ramesha CS, Ringold G. TNF induces c-fos via a novel pathway requiring conversion of arachidonic acid to a lipoxygenase metabolite. EMBO J. 1991;10:109–15.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Montuschi P, Tringali G, Currò D, Ciabattoni G, Parente L, Preziosi P, Navarra P. Evidence that interleukin-1 beta and tumor necrosis factor inhibit gastric fundus motility via the 5-lipoxygenase pathway. Eur J Pharmacol. 1994;252:253–60.PubMedCrossRefGoogle Scholar
  178. 178.
    Monis B, Eynard AR. Abnormal cell proliferation and differentiation and urothelial tumorigenesis in essential fatty acid deficient (EFAD) rats. Prog Lipid Res. 1981;20:691–703.PubMedCrossRefGoogle Scholar
  179. 179.
    Monis B, Eynard AR. Incidence of urothelial tumors in rats deficient in essential fatty acids. J Natl Cancer Inst. 1980;64:73–9.PubMedGoogle Scholar
  180. 180.
    Liepkalns VA, Spector AA. Alteration of the fatty acid composition of Ehrlich ascites tumor cell lipids. Biochem Biophys Res Commun. 1975;63:1043–7.PubMedCrossRefGoogle Scholar
  181. 181.
    Reitz RC, Thompson JA, Morris HP. Mitochondrial and microsomal phospholipids of Morris hepatoma 77771. Cancer Res. 1977;37:561–7.PubMedPubMedCentralGoogle Scholar
  182. 182.
    Dunbar LM, Bailey JM. Enzyme deletions and essential fatty acid metabolism in cultured cells. J Biol Chem. 1975;250:1152–3.Google Scholar
  183. 183.
    Morton RE, Hartz JW, Reitz RC, Waite BM, Morris H. The acyl-CoA desaturases of microsomes from rat liver and the Morris 7777 hepatoma. Biochim Biophys Acta. 1979;573:321–31.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Nassar BA, Das UN, Huang YS, Ells G, Horrobin DF. The effect of chemical hepatocarcinogenesis on liver phospholipid composition in rats fed n-6 and n-3 fatty acid-supplemented diets. Proc Soc Exp Biol Med. 1992;199:365–8.CrossRefPubMedGoogle Scholar
  185. 185.
    Das UN. Essential fatty acids enhance free radical generation and lipid peroxidation to induce apoptosis of tumor cells. Clin Lipidol. 2011;6:463–89.CrossRefGoogle Scholar
  186. 186.
    Tateishi N, Kakutani S, Kawashima H, Shibata H, Morita I. Dietary supplementation of arachidonic acid increases arachidonic acid and lipoxin A4 contents in colon, but does not affect severity or prostaglandin E2 content in murine colitis model. Lipids Health Dis. 2014;13:30.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Tateishi N, Kaneda Y, Kakutani S, Kawashima H, Shibata H, Morita I. Dietary supplementation with arachidonic acid increases arachidonic acid content in paw, but does not affect arthritis severity or prostaglandin E2content in rat adjuvant-induced arthritis model. Lipids Health Dis. 2015;14:3.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Chen Y, Hao H, He S, Cai L, Li Y, Hu S, Ye D, Hoidal J, Wu P, Chen X. Lipoxin A4 and its analogue suppress the tumor growth of transplanted H22 in mice: the role of antiangiogenesis. Mol Cancer Ther. 2010;9:2164–74.PubMedCrossRefGoogle Scholar
  189. 189.
    Hao H, Liu M, Wu P, Cai L, Tang K, Yi P, Li Y, Chen Y, Ye D. Lipoxin A4 and its analog suppress hepatocellular carcinoma via remodeling tumor microenvironment. Cancer Lett. 2011;309:85–94.PubMedCrossRefGoogle Scholar
  190. 190.
    Polavarapu S, Dwarakanath BS, Das UN. Differential action of polyunsaturated fatty acids and eicosanoids on bleomycin-induced cytotoxicity to neuroblastoma cells and lymphocytes. Arch Med Sci. 2018;14:207–29.PubMedCrossRefGoogle Scholar
  191. 191.
    Polavarapu S, Mani AM, Gundala NK, Hari AD, Bathina S, Das UN. Effect of polyunsaturated fatty acids and their metabolites on bleomycin-induced cytotoxic action on human neuroblastoma cells in vitro. PLoS One. 2014;9:e114766.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Kim SH, Roszik J, Cho SN, Ogata D, Milton DR, Peng W, Menter DG, Ekmekcioglu S, Grimm EA. The COX2 effector microsomal PGE2 synthase 1 is a regulator of immunosuppression in cutaneous melanoma. Clin Cancer Res. 2019;25:1650–63.PubMedCrossRefGoogle Scholar
  193. 193.
    Prima V, Kaliberova LN, Kaliberov S, Curiel DT, Kusmartsev S. COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci U S A. 2017;114:1117–22.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Kim SH, Hashimoto Y, Cho SN, Roszik J, Milton DR, Dal F, Kim SF, Menter DG, Yang P, Ekmekcioglu S, Grimm EA. Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression. Pigment Cell Melanoma Res. 2016;29:297–308.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Wang J, Zhang L, Kang D, Yang D, Tang Y. Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulate the level of PD-1 in infiltrating CD8+ T cells in patients with lung cancer. Oncol Lett. 2018;15:552–8.PubMedGoogle Scholar
  196. 196.
    Miao J, Lu X, Hu Y, Piao C, Wu X, Liu X, Huang C, Wang Y, Li D, Liu J. Prostaglandin E2 and PD-1 mediated inhibition of antitumor CTL responses in the human tumor microenvironment. Oncotarget. 2017;8:89802–10.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Chen JH, Perry CJ, Tsui YC, Staron MM, Parish IA, Dominguez CX, Rosenberg DW, Kaech SM. Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. Nat Med. 2015;21:327–34.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Sailaja P, Dwarakanath B, Das UN. Arachidonic acid activates extrinsic apoptotic pathway to enhance tumoricidal action of bleomycin against IMR-32 cells. Prostaglandins Leukot Essent Fatty Acids. 2018;132:16–22.CrossRefGoogle Scholar
  199. 199.
    Anasuya DH, Naidu VGM, Das UN. N-6 and n-3 fatty acids and their metabolites augment inhibitory action of doxorubicin on the proliferation of human neuroblastoma (IMR-32) cells by enhancing lipid peroxidation and suppressing Ras, Myc, and Fos. Biofactors. 2018;44:387–401.CrossRefGoogle Scholar
  200. 200.
    Anasuya DH, Naidu VGM, Das UN. Arachidonic and eicosapentaenoic acids induce oxidative stress to suppress proliferation of human glioma cells. Arch Med Sci. in press.Google Scholar
  201. 201.
    Baranov V, Nagaeva O, Hammarstrom S, Mincheva-Nilsson L. Lipids are a constituent of cytolytic granules. Histochem Cell Biol. 2000;114:167–71.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Viswanathan V, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453–7.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Hangauer MJ, Viswanathan V, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247–50.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Das UN. Tumoricidal action of cis-unsaturated fatty acids and its relationship to free radicals and lipid peroxidation. Cancer Lett. 1991;56:235–43.CrossRefPubMedGoogle Scholar
  205. 205.
    Kroemer G, Pouyssegur J. Tumor cell metabolism: Cancer’s Achilles’ hell. Cancer Cell. 2008;13:472–82.PubMedCrossRefGoogle Scholar
  206. 206.
    Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 569:270–4.Google Scholar
  207. 207.
    Merlo P, Frost B, Peng S, Yang YJ, Park PJ, Feany M. p53 prevents neurodegeneration by regulating synaptic genes. Proc Natl Acad Sci U S A. 2014;111:18055–60.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Tang X, O’Reilly A, Asano M, Merrill JC, Yokoyama KK, Amar S. p53 peptide prevents LITAF-induced TNF-alpha-mediated mouse lung lesions and endotoxic shock. Curr Mol Med. 2011;11:439–52.PubMedCrossRefGoogle Scholar
  209. 209.
    Wu XN, Ye YX, Niu JW, Li Y, Li X, You X, Chen H, Zhao LD, Zeng XF, Zhang FC, Tang FL, He W, Cao XT, Zhang X, Lipsky PE. Defective PTEN regulation contributes to B cell hyperresponsiveness in systemic lupus erythematosus. Sci Transl Med. 2014;6:246ra99.PubMedCrossRefGoogle Scholar
  210. 210.
    Stagakis E, Bertsias G, Verginis P, Nakou M, Hatziapostolou M, Kritikos H, Iliopoulos D, Boumpas DT. Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression. Ann Rheum Dis. 2011;70:1496–506.PubMedCrossRefGoogle Scholar
  211. 211.
    Feng XJ, Liu SX, Wu C, Kang PP, Liu QJ, Hao J, Li HB, Li F, Zhang YJ, Fu XH, Zhang SB, Zuo LF. The PTEN/PI3K/Akt signaling pathway mediates HMGB1-induced cell proliferation by regulating the NF-κB/cyclin D1 pathway in mouse mesangial cells. Am J Physiol Cell Physiol. 2014;306:C1119–28.PubMedCrossRefGoogle Scholar
  212. 212.
    Das UN. Interaction (a) between essential fatty acids, eicosanoids, cytokines, growth factors, and free radicals: relevance to new therapeutic strategies in rheumatoid arthritis and other collagen vascular diseases. Prostaglandins Leukot Essent Fatty Acids. 1991;44:201–10.PubMedCrossRefGoogle Scholar
  213. 213.
    Das UN. Beneficial effect of eicosapentaenoic acid and docosahexaenoic acid in the management of systemic lupus erythematosus and its relationship to the cytokine network. Prostaglandins Leukot Essent Fatty Acids. 1994;51:207–13.PubMedCrossRefGoogle Scholar
  214. 214.
    Das UN. Oxidants, anti-oxidants, essential fatty acids, eicosanoids, cytokines, gene/oncogene expression and apoptosis in systemic lupus erythematosus. J Assoc Physicians India. 1998;46:630–4.PubMedGoogle Scholar
  215. 215.
    Sravan Kumar G, Das UN, Vijay Kumar K, Madhavi DNP, Tan BKH. Effect of n-6 and n-3 fatty acids on the proliferation and secretion of TNF and IL-2 by human lymphocytes in vitro. Nutrition Res. 1992;12:815–23.CrossRefGoogle Scholar
  216. 216.
    Sravan Kumar G, Das UN. Effect of prostaglandins and their precursors on the proliferation of human lymphocytes and their secretion of tumor necrosis factor and various interleukins. Prostaglandins Leukot Essent Fatty Acids. 1994;50:331–4.CrossRefGoogle Scholar
  217. 217.
    Madhavi N, Das UN, et al. Suppression of human T cell growth in vitro by cis-unsaturated fatty acids: relationship to free radicals and lipid peroxidation. Prostaglandins Leukot Essent Fatty Acids. 1994;51:33–40.PubMedCrossRefGoogle Scholar
  218. 218.
    Krishna Mohan I, Das UN. Oxidant stress, anti-oxidants and essential fatty acids in systemic lupus erythematosus. Prostaglandins Leukot Essent Fatty Acids. 1997;56:193–8.CrossRefGoogle Scholar
  219. 219.
    Das UN. Lipoxins, resolvins, protectins, maresins and nitrolipids: connecting lipids, inflammation, and cardiovascular disease risk. Curr Cardiovasc Risk Rep. 2010;4:24–31.CrossRefGoogle Scholar
  220. 220.
    Das UN. Lipoxins as biomarkers of lupus and other inflammatory conditions. Lipids Health Dis. 2011;10:76.PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Das UN. Radiation resistance, invasiveness and metastasis are inflammatory events that could be suppressed by lipoxin a(4). Prostaglandins Leukot Essent Fatty Acids. 2012;86:3–11.PubMedCrossRefGoogle Scholar
  222. 222.
    Das UN. Lipoxins, resolvins, protectins, maresins and nitrolipids and their clinical implications with specific reference to cancer: part I. Clin Lipidol. 2013;8:437–63.CrossRefGoogle Scholar
  223. 223.
    Das UN. Lipoxins, resolvins, protectins, maresins and nitrolipids and their clinical implications with specific reference to diabetes mellitus and other diseases: part II. Clin Lipidol. 2013;8:465–80.CrossRefGoogle Scholar
  224. 224.
    Krishnamoorthy N, Burkett PR, Dalli J, Abdulnour RE, Colas R, Ramon S, Phipps RP, Petasis NA, Kuchroo VK, Serhan CN, Levy BD. Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation. J Immunol. 2015;194:863–7.PubMedCrossRefGoogle Scholar
  225. 225.
    Serhan CN, Chiang N, Dalli J, Levy BD. Lipid mediators in the resolution of inflammation. Cold Spring Harb Perspect Biol. 2014;7:a016311.PubMedCrossRefGoogle Scholar
  226. 226.
    Faragó N, Fehér LZ, Kitajka K, Das UN, Puskás LG. MicroRNA profile of polyunsaturated fatty acid treated glioma cells reveal apoptosis-specific expression changes. Lipids Health Dis. 2011;10:173.PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Siddesha JM, Valente AJ, Yoshida T, Sakamuri SS, Delafontaine P, Iba H, Noda M, Chandrasekar B. Docosahexaenoic acid reverses angiotensin II-induced RECK suppression and cardiac fibroblast migration. Cell Signal. 2014;26:933–41.PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Ghosh-Choudhury T, Mandal CC, Woodruff K, St Clair P, Fernandes G, Choudhury GG, Ghosh-Choudhury N. Fish oil targets PTEN to regulate NFkappaB for downregulation of anti-apoptotic genes in breast tumor growth. Breast Cancer Res Treat. 2009;118:213–28.PubMedCrossRefGoogle Scholar
  229. 229.
    Vasudevan A, Yu Y, Banerjee S, Woods J, Farhana L, Rajendra SG, Patel A, Dyson G, Levi E, Maddipati KR, Majumdar AP, Nangia-Makker P. Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer. Cancer Prev Res (Phila). 2014;7:1138–48.CrossRefGoogle Scholar
  230. 230.
    Das UN. Essential fatty acids and their metabolites as modulators of stem cell biology. Agro Food Ind Hi Tech. 2010;21:2–3.Google Scholar
  231. 231.
    Das UN. Influence of polyunsaturated fatty acids and their metabolites on stem cell biology. Nutrition. 2011;27:21–5.PubMedCrossRefGoogle Scholar
  232. 232.
    Das UN. Essential fatty acids and their metabolites as modulators of stem cell biology with reference to inflammation, cancer and metastasis. Cancer Metastasis Rev. 2011;30:311–24.PubMedCrossRefGoogle Scholar
  233. 233.
    Fillmore N, Huqi A, Jaswal JS, Mori J, Paulin R, Haromy A, Onay-Besikci A, Ionescu L, Thébaud B, Michelakis E, Lopaschuk GD. Effect of fatty acids on human bone marrow mesenchymal stem cell energy metabolism and survival. PLoS One. 2015;10:e0120257.PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Katakura M, Hashimoto M, Okui T, Shahdat HM, Matsuzaki K, Shido O. Omega-3 polyunsaturated fatty acids enhance neuronal differentiation in cultured rat neural stem cells. Stem Cells Int. 2013;2013:490476.PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Lee SH, Kim MH, Han HJ. Arachidonic acid potentiates hypoxia-induced VEGF expression in mouse embryonic stem cells: involvement of notch, Wnt, and HIF-1alpha. Am J Physiol Cell Physiol. 2009;297:C207–16.PubMedCrossRefGoogle Scholar
  236. 236.
    Uversky VN, et al. Pathological unfoldomics of uncontrolled chaos: intrinsically disordered proteins and human diseases. Chem Rev. 2014;114:6844–79.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, Part of Springer Nature 2020

Authors and Affiliations

  • Undurti N. Das
    • 1
    • 2
  1. 1.BioScience Research Centre and Department of MedicineGVP Medical College and HospitalVisakhapatnamIndia
  2. 2.UND Life SciencesBattle GroundUSA

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