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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Dynamics of ARF regulation that control senescence and cancer

  • Ko, Aram (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Han, Su Yeon (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Song, Jaewhan (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University)
  • Received : 2016.07.21
  • Published : 2016.11.30
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Abstract

ARF is an alternative reading frame product of the INK4a/ARF locus, inactivated in numerous human cancers. ARF is a key regulator of cellular senescence, an irreversible cell growth arrest that suppresses tumor cell growth. It functions by sequestering MDM2 (a p53 E3 ligase) in the nucleolus, thus activating p53. Besides MDM2, ARF has numerous other interacting partners that induce either cellular senescence or apoptosis in a p53-independent manner. This further complicates the dynamics of the ARF network. Expression of ARF is frequently disrupted in human cancers, mainly due to epigenetic and transcriptional regulation. Vigorous studies on various transcription factors that either positively or negatively regulate ARF transcription have been carried out. However, recent focus on posttranslational modifications, particularly ubiquitination, indicates wider dynamic controls of ARF than previously known. In this review, we discuss the role and dynamic regulation of ARF in senescence and cancer.

Keywords

References

  1. Kim WY and Sharpless NE (2006) The regulation of INK4/ARF in cancer and aging. Cell 127, 265-275 https://doi.org/10.1016/j.cell.2006.10.003
  2. Gil J and Peters G (2006) Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 7, 667-677 https://doi.org/10.1038/nrm1987
  3. Haupt Y, Maya R, Kazaz A and Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387, 296-299 https://doi.org/10.1038/387296a0
  4. Pomerantz J, Schreiber-Agus N, Liegeois NJ et al (1998) The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 92, 713-723 https://doi.org/10.1016/S0092-8674(00)81400-2
  5. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF and Sherr CJ (1998) Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A 95, 8292-8297 https://doi.org/10.1073/pnas.95.14.8292
  6. Weber JD, Taylor LJ, Roussel MF, Sherr CJ and Bar-Sagi D (1999) Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1, 20-26 https://doi.org/10.1038/8991
  7. Chen D, Shan J, Zhu WG, Qin J and Gu W (2010) Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses. Nature 464, 624-627 https://doi.org/10.1038/nature08820
  8. Ko A, Shin JY, Seo J et al (2012) Acceleration of gastric tumorigenesis through MKRN1-mediated posttranslational regulation of p14ARF. J Natl Cancer Inst 104, 1660-1672 https://doi.org/10.1093/jnci/djs424
  9. Wang X, Zha M, Zhao X et al (2013) Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase. Nat Commun 4, 1551 https://doi.org/10.1038/ncomms2533
  10. DeGregori J, Leone G, Miron A, Jakoi L and Nevins JR (1997) Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci U S A 94, 7245-7250 https://doi.org/10.1073/pnas.94.14.7245
  11. Aslanian A, Iaquinta PJ, Verona R and Lees JA (2004) Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. Genes Dev 18, 1413-1422 https://doi.org/10.1101/gad.1196704
  12. Schmitt CA (2003) Senescence, apoptosis and therapy--cutting the lifelines of cancer. Nat Rev Cancer 3, 286-295 https://doi.org/10.1038/nrc1044
  13. Zindy F, Eischen CM, Randle DH et al (1998) Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 12, 2424-2433 https://doi.org/10.1101/gad.12.15.2424
  14. Bouchard C, Lee S, Paulus-Hock V, Loddenkemper C, Eilers M and Schmitt CA (2007) FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev 21, 2775-2787 https://doi.org/10.1101/gad.453107
  15. Inoue K, Roussel MF and Sherr CJ (1999) Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1. Proc Natl Acad Sci U S A 96, 3993-3998 https://doi.org/10.1073/pnas.96.7.3993
  16. Linggi B, Muller-Tidow C, van de Locht L et al (2002) The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia. Nat Med 8, 743-750 https://doi.org/10.1038/nm726
  17. Sreeramaneni R, Chaudhry A, McMahon M, Sherr CJ and Inoue K (2005) Ras-Raf-Arf signaling critically depends on the Dmp1 transcription factor. Mol Cell Biol 25, 220-232 https://doi.org/10.1128/MCB.25.1.220-232.2005
  18. Zheng Y, Zhao YD, Gibbons M et al (2010) $Tgf{\beta}$ signaling directly induces Arf promoter remodeling by a mechanism involving Smads 2/3 and p38 MAPK. J Biol Chem 285, 35654-35664 https://doi.org/10.1074/jbc.M110.128959
  19. Bulavin DV, Phillips C, Nannenga B et al (2004) Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat Genet 36, 343-350 https://doi.org/10.1038/ng1317
  20. Yoon JH, Choi WI, Jeon BN et al (2014) Human Kruppel-related 3 (HKR3) is a novel transcription activator of alternate reading frame (ARF) gene. J Biol Chem 289, 4018-4031 https://doi.org/10.1074/jbc.M113.526855
  21. Jacobs JJ, Kieboom K, Marino S, DePinho RA and van Lohuizen M (1999) The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164-168 https://doi.org/10.1038/16476
  22. Bracken AP, Kleine-Kohlbrecher D, Dietrich N et al (2007) The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 21, 525-530 https://doi.org/10.1101/gad.415507
  23. Gil J, Bernard D, Martinez D and Beach D (2004) Polycomb CBX7 has a unifying role in cellular lifespan. Nat Cell Biol 6, 67-72 https://doi.org/10.1038/ncb1077
  24. Jacobs JJ, Keblusek P, Robanus-Maandag E et al (2000) Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat Genet 26, 291-299 https://doi.org/10.1038/81583
  25. Cakouros D, Isenmann S, Cooper L et al (2012) Twist-1 induces Ezh2 recruitment regulating histone methylation along the Ink4A/Arf locus in mesenchymal stem cells. Mol Cell Biol 32, 1433-1441 https://doi.org/10.1128/MCB.06315-11
  26. Kuo ML, den Besten W, Bertwistle D, Roussel MF and Sherr CJ (2004) N-terminal polyubiquitination and degradation of the Arf tumor suppressor. Genes Dev 18, 1862-1874 https://doi.org/10.1101/gad.1213904
  27. Eischen CM, Weber JD, Roussel MF, Sherr CJ and Cleveland JL (1999) Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphoma-genesis. Genes Dev 13, 2658-2669 https://doi.org/10.1101/gad.13.20.2658
  28. Wang Y, Blandino G and Givol D (1999) Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin. Oncogene 18, 2643-2649 https://doi.org/10.1038/sj.onc.1202632
  29. Chang BD, Xuan Y, Broude EV et al (1999) Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs. Oncogene 18, 4808-4818 https://doi.org/10.1038/sj.onc.1203078
  30. Moore L, Venkatachalam S, Vogel H et al (2003) Coopera-tivity of p19ARF, Mdm2, and p53 in murine tumorigenesis. Oncogene 22, 7831-7837 https://doi.org/10.1038/sj.onc.1206985
  31. Weber JD, Jeffers JR, Rehg JE et al (2000) p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev 14, 2358-2365 https://doi.org/10.1101/gad.827300
  32. Ha L, Ichikawa T, Anver M et al (2007) ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence. Proc Natl Acad Sci U S A 104, 10968-10973 https://doi.org/10.1073/pnas.0611638104
  33. Eymin B, Karayan L, Seite P et al (2001) Human ARF binds E2F1 and inhibits its transcriptional activity. Oncogene 20, 1033-1041 https://doi.org/10.1038/sj.onc.1204220
  34. Tsuji K, Mizumoto K, Sudo H, Kouyama K, Ogata E and Matsuoka M (2002) p53-independent apoptosis is induced by the p19ARF tumor suppressor. Biochem Biophys Res Commun 295, 621-629 https://doi.org/10.1016/S0006-291X(02)00723-4
  35. Yarbrough WG, Bessho M, Zanation A, Bisi JE and Xiong Y (2002) Human tumor suppressor ARF impedes S-phase progression independent of p53. Cancer Res 62, 1171-1177
  36. Hemmati PG, Gillissen B, von Haefen C et al (2002) Adenovirus-mediated overexpression of p14(ARF) induces p53 and Bax-independent apoptosis. Oncogene 21, 3149-3161 https://doi.org/10.1038/sj.onc.1205458
  37. Eymin B, Leduc C, Coll JL, Brambilla E and Gazzeri S (2003) p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice. Oncogene 22, 1822-1835 https://doi.org/10.1038/sj.onc.1206303
  38. Kelly-Spratt KS, Gurley KE, Yasui Y and Kemp CJ (2004) p19Arf suppresses growth, progression, and metastasis of Hras-driven carcinomas through p53-dependent and -independent pathways. PLoS Biol 2, E242 https://doi.org/10.1371/journal.pbio.0020242
  39. Leduc C, Claverie P, Eymin B et al (2006) p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation. Oncogene 25, 4147-4154 https://doi.org/10.1038/sj.onc.1209446
  40. Itahana K, Bhat KP, Jin A et al (2003) Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol Cell 12, 1151-1164 https://doi.org/10.1016/S1097-2765(03)00431-3
  41. Brady SN, Yu Y, Maggi LB Jr and Weber JD (2004) ARF impedes NPM/B23 shuttling in an Mdm2-sensitive tumor suppressor pathway. Mol Cell Biol 24, 9327-9338 https://doi.org/10.1128/MCB.24.21.9327-9338.2004
  42. Fatyol K and Szalay AA (2001) The p14ARF tumor suppressor protein facilitates nucleolar sequestration of hypoxia-inducible factor-1alpha (HIF-1alpha) and inhibits HIF-1-mediated transcription. J Biol Chem 276, 28421-28429 https://doi.org/10.1074/jbc.M102847200
  43. Kalinichenko VV, Major ML, Wang X et al (2004) Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev 18, 830-850 https://doi.org/10.1101/gad.1200704
  44. Qi Y, Gregory MA, Li Z, Brousal JP, West K and Hann SR (2004) p19ARF directly and differentially controls the functions of c-Myc independently of p53. Nature 431, 712-717 https://doi.org/10.1038/nature02958
  45. Amente S, Gargano B, Diolaiti D, Della Valle G, Lania L and Majello B (2007) p14ARF interacts with N-Myc and inhibits its transcriptional activity. FEBS Lett 581, 821-825 https://doi.org/10.1016/j.febslet.2007.01.062
  46. Rocha S, Garrett MD, Campbell KJ, Schumm K and Perkins ND (2005) Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressor. EMBO J 24, 1157-1169 https://doi.org/10.1038/sj.emboj.7600608
  47. Paliwal S, Pande S, Kovi RC, Sharpless NE, Bardeesy N and Grossman SR (2006) Targeting of C-terminal binding protein (CtBP) by ARF results in p53-independent apoptosis. Mol Cell Biol 26, 2360-2372 https://doi.org/10.1128/MCB.26.6.2360-2372.2006
  48. Xirodimas DP, Chisholm J, Desterro JM, Lane DP and Hay RT (2002) P14ARF promotes accumulation of SUMO-1 conjugated (H)Mdm2. FEBS Lett 528, 207-211 https://doi.org/10.1016/S0014-5793(02)03310-0
  49. Chen L and Chen J (2003) MDM2-ARF complex regulates p53 sumoylation. Oncogene 22, 5348-5357 https://doi.org/10.1038/sj.onc.1206851
  50. Woods YL, Xirodimas DP, Prescott AR, Sparks A, Lane DP and Saville MK (2004) p14 Arf promotes small ubiquitin-like modifier conjugation of Werners helicase. J Biol Chem 279, 50157-50166 https://doi.org/10.1074/jbc.M405414200
  51. Rizos H, Woodruff S and Kefford RF (2005) p14ARF interacts with the SUMO-conjugating enzyme Ubc9 and promotes the sumoylation of its binding partners. Cell Cycle 4, 597-603 https://doi.org/10.4161/cc.4.4.1597
  52. Tago K, Chiocca S and Sherr CJ (2005) Sumoylation induced by the Arf tumor suppressor: a p53-independent function. Proc Natl Acad Sci U S A 102, 7689-7694 https://doi.org/10.1073/pnas.0502978102
  53. Damalas A, Velimezi G, Kalaitzakis A et al (2011) Loss of p14(ARF) confers resistance to heat shock-and oxidative stress-mediated cell death by upregulating beta-catenin. Int J Cancer 128, 1989-1995 https://doi.org/10.1002/ijc.25510
  54. Pan W, Datta A, Adami GR, Raychaudhuri P and Bagchi S (2003) P19ARF inhibits the functions of the HPV16 E7 oncoprotein. Oncogene 22, 5496-5503 https://doi.org/10.1038/sj.onc.1206857
  55. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D and DePinho RA (1996) Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27-37 https://doi.org/10.1016/S0092-8674(00)81079-X
  56. Kamijo T, Bodner S, van de Kamp E, Randle DH and Sherr CJ (1999) Tumor spectrum in ARF-deficient mice. Cancer Res 59, 2217-2222
  57. Sharpless NE, Ramsey MR, Balasubramanian P, Castrillon DH and DePinho RA (2004) The differential impact of p16(INK4a) or p19(ARF) deficiency on cell growth and tumorigenesis. Oncogene 23, 379-385 https://doi.org/10.1038/sj.onc.1207074
  58. Kamijo T, Zindy F, Roussel MF et al (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649-659 https://doi.org/10.1016/S0092-8674(00)80452-3
  59. Sharpless NE, Bardeesy N, Lee KH et al (2001) Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86-91 https://doi.org/10.1038/35092592
  60. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A and van Lohuizen M (1999) Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 13, 2678-2690 https://doi.org/10.1101/gad.13.20.2678
  61. Schmitt CA, McCurrach ME, de Stanchina E, Wallace-Brodeur RR and Lowe SW (1999) INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev 13, 2670-2677 https://doi.org/10.1101/gad.13.20.2670
  62. Chin L, Pomerantz J, Polsky D et al (1997) Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev 11, 2822-2834 https://doi.org/10.1101/gad.11.21.2822
  63. Matheu A, Pantoja C, Efeyan A et al (2004) Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging. Genes Dev 18, 2736-2746 https://doi.org/10.1101/gad.310304
  64. Shintani S, Nakahara Y, Mihara M, Ueyama Y and Matsumura T (2001) Inactivation of the p14(ARF), p15(INK4B) and p16(INK4A) genes is a frequent event in human oral squamous cell carcinomas. Oral Oncol 37, 498-504 https://doi.org/10.1016/S1368-8375(00)00142-1
  65. Konishi N, Nakamura M, Kishi M, Nishimine M, Ishida E and Shimada K (2002) Heterogeneous methylation and deletion patterns of the INK4a/ARF locus within prostate carcinomas. Am J Pathol 160, 1207-1214 https://doi.org/10.1016/S0002-9440(10)62547-3
  66. Sailasree R, Abhilash A, Sathyan KM, Nalinakumari KR, Thomas S and Kannan S (2008) Differential roles of p16INK4A and p14ARF genes in prognosis of oral carcinoma. Cancer Epidemiol Biomarkers Prev 17, 414-420 https://doi.org/10.1158/1055-9965.EPI-07-0284
  67. Ito T, Nishida N, Fukuda Y, Nishimura T, Komeda T and Nakao K (2004) Alteration of the p14(ARF) gene and p53 status in human hepatocellular carcinomas. J Gastroenterol 39, 355-361 https://doi.org/10.1007/s00535-003-1302-9
  68. Berggren P, Kumar R, Sakano S et al (2003) Detecting homozygous deletions in the CDKN2A(p16(INK4a))/ ARF(p14(ARF)) gene in urinary bladder cancer using real-time quantitative PCR. Clin Cancer Res 9, 235-242
  69. Hsu HS, Wang YC, Tseng RC et al (2004) 5' cytosine-phospho-guanine island methylation is responsible for p14ARF inactivation and inversely correlates with p53 overexpression in resected non-small cell lung cancer. Clin Cancer Res 10, 4734-4741 https://doi.org/10.1158/1078-0432.CCR-03-0704
  70. Silva J, Silva JM, Dominguez G et al (2003) Concomitant expression of p16INK4a and p14ARF in primary breast cancer and analysis of inactivation mechanisms. J Pathol 199, 289-297 https://doi.org/10.1002/path.1297
  71. Silva J, Dominguez G, Silva JM et al (2001) Analysis of genetic and epigenetic processes that influence p14ARF expression in breast cancer. Oncogene 20, 4586-4590 https://doi.org/10.1038/sj.onc.1204617
  72. Dominguez G, Carballido J, Silva J et al (2002) p14ARF promoter hypermethylation in plasma DNA as an indicator of disease recurrence in bladder cancer patients. Clin Cancer Res 8, 980-985
  73. Dominguez G, Silva J, Garcia JM et al (2003) Prevalence of aberrant methylation of p14ARF over p16INK4a in some human primary tumors. Mutat Res 530, 9-17 https://doi.org/10.1016/S0027-5107(03)00133-7
  74. Lee M, Sup Han W, Kyoung Kim O et al (2006) Prognostic value of p16INK4a and p14ARF gene hypermethylation in human colon cancer. Pathol Res Pract 202, 415-424 https://doi.org/10.1016/j.prp.2005.11.011
  75. Esteller M, Tortola S, Toyota M et al (2000) Hyper-methylation-associated inactivation of p14(ARF) is in-dependent of p16(INK4a) methylation and p53 mutational status. Cancer Res 60, 129-133
  76. Tannapfel A, Sommerer F, Benicke M et al (2002) Genetic and epigenetic alterations of the INK4a-ARF pathway in cholangiocarcinoma. J Pathol 197, 624-631 https://doi.org/10.1002/path.1139
  77. Tannapfel A, Busse C, Geissler F, Witzigmann H, Hauss J and Wittekind C (2002) INK4a-ARF alterations in liver cell adenoma. Gut 51, 253-258 https://doi.org/10.1136/gut.51.2.253
  78. Iida S, Akiyama Y, Nakajima T et al (2000) Alterations and hypermethylation of the p14(ARF) gene in gastric cancer. Int J Cancer 87, 654-658 https://doi.org/10.1002/1097-0215(20000901)87:5<654::AID-IJC6>3.0.CO;2-P
  79. Zochbauer-Muller S, Fong KM, Virmani AK, Geradts J, Gazdar AF and Minna JD (2001) Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res 61, 249-255
  80. Chaar I, Amara S, Elamine OE et al (2014) Biological significance of promoter hypermethylation of p14/ARF gene: relationships to p53 mutational status in Tunisian population with colorectal carcinoma. Tumour Biol 35, 1439-1449 https://doi.org/10.1007/s13277-013-1198-9
  81. Kasahara T, Bilim V, Hara N, Takahashi K and Tomita Y (2006) Homozygous deletions of the INK4a/ARF locus in renal cell cancer. Anticancer Res 26, 4299-4305
  82. Inda MM, Munoz J, Coullin P et al (2006) High promoter hypermethylation frequency of p14/ARF in supratentorial PNET but not in medulloblastoma. Histopathology 48, 579-587 https://doi.org/10.1111/j.1365-2559.2006.02374.x
  83. Rizos H, Darmanian AP, Holland EA, Mann GJ and Kefford RF (2001) Mutations in the INK4a/ARF melanoma susceptibility locus functionally impair p14ARF. J Biol Chem 276, 41424-41434 https://doi.org/10.1074/jbc.M105299200
  84. Rizos H, Puig S, Badenas C et al (2001) A melanoma-associated germline mutation in exon 1beta inactivates p14ARF. Oncogene 20, 5543-5547 https://doi.org/10.1038/sj.onc.1204728
  85. Hewitt C, Lee Wu C, Evans G et al (2002) Germline mutation of ARF in a melanoma kindred. Hum Mol Genet 11, 1273-1279 https://doi.org/10.1093/hmg/11.11.1273
  86. Randerson-Moor JA, Harland M, Williams S et al (2001) A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet 10, 55-62 https://doi.org/10.1093/hmg/10.1.55
  87. Gazzeri S, Della Valle V, Chaussade L, Brambilla C, Larsen CJ and Brambilla E (1998) The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer. Cancer Res 58, 3926-3931

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