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http://dx.doi.org/10.5483/BMBRep.2016.49.11.120

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)
Publication Information
BMB Reports / v.49, no.11, 2016 , pp. 598-606 More about this Journal
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
ARF; ARF knockout mice; Cancer; Posttranslational regulation; Senescence; Tumorigenesis; Ubiquitination;
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1 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   DOI
2 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
3 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   DOI
4 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   DOI
5 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   DOI
6 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
7 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   DOI
8 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
9 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   DOI
10 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   DOI
11 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   DOI
12 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   DOI
13 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   DOI
14 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   DOI
15 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
16 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   DOI
17 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   DOI
18 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   DOI
19 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
20 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   DOI
21 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   DOI
22 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   DOI
23 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
24 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   DOI
25 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   DOI
26 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
27 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   DOI
28 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   DOI
29 Schmitt CA (2003) Senescence, apoptosis and therapy--cutting the lifelines of cancer. Nat Rev Cancer 3, 286-295   DOI
30 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   DOI
31 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   DOI
32 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   DOI
33 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   DOI
34 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   DOI
35 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   DOI
36 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   DOI
37 Rizos H, Puig S, Badenas C et al (2001) A melanoma-associated germline mutation in exon 1beta inactivates p14ARF. Oncogene 20, 5543-5547   DOI
38 Hewitt C, Lee Wu C, Evans G et al (2002) Germline mutation of ARF in a melanoma kindred. Hum Mol Genet 11, 1273-1279   DOI
39 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   DOI
40 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
41 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   DOI
42 Haupt Y, Maya R, Kazaz A and Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387, 296-299   DOI
43 Moore L, Venkatachalam S, Vogel H et al (2003) Coopera-tivity of p19ARF, Mdm2, and p53 in murine tumorigenesis. Oncogene 22, 7831-7837   DOI
44 Weber JD, Jeffers JR, Rehg JE et al (2000) p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev 14, 2358-2365   DOI
45 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   DOI
46 Kim WY and Sharpless NE (2006) The regulation of INK4/ARF in cancer and aging. Cell 127, 265-275   DOI
47 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   DOI
48 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   DOI
49 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   DOI
50 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   DOI
51 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   DOI
52 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   DOI
53 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   DOI
54 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   DOI
55 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   DOI
56 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   DOI
57 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   DOI
58 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   DOI
59 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   DOI
60 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   DOI
61 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   DOI
62 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   DOI
63 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   DOI
64 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   DOI
65 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   DOI
66 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   DOI
67 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   DOI
68 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   DOI
69 Leduc C, Claverie P, Eymin B et al (2006) p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation. Oncogene 25, 4147-4154   DOI
70 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   DOI
71 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   DOI
72 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   DOI
73 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   DOI
74 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   DOI
75 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   DOI
76 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   DOI
77 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   DOI
78 Sharpless NE, Bardeesy N, Lee KH et al (2001) Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86-91   DOI
79 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   DOI
80 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   DOI
81 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   DOI
82 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   DOI
83 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   DOI
84 Chen L and Chen J (2003) MDM2-ARF complex regulates p53 sumoylation. Oncogene 22, 5348-5357   DOI
85 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   DOI
86 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   DOI
87 Eymin B, Karayan L, Seite P et al (2001) Human ARF binds E2F1 and inhibits its transcriptional activity. Oncogene 20, 1033-1041   DOI