The role of PML ubiquitination in human malignancies

Journal of Biomedical Science

Wei-Chien Yuan²  Yu-Ru Lee¹  Ruey-Hwa Chen² 

[1] Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan;Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan

关键词: Tumor suppression;    Ubiquitination;    PML;   

Others  :  824573
DOI  :  10.1186/1423-0127-19-81

 received in 2012-08-22, accepted in 2012-08-27,  发布年份 2012

【 摘 要 】

Tumor suppressors are frequently downregulated in human cancers and understanding of the mechanisms through which tumor cells restrict the expression of tumor suppressors is important for the prognosis and intervention of diseases. The promyelocytic leukemia (PML) protein plays a critical role in multiple tumor suppressive functions, such as growth inhibition, apoptosis, replicative senescence, suppression of oncogenic transformation, and inhibition of migration and angiogenesis. These tumor suppression functions are recapitulated in several mouse models. The expression of PML protein is frequently downregulated in diverse types of human tumors and this downregulation often correlates with tumor progression. Recent evidence has emerged that PML is aberrantly degraded in various types of tumors through ubiquitination-dependent mechanisms. Here, we summarize our current understanding of the PML ubiquitination/degradation pathways in human cancers. We point out that multiple pathways lead to PML ubiquitination and degradation. Furthermore, the PML ubiquitination processes are often dependent on other types of posttranslational modifications, such as phosphorylation, prolylisomerization, and sumoylation. Such feature indicates a highly regulated nature of PML ubiquitination in different cellular conditions and cell contexts, thus providing many avenues of opportunity to intervene PML ubiquitination pathways. We discuss the potential of targeting PML ubiquitination pathways for anti-cancer therapeutic strategies.

【 授权许可】

   
2012 Chen et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]de The H, Chomienne C, Lanotte M, Degos L, Dejean A: The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 1990, 347:558-561.
• [2]Fagioli M, Alcalay M, Pandolfi PP, Venturini L, Mencarelli A, Simeone A, Acampora D, Grignani F, Pelicci PG: Alternative splicing of PML transcripts predicts coexpression of several carboxy-terminally different protein isoforms. Oncogene 1992, 7:1083-1091.
• [3]Jensen K, Shiels C, Freemont PS: PML protein isoforms and the RBCC/TRIM motif. Oncogene 2001, 20:7223-7233.
• [4]Bernardi R, Pandolfi PP: Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol 2007, 8:1006-1016.
• [5]Lallemand-Breitenbach V, de The H: PML nuclear bodies. Cold Spring Harb Perspect Biol 2010, 2:a000661.
• [6]Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP: The mechanisms of PML-nuclear body formation. Mol Cell 2006, 24:331-339.
• [7]Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C, Grosveld F, Pandolfi PP: Role of PML in cell growth and the retinoic acid pathway. Science 1998, 279:1547-1551.
• [8]Scaglioni PP, Yung TM, Cai LF, Erdjument-Bromage H, Kaufman AJ, Singh B, Teruya-Feldstein J, Tempst P, Pandolfi PP: A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 2006, 126:269-283.
• [9]Guo A, Salomoni P, Luo J, Shih A, Zhong S, Gu W, Pandolfi PP: The function of PML in p53-dependent apoptosis. Nat Cell Biol 2000, 2:730-736.
• [10]Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R, Pandolfi PP: PML is essential for multiple apoptotic pathways. Nat Genet 1998, 20:266-272.
• [11]Bernardi R, Pandolfi PP: Role of PML and the PML-nuclear body in the control of programmed cell death. Oncogene 2003, 22:9048-9057.
• [12]Takahashi Y, Lallemand-Breitenbach V, Zhu J, de The H: PML nuclear bodies and apoptosis. Oncogene. 2004, 23:2819-2824.
• [13]Lin DY, Huang YS, Jeng JC, Kuo HY, Chang CC, Chao TT, Ho CC, Chen YC, Lin TP, Fang HI, Hung CC, Suen CS, Hwang MJ, Chang KS, Maul GG, Shih HM: Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol Cell 2006, 24:341-354.
• [14]Croxton R, Puto LA, de Belle I, Thomas M, Torii S, Hanaii F, Cuddy M, Reed JC: Daxx represses expression of a subset of antiapoptotic genes regulated by nuclear factor-kappaB. Cancer Res 2006, 66:9026-9035.
• [15]Giorgi C, Ito K, Lin HK, Santangelo C, Wieckowski MR, Lebiedzinska M, Bononi A, Bonora M, Duszynski J, Bernardi R, Rizzuto R, Tacchetti C, Pinton P, Pandolfi PP: PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 2010, 330:1247-1251.
• [16]Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi PP, Pelicci PG: PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 2000, 406:207-210.
• [17]Bischof O, Kirsh O, Pearson M, Itahana K, Pelicci PG, Dejean A: Deconstructing PML-induced premature senescence. EMBO J 2002, 21:3358-3369.
• [18]Mallette FA, Goumard S, Gaumont-Leclerc MF, Moiseeva O, Ferbeyre G: Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence. Oncogene 2004, 23:91-99.
• [19]Vernier M, Bourdeau V, Gaumont-Leclerc MF, Moiseeva O, Begin V, Saad F, Mes-Masson AM, Ferbeyre G: Regulation of E2Fs and senescence by PML nuclear bodies. Genes Dev 2011, 25:41-50.
• [20]Martin N, Benhamed M, Nacerddine K, Demarque MD, van Lohuizen M, Dejean A, Bischof O: Physical and functional interaction between PML and TBX2 in the establishment of cellular senescence. EMBO J 2012, 31:95-109.
• [21]Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP: Identification of a tumour suppressor network opposing nuclear Akt function. Nature 2006, 441:523-527.
• [22]Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP: PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 2006, 442:779-785.
• [23]Reineke EL, Liu Y, Kao HY: Promyelocytic leukemia protein controls cell migration in response to hydrogen peroxide and insulin-like growth factor-1. J Biol Chem 2010, 285:9485-9492.
• [24]Dellaire G, Bazett-Jones DP: PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. BioEssays 2004, 26:963-977.
• [25]Dellaire G, Ching RW, Dehghani H, Ren Y, Bazett-Jones DP: The number of PML nuclear bodies increases in early S phase by a fission mechanism. J Cell Sci 2006, 119:1026-1033.
• [26]Gurrieri C, Capodieci P, Bernardi R, Scaglioni PP, Nafa K, Rush LJ, Verbel DA, Cordon-Cardo C, Pandolfi PP: Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J Natl Cancer Inst 2004, 96:269-279.
• [27]Wang ZY, Chen Z: Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008, 111:2505-2515.
• [28]Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honore N, Doubeikovsky A, Duprez E, Pandolfi PP, Puvion E, Freemont P, de The H: Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor alpha degradation. J Exp Med 2001, 193:1361-1371.
• [29]Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, Liang WX, Song AX, Lallemand-Breitenbach V, Jeanne M, Zhang QY, Yang HY, Huang QH, Zhou GB, Tong JH, Zhang Y, Wu JH, Hu HY, de The H, Chen SJ, Chen Z: Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 2010, 328:240-243.
• [30]Jeanne M, Lallemand-Breitenbach V, Ferhi O, Koken M, Le Bras M, Duffort S, Peres L, Berthier C, Soilihi H, Raught B, de The H: PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell 2010, 18:88-98.
• [31]Rabellino A, Carter B, Konstantinidou G, Wu SY, Rimessi A, Byers LA, Heymach JV, Girard L, Chiang CM, Teruya-Feldstein J, Scaglioni PP: The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. Cancer Res 2012, 72:2275-2284.
• [32]Sun H, Leverson JD, Hunter T: Conserved function of RNF4 family proteins in eukaryotes: targeting a ubiquitin ligase to SUMOylated proteins. EMBO J 2007, 26:4102-12.
• [33]Geoffroy MC, Jaffray EG, Walker KJ, Hay RT: Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies. Mol Biol Cell 2010, 21:4227-39.
• [34]Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT: RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol 2008, 10:538-46.
• [35]Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, Zhou J, Zhu J, Raught B, de The H: Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol 2008, 10:547-55.
• [36]Lee YR, Yuan WC, Ho HC, Chen CH, Shih HM, Chen RH: The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses. EMBO J 2010, 29:1748-61.
• [37]Yuan WC, Lee YR, Huang SF, Lin YM, Chen TY, Chung HC, Tsai CH, Chen HY, Chiang CT, Lai CK, Lu LT, Chen CH, Gu DL, Pu YS, Jou YS, Lu KP, Hsiao PW, Shih HM, Chen RH: A Cullin3-KLHL20 Ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression. Cancer Cell 2011, 20:214-28.
• [38]Scheffner M, Huibregtse JM, Vierstra RD, Howley PM: The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993, 75:495-505.
• [39]Rotin D, Kumar S: Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 2009, 10:398-409.
• [40]Louria-Hayon I, Alsheich-Bartok O, Levav-Cohen Y, Silberman I, Berger M, Grossman T, Matentzoglu K, Jiang YH, Muller S, Scheffner M, Haupt S, Haupt Y: E6AP promotes the degradation of the PML tumor suppressor. Cell Death Differ 2009, 16:1156-66.
• [41]Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, Palmiter RD, Brinster RL: The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 1985, 318:533-8.
• [42]Langdon WY, Harris AW, Cory S, Adams JM: The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice. Cell 1986, 47:11-8.
• [43]Wolyniec K, Shortt J, de Stanchina E, Levav-Cohen Y, Alsheich-Bartok O, Louria-Hayon I, Corneille V, Kumar B, Woods SJ, Opat S, Johnstone RW, Scott CL, Segal D, Pandolfi PP, Fox S, Strasser A, Jiang YH, Lowe SW, Haupt S, Haupt Y: E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis. Blood 2012, 120:822-32.
• [44]Ahmed K, Gerber DA, Cochet C: Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol 2002, 12:226-30.
• [45]Chang CC, Naik MT, Huang YS, Jeng JC, Liao PH, Kuo HY, Ho CC, Hsieh YL, Lin CH, Huang NJ, Naik NM, Kung CC, Lin SY, Chen RH, Chang KS, Huang TH, Shih HM: Structural and functional roles of Daxx SIM phosphorylation in SUMO paralog-selective binding and apoptosis modulation. Mol Cell 2011, 42:62-74.
• [46]Stehmeier P, Muller S: Phospho-regulated SUMO interaction modules connect the SUMO system to CK2 signaling. Mol Cell 2009, 33:400-9.
• [47]Scaglioni PP, Yung TM, Choi S, Baldini C, Konstantinidou G, Pandolfi PP: CK2 mediates phosphorylation and ubiquitin-mediated degradation of the PML tumor suppressor. Mol Cell Biochem 2008, 316:149-54.
• [48]Lim JH, Liu Y, Reineke E, Kao HY: Mitogen-activated protein kinase extracellular signal-regulated kinase 2 phosphorylates and promotes Pin1 protein-dependent promyelocytic leukemia protein turnover. J Biol Chem 2011, 286:44403-11.
• [49]Reineke EL, Lam M, Liu Q, Liu Y, Stanya KJ, Chang KS, Means AR, Kao HY: Degradation of the tumor suppressor PML by Pin1 contributes to the cancer phenotype of breast cancer MDA-MB-231 cells. Mol Cell Biol 2008, 28:997-1006.
• [50]Sun Y: Overview of approaches for screening for ubiquitin ligase inhibitors. Methods Enzymol 2005, 399:654-63.
• [51]Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Critchley S, Cullis CA, Doucette A, Garnsey JJ, Gaulin JL, Gershman RE, Lublinsky AR, McDonald A, Mizutani H, Narayanan U, Olhava EJ, Peluso S, Rezaei M, Sintchak MD, Talreja T, Thomas MP, Traore T, Vyskocil S, Weatherhead GS, Yu J, Zhang J, et al.: An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 2009, 458:732-6.