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Regulation of apoptosis by PML and the PML-NBs

Oncogene volume 27, pages 6299–6312 (2008)Cite this article

Abstract

The promyelocytic leukemia protein (PML) is a tumor suppressor identified in acute PML and implicated in the pathogenesis of a variety of tumors. PML is essential for the proper assembly of a nuclear macromolecular structure called the PML nuclear body (PML-NB). PML and PML-NBs are functionally promiscuous and have been associated with the regulation of several cellular functions. Above all these is the control of apoptosis, a function of PML whose physiological relevance is emphasized by in vivo studies that demonstrate that mice and cells lacking Pml are resistant to a vast variety of apoptotic stimuli. The function of PML in regulating apoptosis is not confined to a linear pathway; rather, PML works within a regulatory network that finely tunes various apoptotic pathways, depending on the cellular context and the apoptotic stimulus. Here, we will summarize earlier and recent advances on the molecular mechanisms by which PML regulates apoptosis and the implication of these findings for cancer pathogenesis.

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References

  • Alsheich-Bartok O, Haupt S, Alkalay-Snir I, Saito S, Appella E, Haupt Y . (2008). PML enhances the regulation of p53 by CK1 in response to DNA damage. Oncogene 27: 3653–3661.

    Article  CAS  PubMed  Google Scholar 

  • Bellodi C, Kindle K, Bernassola F, Cossarizza A, Dinsdale D, Melino G et al. (2006). A cytoplasmic PML mutant inhibits p53 function. Cell Cycle 5: 2688–2692.

    Article  CAS  PubMed  Google Scholar 

  • Bernardi R, Pandolfi PP . (2003). Role of PML and the PML-nuclear body in the control of programmed cell death. Oncogene 22: 9048–9057.

    Article  CAS  PubMed  Google Scholar 

  • Bernardi R, Pandolfi PP . (2007). Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol 8: 1006–1016.

    Article  CAS  PubMed  Google Scholar 

  • Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP . (2004). PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol 6: 665–672.

    Article  CAS  PubMed  Google Scholar 

  • Best JL, Ganiatsas S, Agarwal S, Changou A, Salomoni P, Shirihai O et al. (2002). SUMO-1 protease-1 regulates gene transcription through PML. Mol Cell 10: 843–855.

    Article  CAS  PubMed  Google Scholar 

  • Bischof O, Kirsh O, Pearson M, Itahana K, Pelicci PG, Dejean A . (2002). Deconstructing PML-induced premature senescence. EMBO J 21: 3358–3369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bissonnette N, Hunting DJ . (1998). p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage. Oncogene 16: 3461–3469.

    Article  CAS  PubMed  Google Scholar 

  • Boisvert FM, Hendzel MJ, Bazett-Jones DP . (2000). Promyelocytic leukemia (PML) nuclear bodies are protein structures that do not accumulate RNA. J Cell Biol 148: 283–292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borden KL . (2002). Pondering the promyelocytic leukemia protein (PML) puzzle: possible functions for PML nuclear bodies. Mol Cell Biol 22: 5259–5269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buschbeck M, Uribesalgo I, Ledl A, Gutierrez A, Minucci S, Muller S et al. (2006). PML4 induces differentiation by Myc destabilization. Oncogene 26: 3415–3422.

    Article  PubMed  CAS  Google Scholar 

  • Cao X, Clavijo C, Li X, Lin HH, Chen Y, Shih HM et al. (2008). SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome. Mol Cancer Ther 7: 923–934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carbone R, Pearson M, Minucci S, Pelicci PG . (2002). PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage. Oncogene 21: 1633–1640.

    Article  CAS  PubMed  Google Scholar 

  • Chang HJ, Yoo BC, Kim SW, Lee BL, Kim WH . (2007). Significance of PML and p53 protein as molecular prognostic markers of gallbladder carcinomas. Pathol Oncol Res 13: 326–335.

    Article  CAS  PubMed  Google Scholar 

  • Chang HY, Nishitoh H, Yang X, Ichijo H, Baltimore D . (1998). Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science 281: 1860–1863.

    Article  CAS  PubMed  Google Scholar 

  • Chang KS, Fan YH, Andreeff M, Liu J, Mu ZM . (1995). The PML gene encodes a phosphoprotein associated with the nuclear matrix. Blood 85: 3646–3653.

    Article  CAS  PubMed  Google Scholar 

  • Cho Y, Lee I, Maul GG, Yu E . (1998). A novel nuclear substructure, ND10: distribution in normal and neoplastic human tissues. Int J Mol Med 1: 717–724.

    CAS  PubMed  Google Scholar 

  • Condemine W, Takahashi Y, Zhu J, Puvion-Dutilleul F, Guegan S, Janin A et al. (2006). Characterization of endogenous human promyelocytic leukemia isoforms. Cancer Res 66: 6192–6198.

    Article  CAS  PubMed  Google Scholar 

  • Croxton R, Puto LA, de Belle I, Thomas M, Torii S, Hanaii F et al. (2006). Daxx represses expression of a subset of antiapoptotic genes regulated by nuclear factor-kappaB. Cancer Res 66: 9026–9035.

    Article  CAS  PubMed  Google Scholar 

  • D’Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S et al. (2002). Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat Cell Biol 4: 11–19.

    Article  PubMed  CAS  Google Scholar 

  • Daniel MT, Koken M, Romagne O, Barbey S, Bazarbachi A, Stadler M et al. (1993). PML protein expression in hematopoietic and acute promyelocytic leukemia cells. Blood 82: 1858–1867.

    Article  CAS  PubMed  Google Scholar 

  • de Stanchina E, Querido E, Narita M, Davuluri RV, Pandolfi PP, Ferbeyre G et al. (2004). PML is a direct p53 target that modulates p53 effector functions. Mol Cell 13: 523–535.

    Article  CAS  PubMed  Google Scholar 

  • de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A . (1991). The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66: 675–684.

    Article  CAS  PubMed  Google Scholar 

  • Dellaire G, Bazett-Jones DP . (2004). PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. Bioessays 26: 963–977.

    Article  CAS  PubMed  Google Scholar 

  • Dellaire G, Ching RW, Ahmed K, Jalali F, Tse KC, Bristow RG et al. (2006). Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR. J Cell Biol 175: 55–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emelyanov AV, Kovac CR, Sepulveda MA, Birshtein BK . (2002). The interaction of Pax5 (BSAP) with Daxx can result in transcriptional activation in B cells. J Biol Chem 277: 11156–11164.

    Article  CAS  PubMed  Google Scholar 

  • Everett RD, Meredith M, Orr A, Cross A, Kathoria M, Parkinson J . (1997). A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. EMBO J 16: 1519–1530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferbeyre G, de Stanchina E, Querido E, Baptiste N, Prives C, Lowe SW . (2000). PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 14: 2015–2027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fogal V, Gostissa M, Sandy P, Zacchi P, Sternsdorf T, Jensen K et al. (2000). Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J 19: 6185–6195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu C, Ahmed K, Ding H, Ding X, Lan J, Yang Z et al. (2005). Stabilization of PML nuclear localization by conjugation and oligomerization of SUMO-3. Oncogene 24: 5401–5413.

    Article  CAS  PubMed  Google Scholar 

  • Guo A, Salomoni P, Luo J, Shih A, Zhong S, Gu W et al. (2000). The function of PML in p53-dependent apoptosis. Nat Cell Biol 2: 730–736.

    Article  CAS  PubMed  Google Scholar 

  • Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES . (2002). Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. J Biol Chem 277: 13430–13437.

    Article  CAS  PubMed  Google Scholar 

  • Gurrieri C, Capodieci P, Bernardi R, Scaglioni PP, Nafa K, Rush LJ et al. (2004a). Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J Natl Cancer Inst 96: 269–279.

    Article  CAS  PubMed  Google Scholar 

  • Gurrieri C, Nafa K, Merghoub T, Bernardi R, Capodieci P, Biondi A et al. (2004b). Mutations of the PML tumor suppressor gene in acute promyelocytic leukemia. Blood 103: 2358–2362.

    Article  CAS  PubMed  Google Scholar 

  • Halazonetis TD, Gorgoulis VG, Bartek J . (2008). An oncogene-induced DNA damage model for cancer development. Science 319: 1352–1355.

    Article  CAS  PubMed  Google Scholar 

  • Hayakawa F, Privalsky ML . (2004). Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. Cancer Cell 5: 389–401.

    Article  CAS  PubMed  Google Scholar 

  • Hayashi N, Shirakura H, Uehara T, Nomura Y . (2006). Relationship between SUMO-1 modification of caspase-7 and its nuclear localization in human neuronal cells. Neurosci Lett 397: 5–9.

    Article  CAS  PubMed  Google Scholar 

  • Hofmann TG, Moller A, Sirma H, Zentgraf H, Taya Y, Droge W et al. (2002). Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat Cell Biol 4: 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Hofmann TG, Will H . (2003). Body language: the function of PML nuclear bodies in apoptosis regulation. Cell Death Differ 10: 1290–1299.

    Article  CAS  PubMed  Google Scholar 

  • Imai Y, Kimura T, Murakami A, Yajima N, Sakamaki K, Yonehara S . (1999). The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis. Nature 398: 777–785.

    Article  CAS  PubMed  Google Scholar 

  • Ishov AM, Sotnikov AG, Negorev D, Vladimirova OV, Neff N, Kamitani T et al. (1999). PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1. J Cell Biol 147: 221–234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y et al. (2008). PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453: 1072–1078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen K, Shiels C, Freemont PS . (2001). PML protein isoforms and the RBCC/TRIM motif. Oncogene 20: 7223–7233.

    Article  CAS  PubMed  Google Scholar 

  • Kakizuka A, Miller Jr WH, Umesono K, Warrell Jr RP, Frankel SR, Murty VV et al. (1991). Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 66: 663–674.

    Article  CAS  PubMed  Google Scholar 

  • Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A . (2000). Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12: 611–620.

    Article  CAS  PubMed  Google Scholar 

  • Komura N, Asakawa M, Umezawa K, Segawa K . (2007). Tyrosine kinase inhibitor, methyl 2,5-dihydromethylcinnimate, induces PML nuclear body formation and apoptosis in tumor cells. Exp Cell Res 313: 2753–2765.

    Article  CAS  PubMed  Google Scholar 

  • Krieghoff E, Milovic-Holm K, Hofmann TG . (2007). FLASH meets nuclear bodies: CD95 receptor signals via a nuclear pathway. Cell Cycle 6: 771–775.

    Article  CAS  PubMed  Google Scholar 

  • Kurki S, Latonen L, Laiho M . (2003). Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization. J Cell Sci 116: 3917–3925.

    Article  CAS  PubMed  Google Scholar 

  • Lackinger D, Kaina B . (2000). Primary mouse fibroblasts deficient for c-Fos, p53 or for both proteins are hypersensitive to UV light and alkylating agent-induced chromosomal breakage and apoptosis. Mutat Res 457: 113–123.

    Article  CAS  PubMed  Google Scholar 

  • Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L et al. (2008). Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol 10: 547–555.

    Article  CAS  PubMed  Google Scholar 

  • Lassus P, Opitz-Araya X, Lazebnik Y . (2002). Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science 297: 1352–1354.

    Article  CAS  PubMed  Google Scholar 

  • Le XF, Vallian S, Mu ZM, Hung MC, Chang KS . (1998). Recombinant PML adenovirus suppresses growth and tumorigenicity of human breast cancer cells by inducing G1 cell cycle arrest and apoptosis. Oncogene 16: 1839–1849.

    Article  CAS  PubMed  Google Scholar 

  • Lehembre F, Muller S, Pandolfi PP, Dejean A . (2001). Regulation of Pax3 transcriptional activity by SUMO-1-modified PML. Oncogene 20: 1–9.

    Article  CAS  PubMed  Google Scholar 

  • Li H, Leo C, Zhu J, Wu X, O’Neil J, Park EJ et al. (2000). Sequestration and inhibition of Daxx-mediated transcriptional repression by PML. Mol Cell Biol 20: 1784–1796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J et al. (2002). Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416: 648–653.

    Article  CAS  PubMed  Google Scholar 

  • Lin HK, Bergmann S, Pandolfi PP . (2004). Cytoplasmic PML function in TGF-beta signalling. Nature 431: 205–211.

    Article  CAS  PubMed  Google Scholar 

  • Liu JH, Mu ZM, Chang KS . (1995). PML suppresses oncogenic transformation of NIH/3T3 cells by activated neu. J Exp Med 181: 1965–1973.

    Article  CAS  PubMed  Google Scholar 

  • Louria-Hayon I, Grossman T, Sionov RV, Alsheich O, Pandolfi PP, Haupt Y . (2003). The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation. J Biol Chem 278: 33134–33141.

    Article  CAS  PubMed  Google Scholar 

  • McNally BA, Trgovcich J, Maul GG, Liu Y, Zheng P . (2008). A role for cytoplasmic PML in cellular resistance to viral infection. PLoS ONE 3: e2277.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Meinecke I, Cinski A, Baier A, Peters MA, Dankbar B, Wille A et al. (2007). Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Proc Natl Acad Sci USA 104: 5073–5078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melnick A, Licht JD . (1999). Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93: 3167–3215.

    Article  CAS  PubMed  Google Scholar 

  • Michaelson JS, Bader D, Kuo F, Kozak C, Leder P . (1999). Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev 13: 1918–1923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michaelson JS, Leder P . (2003). RNAi reveals anti-apoptotic and transcriptionally repressive activities of DAXX. J Cell Sci 116: 345–352.

    Article  CAS  PubMed  Google Scholar 

  • Milovic-Holm K, Krieghoff E, Jensen K, Will H, Hofmann TG . (2007). FLASH links the CD95 signaling pathway to the cell nucleus and nuclear bodies. EMBO J 26: 391–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moller A, Sirma H, Hofmann TG, Rueffer S, Klimczak E, Droge W et al. (2003). PML is required for homeodomain-interacting protein kinase 2 (HIPK2)-mediated p53 phosphorylation and cell cycle arrest but is dispensable for the formation of HIPK domains. Cancer Res 63: 4310–4314.

    PubMed  Google Scholar 

  • Morgan M, Thorburn J, Pandolfi PP, Thorburn A . (2002). Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms. J Cell Biol 157: 975–984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mu ZM, Le XF, Vallian S, Glassman AB, Chang KS . (1997). Stable overexpression of PML alters regulation of cell cycle progression in HeLa cells. Carcinogenesis 18: 2063–2069.

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay D, Ayaydin F, Kolli N, Tan SH, Anan T, Kametaka A et al. (2006). SUSP1 antagonizes formation of highly SUMO2/3-conjugated species. J Cell Biol 174: 939–949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nguyen LA, Pandolfi PP, Aikawa Y, Tagata Y, Ohki M, Kitabayashi I . (2005). Physical and functional link of the leukemia-associated factors AML1 and PML. Blood 105: 292–300.

    Article  CAS  PubMed  Google Scholar 

  • Pandolfi PP, Grignani F, Alcalay M, Mencarelli A, Biondi A, LoCoco F et al. (1991). Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene 6: 1285–1292.

    CAS  PubMed  Google Scholar 

  • Paroni G, Henderson C, Schneider C, Brancolini C . (2002). Caspase-2 can trigger cytochrome C release and apoptosis from the nucleus. J Biol Chem 277: 15147–15161.

    Article  CAS  PubMed  Google Scholar 

  • Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S et al. (2000). PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406: 207–210.

    Article  CAS  PubMed  Google Scholar 

  • Petrie K, Zelent A . (2008). Marked for death. Nat Cell Biol 10: 507–509.

    Article  CAS  PubMed  Google Scholar 

  • Piazza F, Gurrieri C, Pandolfi PP . (2001). The theory of APL. Oncogene 20: 7216–7222.

    Article  CAS  PubMed  Google Scholar 

  • Quignon F, De Bels F, Koken M, Feunteun J, Ameisen JC, de The H . (1998). PML induces a novel caspase-independent death process. Nat Genet 20: 259–265.

    Article  CAS  PubMed  Google Scholar 

  • Reineke EL, Lam M, Liu Q, Liu Y, Stanya KJ, Chang KS et al. (2008). Degradation of the tumor suppressor PML by Pin1 contributes to the cancer phenotype of breast cancer MDA-MB-231 cells. Mol Cell Biol 28: 997–1006.

    Article  CAS  PubMed  Google Scholar 

  • Salomoni P, Bernardi R, Bergmann S, Changou A, Tuttle S, Pandolfi PP . (2005). The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage. Blood 105: 3686–3690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanchez-Pulido L, Valencia A, Rojas AM . (2007). Are promyelocytic leukaemia protein nuclear bodies a scaffold for caspase-2 programmed cell death? Trends Biochem Sci 32: 400–406.

    Article  CAS  PubMed  Google Scholar 

  • Scaglioni PP, Yung TM, Cai LF, Erdjument-Bromage H, Kaufman AJ, Singh B et al. (2006). A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 126: 269–283.

    Article  CAS  PubMed  Google Scholar 

  • Seeler JS, Dejean A . (2003). Nuclear and unclear functions of SUMO. Nat Rev Mol Cell Biol 4: 690–699.

    Article  CAS  PubMed  Google Scholar 

  • Seker H, Rubbi C, Linke SP, Bowman ED, Garfield S, Hansen L et al. (2003). UV-C-induced DNA damage leads to p53-dependent nuclear trafficking of PML. Oncogene 22: 1620–1628.

    Article  CAS  PubMed  Google Scholar 

  • Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP . (2006). The mechanisms of PML-nuclear body formation. Mol Cell 24: 331–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith ML, Fornace Jr AJ . (1997). p53-mediated protective responses to UV irradiation. Proc Natl Acad Sci USA 94: 12255–12257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stadler M, Chelbi-Alix MK, Koken MH, Venturini L, Lee C, Saib A et al. (1995). Transcriptional induction of the PML growth suppressor gene by interferons is mediated through an ISRE and a GAS element. Oncogene 11: 2565–2573.

    CAS  PubMed  Google Scholar 

  • Tagata Y, Yoshida H, Nguyen LA, Kato H, Ichikawa H, Tashiro F et al. (2008). Phosphorylation of PML is essential for activation of C/EBP epsilon and PU.1 to accelerate granulocytic differentiation. Leukemia 22: 273–280.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi Y, Lallemand-Breitenbach V, Zhu J, de The H . (2004). PML nuclear bodies and apoptosis. Oncogene 23: 2819–2824.

    Article  CAS  PubMed  Google Scholar 

  • Tan JA, Sun Y, Song J, Chen Y, Krontiris TG, Durrin LK . (2008). Sumo conjugation to the MAR-binding protein, special at-rich sequence binding protein-1, targets it to promyelocytic nuclear bodies where it undergoes caspase cleavage. J Biol Chem 283: 18124–18134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang J, Xie W, Yang X . (2005). Association of caspase-2 with the promyelocytic leukemia protein nuclear bodies. Cancer Biol Ther 4: 645–649.

    Article  CAS  PubMed  Google Scholar 

  • Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG et al. (2008). RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol 10: 538–546.

    Article  CAS  PubMed  Google Scholar 

  • Torii S, Egan DA, Evans RA, Reed JC . (1999). Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs). EMBO J 18: 6037–6049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A et al. (2000). Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288: 870–874.

    Article  CAS  PubMed  Google Scholar 

  • Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP . (2006). Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441: 523–527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waldman T, Lengauer C, Kinzler KW, Vogelstein B . (1996). Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381: 713–716.

    Article  CAS  PubMed  Google Scholar 

  • Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R et al. (1998). PML is essential for multiple apoptotic pathways. Nat Genet 20: 266–272.

    Article  CAS  PubMed  Google Scholar 

  • Wei X, Yu ZK, Ramalingam A, Grossman SR, Yu JH, Bloch DB et al. (2003). Physical and functional interactions between PML and MDM2. J Biol Chem 278: 29288–29297.

    Article  CAS  PubMed  Google Scholar 

  • Wu WS, Xu ZX, Hittelman WN, Salomoni P, Pandolfi PP, Chang KS . (2003). Promyelocytic leukemia protein sensitizes tumor necrosis factor alpha-induced apoptosis by inhibiting the NF-kappaB survival pathway. J Biol Chem 278: 12294–12304.

    Article  CAS  PubMed  Google Scholar 

  • Yang S, Jeong JH, Brown AL, Lee CH, Pandolfi PP, Chung JH et al. (2006). Promyelocytic leukemia activates Chk2 by mediating Chk2 autophosphorylation. J Biol Chem 281: 26645–26654.

    Article  CAS  PubMed  Google Scholar 

  • Yang S, Kuo C, Bisi JE, Kim MK . (2002). PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nat Cell Biol 4: 865–870.

    Article  CAS  PubMed  Google Scholar 

  • Yang X, Khosravi-Far R, Chang HY, Baltimore D . (1997). Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 89: 1067–1076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshida H, Ichikawa H, Tagata Y, Katsumoto T, Ohnishi K, Akao Y et al. (2007). PML-RARA inhibits PML IV enhancement of PU.1-induced C/EBP{epsilon} expression in myeloid differentiation. Mol Cell Biol 27: 273–280.

    Article  CAS  Google Scholar 

  • Zhong S, Muller S, Ronchetti S, Freemont PS, Dejean A, Pandolfi PP . (2000a). Role of SUMO-1-modified PML in nuclear body formation. Blood 95: 2748–2752.

    Article  CAS  PubMed  Google Scholar 

  • Zhong S, Salomoni P, Pandolfi PP . (2000b). The transcriptional role of PML and the nuclear body. Nat Cell Biol 2: E85–E90.

    Article  CAS  PubMed  Google Scholar 

  • Zhong S, Salomoni P, Ronchetti S, Guo A, Ruggero D, Pandolfi PP . (2000c). Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. J Exp Med 191: 631–640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu H, Wu L, Maki CG . (2003). MDM2 and promyelocytic leukemia antagonize each other through their direct interaction with p53. J Biol Chem 278: 49286–49292.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all past and present members of the Pandolfi lab at Memorial Sloan-Kettering Cancer Center and at Beth Israel Deaconess Medical Center for useful discussion and support. This work is supported by the NCI, through grants to PPP and RB.

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  1. R Bernardi

    Present address: 3Current address: Molecular Oncology Program, San Raffaele Institute, via Olgettina 58, 20132 Milan, Italy,

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  1. Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA, USA

    R Bernardi, A Papa & P P Pandolfi

  2. Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    R Bernardi, A Papa & P P Pandolfi

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Bernardi, R., Papa, A. & Pandolfi, P. Regulation of apoptosis by PML and the PML-NBs. Oncogene 27, 6299–6312 (2008). https://doi.org/10.1038/onc.2008.305

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