Structure, Organization, and Dynamics of Promyelocytic Leukemia Protein Nuclear Bodies
1998; Elsevier BV; Volume: 63; Issue: 2 Linguagem: Inglês
10.1086/301991
ISSN1537-6605
AutoresMaria Hodges, Catherine Tissot, Kathy Howe, David Grimwade, Paul S. Freemont,
Tópico(s)Antioxidant Activity and Oxidative Stress
ResumoThe interphase nucleus compartmentalizes its components to give rise to a highly organized and tightly controlled environment. Individual chromosomes occupy discrete areas, termed "chromosome territories," that are separated from each other by a channel called the "interchromosomal domain" (reviewed in Lamond and Earnshaw, 1998Lamond AI Earnshaw WC Structure and function in the nucleus.Science. 1998; 280: 547-553Crossref PubMed Scopus (756) Google Scholar). Actively transcribed genes tend to be at the periphery of chromosomal territories, whereas newly made RNA transcripts localize into the interchromosomal domain, where they can undergo further processing and transport. Movement within the nucleus (Ferreira et al., 1997Ferreira J Paolella G Ramos C Lamond AI Spatial organization of large-scale chromatin domains in the nucleus: a magnified view of single chromosome territories.J Cell Biol. 1997; 139: 1597-1610Crossref PubMed Scopus (196) Google Scholar) may permit chromosomes to enter "factories" that contain all the necessary enzymatic machinery for replication (reviewed in Jackson, 1995Jackson DA Nuclear organization: uniting replication foci chromatin domains and chromosome structure.Bioessays. 1995; 17: 587-591Crossref PubMed Scopus (41) Google Scholar). Of the many discrete domains identified throughout the nucleus, the largest are nucleoli, sites of ribosomal RNA synthesis and processing, and sites of preribosomal particle assembly (reviewed in Scheer and Weisenberger, 1994Scheer U Weisenberger D The nucleolus.Curr Opin Cell Biol. 1994; 6: 354-359Crossref PubMed Scopus (183) Google Scholar). Other subnuclear bodies that appear as punctate structures under immunofluorescence (IF) microscopy include various dynamic structures involved in the maintenance and replication of DNA and RNA synthesis, processing, and transport (reviewed in Nickerson et al., 1995Nickerson JA Blencowe BJ Penman S The architectural organization of nuclear metabolism.Int Rev Cytol. 1995; 162A: 67-123PubMed Google Scholar): replication foci, transcript foci, speckled domains, coiled bodies, gems, and promyelocytic leukemia protein (PML) nuclear bodies. Spliceosomal small nuclear (sn) ribonucleoprotein (RNP) components and a subset of non-snRNP splicing factors can be found concentrated in discrete subnuclear domains called "coiled bodies" (Matera and Frey, 1998Matera AG Frey MR Coiled bodies and gems: Janus or Gemini?.Am J Hum Genet. 1998; 63 (in this issue): 317-321Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar [in this issue]). It is becoming increasingly apparent that the nucleus has an organization and contains a number of discrete macromolecular domains that coordinate a variety of nuclear processes. Among these domains is a class of nuclear bodies that were originally described as an autoantigenic target in patients with primary biliary cirrhosis and were termed "multiple nuclear dots" (reviewed in Sternsdorf et al., 1997Sternsdorf T Grotzinger T Jensen K Will H Nuclear dots: actors on many stages.Immunobiology. 1997; 198: 307-331Crossref PubMed Scopus (132) Google Scholar). Several subsequent IF studies showed that the human acute promyelocytic leukemia (APL) proto-oncoprotein PML localizes to these distinctive nuclear dots. They are known by a variety of names, including "PML NBs" (PML nuclear bodies), "ND10" (nuclear domain 10), "Kr bodies," "PODs" (PML oncogenic domains), and "PML bodies" (reviewed in Doucas and Evans, 1996Doucas V Evans RM The PML nuclear compartment and cancer.Biochim Biophys Acta. 1996; 1288: M25-M29PubMed Google Scholar). PML nuclear bodies vary in number between 10 and 30 per nucleus, and they typically have a diameter of between 0.2 and 1μm, although their morphology and size alters during the cell cycle. Analysis with immunoelectron microscopy has shown PML nuclear bodies to be doughnut-like in shape, with a dense fibrillar ring containing PML surrounding a central core that does not contain PML (reviewed in Sternsdorf et al., 1997Sternsdorf T Grotzinger T Jensen K Will H Nuclear dots: actors on many stages.Immunobiology. 1997; 198: 307-331Crossref PubMed Scopus (132) Google Scholar). PML nuclear bodies appear to be nuclear matrix–associated, because they are resistant to RNase and DNase (Ascoli and Maul, 1991Ascoli CA Maul GG Identification of a novel nuclear domain.J Cell Biol. 1991; 112: 785-795Crossref PubMed Scopus (255) Google Scholar) and they are detectable in the residual insoluble fraction, although a soluble nuclear fraction of PML has also been observed (Muller et al., 1998Muller S Matunis MJ Dejean A Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus.EMBO J. 1998; 17: 61-70Crossref PubMed Scopus (568) Google Scholar; M. N. Boddy and P. S. Freemont, unpublished observations). At least 15 components have been identified as part of the PML bodies (see fig. 1); some will be discussed in this review. PML, one of the defining components of PML nuclear bodies, acts as a cell-growth suppressor (Mu et al., 1994Mu ZM Chin KV Liu JH Lozano G Chang KS PML, a growth suppressor disrupted in acute promyelocytic leukemia.Mol Cell Biol. 1994; 14: 6858-6867Crossref PubMed Scopus (292) Google Scholar; Ahn et al., 1995Ahn MJ Langenfeld J Moasser MM Rusch V Dmitrovsky E Growth suppression of transformed human bronchial epithelial cells by all-trans-retinoic acid occurs through specific retinoid receptors.Oncogene. 1995; 11: 2357-2364PubMed Google Scholar; Koken et al., 1995Koken MH Linares-Cruz G Quignon F Viron A Chelbi-Alix MK Sobczak-Thepot J Juhlin L et al.The PML growth-suppressor has an altered expression in human oncogenesis.Oncogene. 1995; 10: 1315-1324PubMed Google Scholar; Le et al., 1996Le XF Yang P Chang KS Analysis of the growth and transformation suppressor domains of promyelocytic leukemia gene PML.J Biol Chem. 1996; 271: 130-135Crossref PubMed Scopus (121) Google Scholar). This protein exists in many different isoforms, which vary in size from 47 to 160 kD and are generated by alternative splicing and variable C-terminal lengths (reviewed in Grimwade and Solomon, 1997Grimwade D Solomon E Characterisation of the PML/RARα rearrangement associated with t(15;17) acute promyelocytic leukemia.Curr Top Microbiol Immunol. 1997; 220: 81-112Crossref PubMed Scopus (43) Google Scholar), but all isoforms contain several conserved cysteine-rich zinc-binding motifs, known as the RING finger, B1, and B2 B-boxes (reviewed in Saurin et al., 1996Saurin AJ Borden KL Boddy MN Freemont PS Does this have a familiar RING?.Trends Biochem Sci. 1996; 21: 208-214Abstract Full Text PDF PubMed Scopus (601) Google Scholar). These domains are followed by a predicted α-helical coiled-coil region, all of which together form a tripartite motif known as the RBCC motif, which is thought to mediate assembly of PML nuclear bodies. Recently, it has been shown that the coiled-coil domain can form a hetero-oligomeric interaction with another RBCC protein called ret finger protein (RFP), another component of PML nuclear bodies (Cao et al., 1998Cao T Duprez E Borden KL Freemont PS Etkin LD Ret finger protein is a normal component of PML nuclear bodies and interacts directly with PML.J Cell Sci. 1998; 111: 1319-1329Crossref PubMed Google Scholar). RFP becomes oncogenic when fused to the RET proto-oncogene (Takahashi et al., 1988Takahashi M Inaguma Y Hiai H Hirose F Developmentally regulated expression of a human "finger"–containing gene encoded by the 5′ half of the ret transforming gene.Mol Cell Biol. 1988; 8: 1853-1856Crossref PubMed Scopus (217) Google Scholar). RFP associates with only a subset of PML nuclear bodies, possibly reflecting the dynamic nature of these structures. ISG20 colocalizes with PML nuclear bodies and has homology with the Xenopus protein XPMC2, a negative regulator of cell division (Gongora et al., 1997Gongora C David G Pintard L Tissot C Hua TD Dejean A Mechti N Molecular cloning of a new interferon-induced PML nuclear body-associated protein.J Biol Chem. 1997; 272: 19457-19463Crossref PubMed Scopus (106) Google Scholar). INT-6, a putative dominant negative oncoprotein, also colocalizes with PML nuclear bodies (Desbois et al., 1996Desbois C Rousset R Bantignies F Jalinot P Exclusion of Int-6 from PML nuclear bodies by binding to the HTLV-I Tax oncoprotein.Science. 1996; 273: 951-953Crossref PubMed Scopus (127) Google Scholar), which are delocalized as a result of viral infection (see below). PIC1/SUMO-1 is a ubiquitin-like protein that covalently modifies PML (Boddy et al., 1996Boddy MN Howe K Etkin LD Solomon E Freemont PS PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukemia.Oncogene. 1996; 13: 971-982PubMed Google Scholar; Muller et al., 1998Muller S Matunis MJ Dejean A Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus.EMBO J. 1998; 17: 61-70Crossref PubMed Scopus (568) Google Scholar). This modification is reversible and phosphorylation-dependent, with the unmodified PML found in the soluble nucleoplasmic fraction, whereas the modified form apparently partitions into the nuclear matrix (Muller et al., 1998Muller S Matunis MJ Dejean A Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus.EMBO J. 1998; 17: 61-70Crossref PubMed Scopus (568) Google Scholar). PIC1/SUMO-1 has 73% homology at the protein level with the SMT3 protein from Saccharomyces cerevisiae (Boddy et al., 1996Boddy MN Howe K Etkin LD Solomon E Freemont PS PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukemia.Oncogene. 1996; 13: 971-982PubMed Google Scholar). SMT3 is an essential yeast gene and was described as a high copy suppressor of mutations in MIF2, whose product is required for mitotic spindle integrity at anaphase. The mechanisms by which PIC1/SUMO-1 is conjugated to and removed from PML are beginning to be understood. One member of the ubiquitin-specific protease family, HAUSP, is found in PML nuclear bodies (Everett et al., 1997Everett RD Meredith M Orr A Cross A Kathoria M Parkinson J A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein.EMBO J. 1997; 16: 1519-1530Crossref PubMed Scopus (301) Google Scholar), but it fails to cleave PIC1/SUMO-1 modified proteins (Everett et al., 1998Everett RD Freemont P Saitoh H Dasso M Orr A Kathoria M Parkinson J The disruption of ND10 during herpes simplex virus infection correlates with the Vmw110 and proteasome-dependent loss of several PML isoforms.J Virol. 1998; 72: 6581-6591Crossref PubMed Google Scholar). Cyclic AMP response element–binding factor (CREB)-binding protein (CBP) is a coactivator for a variety of transcription factors, including nuclear hormone receptors, and it possesses histone acetyl transferase activity (reviewed in Shikama et al., 1997Shikama N Lyon J La Thangue NB The p300/CBP family: integrating signals with transcription factors and chromatin.Trends Cell Biol. 1997; 7: 230-236Abstract Full Text PDF PubMed Scopus (415) Google Scholar). In interphase nuclei, CBP has a microparticulate distribution with a few larger dots, which colocalize with PML nuclear bodies, suggesting a transient or indirect association (LaMorte et al., 1998LaMorte VJ Dyck JA Ochs RL Evans RM Localization of nascent RNA and CREB binding protein with the PML-containing nuclear body.Proc Natl Acad Sci USA. 1998; 95: 4991-4996Crossref PubMed Scopus (219) Google Scholar). Retinoblastoma protein (pRB), which regulates cell proliferation by controlling a set of transcription factors, has been localized to PML nuclear bodies and forms a stable complex with PML when pRB is hypophosphorylated (Alcalay et al., 1998Alcalay M Tomassoni L Colombo E Stoldt S Grignani F Fagioli M Szekely L et al.The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein.Mol Cell Biol. 1998; 18: 1084-1093Crossref PubMed Scopus (146) Google Scholar). Nascent RNA has also been localized to the interior, electron-dense part of some PML nuclear bodies, suggesting that these structures act as a transcriptional regulator (LaMorte et al., 1998LaMorte VJ Dyck JA Ochs RL Evans RM Localization of nascent RNA and CREB binding protein with the PML-containing nuclear body.Proc Natl Acad Sci USA. 1998; 95: 4991-4996Crossref PubMed Scopus (219) Google Scholar). Two dramatic examples of the dynamic nature of PML bodies are the disruption of these structures in APL (fig. 2) and their enlargement in virally infected cells. The PML protein occurs in similar-sized structures in both the nucleus and the cytoplasm (Stuurman et al., 1997Stuurman N Floore A Middelkoop E van Driel R de Jong L PML shuttles between nuclear bodies and the cytoplasm.Cell Mol Biol Lett. 1997; 2: 137-150Google Scholar), and the continual incorporation and release of PML from nuclear bodies has led to the suggestion that PML (and possibly other components of the PML nuclear bodies) shuttles between nuclear and cytoplasmic structures (Stuurman et al., 1997Stuurman N Floore A Middelkoop E van Driel R de Jong L PML shuttles between nuclear bodies and the cytoplasm.Cell Mol Biol Lett. 1997; 2: 137-150Google Scholar). The number and size of PML nuclear bodies varies throughout the cell cycle. The smallest average number is seen in G0, slowly increasing during progression to G1, with the highest number observed in S phase (Terris et al., 1995Terris B Baldin V Dubois S Degott C Flejou JF Henin D Dejean A PML nuclear bodies are general targets for inflammation and cell proliferation.Cancer Res. 1995; 55: 1590-1597PubMed Google Scholar; Koken et al., 1995Koken MH Linares-Cruz G Quignon F Viron A Chelbi-Alix MK Sobczak-Thepot J Juhlin L et al.The PML growth-suppressor has an altered expression in human oncogenesis.Oncogene. 1995; 10: 1315-1324PubMed Google Scholar). A weak, nuclear-diffuse form of PML is visible by IF at G0, intensifying as the cell progresses to S phase (Koken et al., 1995Koken MH Linares-Cruz G Quignon F Viron A Chelbi-Alix MK Sobczak-Thepot J Juhlin L et al.The PML growth-suppressor has an altered expression in human oncogenesis.Oncogene. 1995; 10: 1315-1324PubMed Google Scholar; Terris et al., 1995Terris B Baldin V Dubois S Degott C Flejou JF Henin D Dejean A PML nuclear bodies are general targets for inflammation and cell proliferation.Cancer Res. 1995; 55: 1590-1597PubMed Google Scholar). Sp100 and PML colocalize at all stages during the cell cycle except during mitosis, when PML forms large aggregates at the periphery of the cell and Sp100 is distributed more diffusely (reviewed in Sternsdorf et al., 1997Sternsdorf T Grotzinger T Jensen K Will H Nuclear dots: actors on many stages.Immunobiology. 1997; 198: 307-331Crossref PubMed Scopus (132) Google Scholar). The localization of all the components throughout the cell cycle is not known, but many of the transitory interactions among components of PML nuclear bodies are likely to be sensitive to the cell cycle. Several components, including pRB, are themselves implicated in cell cycle regulation. PML, too, regulates cell cycle progression by modulating the expression of cell cycle regulatory proteins, including Cdk2 and cyclin E (Mu et al., 1997Mu ZM Le XF Vallian S Glassman AB Chang KS Stable overexpression of PML alters regulation of cell cycle progression in HeLa cells.Carcinogenesis. 1997; 18: 2063-2069Crossref PubMed Scopus (72) Google Scholar). It will be interesting to determine in more detail the role of PML nuclear bodies and their components in cell cycle regulation. A number of chemical reagents or alterations in cell growth conditions can significantly affect the morphology and number of PML nuclear bodies. Cystine-deficient media, for example, cause a reversible increase in the size of the nuclear bodies, whereas histidine- or methionine-deficient media have no such effect (Kamei, 1997Kamei H Cystine starvation induces reversible large-body formation from nuclear bodies in T24 cells.Exp Cell Res. 1997; 237: 207-216Crossref PubMed Scopus (12) Google Scholar). PML nuclear bodies are also affected by stress factors such as heavy metals and heat shock proteins. Heat shock changes the PML nuclear-body distribution into a microspeckled pattern, and, as the cell recovers, tracklike structures are observed, which finally form normal nuclear bodies (Maul et al., 1995Maul GG Yu E Ishov AM Epstein AL Nuclear domain 10 (ND10) associated proteins are also present in nuclear bodies and redistribute to hundreds of nuclear sites after stress.J Cell Biochem. 1995; 59: 498-513Crossref PubMed Scopus (130) Google Scholar). Mutagenesis based on the three-dimensional structure of the PML RING finger revealed that a number of domains of PML, in particular the RBCC motif, can influence the formation of PML nuclear bodies (Borden et al., 1995Borden KL Boddy MN Lally J O'Reilly NJ Martin S Howe K Solomon E et al.The solution structure of the RING finger domain from the acute promyelocytic leukemia proto-oncoprotein PML.EMBO J. 1995; 14: 1532-1541Crossref PubMed Scopus (296) Google Scholar; Boddy et al., 1997Boddy MN Duprez E Borden KL Freemont PS Surface residue mutations of the PML RING finger domain alter the formation of nuclear matrix–associated PML bodies.J Cell Sci. 1997; 110: 2197-2205Crossref PubMed Google Scholar). Mutations of the RING finger cysteines result in a nuclear-diffuse but matrix-associated PML when overexpressed, whereas specific surface residue mutations result in abnormally large PML nuclear bodies (Boddy et al., 1997Boddy MN Duprez E Borden KL Freemont PS Surface residue mutations of the PML RING finger domain alter the formation of nuclear matrix–associated PML bodies.J Cell Sci. 1997; 110: 2197-2205Crossref PubMed Google Scholar). Other studies have shown that the B-box and coiled-coil domains also influence nuclear-body formation (Kastner et al., 1992Kastner P Perez A Lutz Y Rochette-Egly C Gaub MP Durand B Lanotte M et al.Structure localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins.EMBO J. 1992; 11: 629-642Crossref PubMed Scopus (413) Google Scholar; Borden et al., 1996Borden KL Lally JM Martin SR O'Reilly NJ Solomon E Freemont PS In vivo and in vitro characterization of the B1 and B2 zinc-binding domains from the acute promyelocytic leukemia protooncoprotein PML.Proc Natl Acad Sci USA. 1996; 93: 1601-1606Crossref PubMed Scopus (93) Google Scholar). PML can homo-oligomerize through the coiled-coil domain, although this is not sufficient for the formation of PML nuclear bodies in vivo (Borden et al., 1996Borden KL Lally JM Martin SR O'Reilly NJ Solomon E Freemont PS In vivo and in vitro characterization of the B1 and B2 zinc-binding domains from the acute promyelocytic leukemia protooncoprotein PML.Proc Natl Acad Sci USA. 1996; 93: 1601-1606Crossref PubMed Scopus (93) Google Scholar). Loss of PML nuclear-body formation has also been linked to a loss of growth and transformation activity of PML (Le et al., 1996Le XF Yang P Chang KS Analysis of the growth and transformation suppressor domains of promyelocytic leukemia gene PML.J Biol Chem. 1996; 271: 130-135Crossref PubMed Scopus (121) Google Scholar), although recent contradictory studies suggest that localization of PML to PML nuclear bodies is not necessary for it to suppress cell growth (Fagioli et al., 1998Fagioli M Alcalay M Tomassoni L Ferrucci PF Mencarelli A Riganelli D Grignani F et al.Cooperation between the RING and B1-B2 and coiled coil domains of PML is necessary for its effect on cell survival.Oncogene. 1998; 16: 2905-2913Crossref PubMed Scopus (60) Google Scholar). Interferons are a family of secreted cytokines with antiviral, antiproliferative, and immunomodulatory activities (reviewed in Darnell et al., 1994Darnell Jr, JE Kerr IM Stark GR Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.Science. 1994; 264: 1415-1421Crossref PubMed Scopus (4764) Google Scholar). IFN treatment leads to an enlargement in both the size and the number of PML nuclear bodies. The expression of PML, Sp100, and ISG20 (reviewed in Sternsdorf et al., 1997Sternsdorf T Grotzinger T Jensen K Will H Nuclear dots: actors on many stages.Immunobiology. 1997; 198: 307-331Crossref PubMed Scopus (132) Google Scholar) are all inducible by both type I (α/β) and type II (γ) IFNs. PML has been shown to contribute to the IFN antiviral action (Doucas et al., 1996Doucas V Ishov AM Romo A Juguilon H Weitzman MD Evans RM Maul GG Adenovirus replication is coupled with the dynamic properties of the PML nuclear structure.Genes Dev. 1996; 10: 196-207Crossref PubMed Scopus (270) Google Scholar; Chelbi-Alix et al., 1998Chelbi-Alix MK Quignon F Pelicano L Koken MH de The H Resistance to virus infection conferred by the interferon-induced promyelocytic leukemia protein.J Virol. 1998; 72: 1043-1051Crossref PubMed Google Scholar). Altered localization of PML and structural changes within PML nuclear bodies have been shown to occur during DNA and RNA viral infections (reviewed in Doucas and Evans, 1996Doucas V Evans RM The PML nuclear compartment and cancer.Biochim Biophys Acta. 1996; 1288: M25-M29PubMed Google Scholar; Sternsdorf et al., 1997Sternsdorf T Grotzinger T Jensen K Will H Nuclear dots: actors on many stages.Immunobiology. 1997; 198: 307-331Crossref PubMed Scopus (132) Google Scholar). Some examples are as follows: the T-cell leukemia virus type 1 (HTLV-1) tax oncoprotein, which induces the specific redistribution of INT-6 (Desbois et al., 1996Desbois C Rousset R Bantignies F Jalinot P Exclusion of Int-6 from PML nuclear bodies by binding to the HTLV-I Tax oncoprotein.Science. 1996; 273: 951-953Crossref PubMed Scopus (127) Google Scholar), and the adenovirus, which targets the viral protein E4-ORF3 to PML nuclear bodies and causes their reorganization from spherical to fibrous structures (termed "nuclear tracks"; reviewed in Doucas and Evans, 1996Doucas V Evans RM The PML nuclear compartment and cancer.Biochim Biophys Acta. 1996; 1288: M25-M29PubMed Google Scholar). Nuclear bodies are also reorganized after human cytomegalovirus (CMV) infection (Kelly et al., 1995Kelly C Van Driel R Wilkinson GW Disruption of PML-associated nuclear bodies during human cytomegalovirus infection.J Gen Virol. 1995; 76: 2887-2893Crossref PubMed Scopus (88) Google Scholar; Korioth et al., 1996Korioth F Maul GG Plachter B Stamminger T Frey J The nuclear domain 10 (ND10) is disrupted by the human cytomegalovirus gene product IE1.Exp Cell Res. 1996; 229: 155-158Crossref PubMed Scopus (190) Google Scholar) The herpes simplex virus type 1 (HSV-1) immediate-early protein Vmw110 (also called "ICP0") transiently colocalizes with and subsequently disrupts PML nuclear bodies (Everett and Maul, 1994Everett RD Maul GG HSV-1 IE protein Vmw110 causes redistribution of PML.EMBO J. 1994; 13: 5062-5069Crossref PubMed Scopus (335) Google Scholar). Recently, it has been shown that Vmw110 binds specifically to HAUSP (see above), which, at early stages of viral infection, increases the proportion of PML nuclear bodies that contain HAUSP (Everett et al., 1997Everett RD Meredith M Orr A Cross A Kathoria M Parkinson J A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein.EMBO J. 1997; 16: 1519-1530Crossref PubMed Scopus (301) Google Scholar). The cytoplasmic RNA virus lymphocytic choriomeningitis (LCMV) also affects the distribution of PML nuclear bodies, with the Z protein of LCMV interacting with PML to form large cytoplasmic bodies (Borden et al., 1998Borden KL Campbell Dwyer EJ Salvato MS An arenavirus RING (zinc-binding) protein binds the oncoprotein promyelocyte leukemia protein (PML) and relocates PML nuclear bodies to the cytoplasm.J Virol. 1998; 72: 758-766Crossref PubMed Google Scholar). Nuclear bodies are sites for the early stages of transcription and replication of DNA and RNA viruses and are also sites for the subsequent cellular antiviral defense mechanisms using IFNs. Despite the indications that the proper organization of PML-body components is essential for normal cell proliferation, the functions of these bodies remains elusive after numerous and wide-ranging studies. Recent results, with the ablation of PML by homologous recombination, show that mice are viable but more susceptible to tumorigenesis and infections (Wang et al., 1998Wang ZG Delva L Gaboli M Rivi R Giorgio M Cordon-Cardo C Grosveld F et al.Role of PML in cell growth and the retinoic acid pathway.Science. 1998; 279: 1547-1551Crossref PubMed Scopus (446) Google Scholar). The phenotype of these PML−/− mice supports the role of PML as a negative growth regulator and tumor suppressor and as a specific regulator of hematopoietic differentiation (Wang et al., 1998Wang ZG Delva L Gaboli M Rivi R Giorgio M Cordon-Cardo C Grosveld F et al.Role of PML in cell growth and the retinoic acid pathway.Science. 1998; 279: 1547-1551Crossref PubMed Scopus (446) Google Scholar). The presence of nascent RNA and the transcriptional coactivator CBP within the internal core of PML nuclear bodies suggests that these structures act as transcriptional regulators (LaMorte et al., 1998LaMorte VJ Dyck JA Ochs RL Evans RM Localization of nascent RNA and CREB binding protein with the PML-containing nuclear body.Proc Natl Acad Sci USA. 1998; 95: 4991-4996Crossref PubMed Scopus (219) Google Scholar), and, indeed, Alcalay et al., 1998Alcalay M Tomassoni L Colombo E Stoldt S Grignani F Fagioli M Szekely L et al.The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein.Mol Cell Biol. 1998; 18: 1084-1093Crossref PubMed Scopus (146) Google Scholar have found that PML can abolish activation of glucocorticoid receptor–regulated transcription by pRB. PML nuclear bodies have also been observed to be closely associated with replication domains in middle to late S phase (Grande et al., 1996Grande MA van der Kraan I van Steensel B Schul W de The H van der Voort HT de Jong L et al.PML-containing nuclear bodies: their spatial distribution in relation to other nuclear components.J Cell Biochem. 1996; 63: 280-291Crossref PubMed Scopus (98) Google Scholar). Also, viral transcripts and replication factories produced during viral infections have been localized to areas adjacent to PML bodies, suggesting that viral transcription requires some PML nuclear-body components (Ishov et al., 1997Ishov AM Sternberg RM Maul GG Human cytomegalovirus immediate early interaction with host nuclear structures: definition of an immediate transcript environment.J Cell Biol. 1997; 138: 5-6Crossref PubMed Scopus (178) Google Scholar). The exact molecular mechanism by which PML and PML nuclear bodies carry out any of these functions, however, remains to be elucidated. One possibility is that PML nuclear bodies act as "nuclear dumps" or storage "PODS," where different proteins can be deposited or stored and subsequently distributed where necessary. An alternative theory is that PML bodies localize PML NB components to their functionally active site either within the nuclear body or adjacent to it. In addition to being targeted by a wide range of viral infections, PML nuclear bodies, particularly PML, are involved in other human disease processes. Indeed, it was the characterization of genetic changes underlying APL that actually led to the discovery of PML and its localization within nuclear-body structures (reviewed in Grimwade and Solomon, 1997Grimwade D Solomon E Characterisation of the PML/RARα rearrangement associated with t(15;17) acute promyelocytic leukemia.Curr Top Microbiol Immunol. 1997; 220: 81-112Crossref PubMed Scopus (43) Google Scholar). APL, one of the commonest subtypes of acute myeloid leukemia, is characterized by a block in differentiation leading to replacement of the bone marrow with abnormal promyelocytes. This differentiation block can be overcome by retinoids such as all-trans-retinoic acid (ATRA), which induces complete remission in the majority of patients and has transformed clinical practice (Grimwade and Solomon, 1997Grimwade D Solomon E Characterisation of the PML/RARα rearrangement associated with t(15;17) acute promyelocytic leukemia.Curr Top Microbiol Immunol. 1997; 220: 81-112Crossref PubMed Scopus (43) Google Scholar, and references therein). A reciprocal translocation, t(15;17) (q22;q21), which leads to a rearrangement between genes encoding PML and RARα, is almost invariably found in APL tumor cells (Grimwade and Solomon, 1997Grimwade D Solomon E Characterisation of the PML/RARα rearrangement associated with t(15;17) acute promyelocytic leukemia.Curr Top Microbiol Immunol. 1997; 220: 81-112Crossref PubMed Scopus (43) Google Scholar). RARα is a member of the steroid hormone nuclear receptor family that mediates the effect of retinoic acid at specific DNA response elements. When RARα is complexed with its ligand, the corepressor complex, which includes SMRT (silencing mediator of retinoid and thyroid receptor) or N-CoR and histone deacetylase (HDAC), dissociates from the receptor, thus allowing transcriptional activation (Chambon, 1996Chambon P A decade of molecular biology of retinoic acid receptors.FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2524) Google Scholar). In addition, retinoid responses are dependent on members of the distinct retinoid–X-receptor family, which heterodimerize with RARα and mediate high-affinity binding to specific DNA respon
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