Promyelocytic Leukemia Protein PML Research Articles

Fresh and ozonized black carbon promoted DNA damage and repair responses in A549 cells.

Nano-sized ambient black carbon (BC) is hypothesized to pose a serious threat to human health. After emission into the air, the atmospheric oxidation process can modify its physiochemical properties and change its biological responses. In this study, we aimed to compare different DNA damage and repair responses promoted by fresh BC (FBC) and ozone oxidized-BC (OBC). The cell apoptosis, cell arrest, DNA damage and repair were investigated in A549 cells after treatment with FBC and OBC. Associated gene expressions were measured with the reverse transcription quantitative polymerase chain reaction (RT-qPCR) method. Both FBC and OBC could induce cell apoptosis in A549 cells with up-regulated gene of promyelocytic leukemia protein (pml) and down-regulated gene of anti-apoptotic B-cell lymphoma-2 (bcl-2). FBC caused cell cycle arrest at S and G2/M phases, which was associated with up-regulated ataxia telangiectasia mutated (atm), checkpoint kinase 2 (chk2), structural maintenance of chromosomes 1 (smc1) and cell division cycle 25 homolog A (cdc25a) genes. OBC promoted cell cycle arrest at the S phase with up-regulated genes of atm, chk2 and smc1. Both FBC and OBC induced oxidative DNA damage and time-dependent DNA repair responses with increased gene expressions of breast cancer susceptibility protein 1 (brca1), recombination protein A paralog B (rad51b), methyl methanesulfonate-sensitivity protein 22-like and tonsoku-like (mms22l). Compared to FBC, OBC could cause more sufficient DNA damage repair responses through cell cycle arrest at the S phase, resulting in relatively weaker DNA damages.

Promyelocytic leukemia protein in mesenchymal stem cells is essential for leukemia progression.

The dynamic interactions between leukemic cells and cells resident within the bone marrow microenvironment are vital for leukemia progression. The lack of detailed knowledge about the cellular and molecular mechanisms involved in this cross-talk restricts the design of effective treatments. Guarnerio et al. (2018) by using state-of-the-art techniques, including sophisticated Cre/loxP technologies in combination with leukemia mouse models, reveal that mesenchymal stem cells via promyelocytic leukemia protein (Pml) maintain leukemic cells in the bone marrow niche. Strikingly, genetic deletion of Pml in mesenchymal stem cells raised survival of leukemic mice under chemotherapeutic treatment. The emerging knowledge from this research provides a novel target in the bone marrow niche for therapeutic benefit in leukemia.

Functions and dys-functions of promyelocytic leukemia protein PML

The promyelocytic leukemia protein PML has been previously recognized as a critical and essential regulator of a broad number of cellular functions. At nuclear level PML forms the PML-nuclear bodies, where it can sequester and influence the post-translational modification of a wide number of proteins, ultimately affecting their regulative role in DNA transcription. In such a way, PML acts as a key player in strategic cellular activities like as the antiviral defense, in the regulation of the cell cycle, in senescence and programmed cell death. In addition, PML can redistribute also at cytoplasmic level, where it associates to the endoplasmic reticulum or is recruited to mitochondrial-associated membranes. Here it can interact with key cellular proteins like as p53 and influence cell metabolism, mitochondrial calcium upload and autophagy. Altogether, all these findings depict PML as a protein able to exert a widespread action mainly focused on pro-apoptotic and cytostatic activities. Anyway, presence of “Janus-like” pro-tumoral behaviors have been reported, prompting for further investigation to better dissect and highlight all the possible roles that PML can assume in the different physiological or pathological environments. In this review, we discuss the role of PML in multiple cellular functions and pathologic scenarios and summarize the players that control PML protein both at nuclear and at cytoplasmic level.

Hhex induces promyelocyte self-renewal and cooperates with growth factor independence to cause myeloid leukemia in mice

AbstractThe hematopoietically expressed homeobox (Hhex) transcription factor is overexpressed in human myeloid leukemias. Conditional knockout models of murine acute myeloid leukemia indicate that Hhex maintains leukemia stem cell self-renewal by enabling Polycomb-mediated epigenetic repression of the Cdkn2a tumor suppressor locus, encoding p16Ink4a and p19Arf. However, whether Hhex overexpression also affects hematopoietic differentiation is unknown. To study this, we retrovirally overexpressed Hhex in hematopoietic progenitors. This enabled serial replating of myeloid progenitors, leading to the rapid establishment of interleukin-3 (IL-3)–dependent promyelocytic cell lines. Use of a Hhex-ERT2 fusion protein demonstrated that continuous nuclear Hhex is required for transformation, and structure function analysis demonstrated a requirement of the DNA-binding and N-terminal–repressive domains of Hhex for promyelocytic transformation. This included the N-terminal promyelocytic leukemia protein (Pml) interaction domain, although deletion of Pml failed to prevent Hhex-induced promyelocyte transformation, implying other critical partners. Furthermore, deletion of p16Ink4a or p19Arf did not promote promyelocyte transformation, indicating that repression of distinct Hhex target genes is required for this process. Indeed, transcriptome analysis showed that Hhex overexpression resulted in repression of several myeloid developmental genes. To test the potential for Hhex overexpression to contribute to leukemic transformation, Hhex-transformed promyelocyte lines were rendered growth factor–independent using a constitutively active IL-3 receptor common β subunit (βcV449E). The resultant cell lines resulted in a rapid promyelocytic leukemia in vivo. Thus, Hhex overexpression can contribute to myeloid leukemia via multiple mechanisms including differentiation blockade and enabling epigenetic repression of the Cdkn2a locus.

PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes.

Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients.

Analysis of the SUMO2 Proteome during HSV-1 Infection.

Covalent linkage to members of the small ubiquitin-like (SUMO) family of proteins is an important mechanism by which the functions of many cellular proteins are regulated. Sumoylation has roles in the control of protein stability, activity and localization, and is involved in the regulation of transcription, gene expression, chromatin structure, nuclear transport and RNA metabolism. Sumoylation is also linked, both positively and negatively, with the replication of many different viruses both in terms of modification of viral proteins and modulation of sumoylated cellular proteins that influence the efficiency of infection. One prominent example of the latter is the widespread reduction in the levels of cellular sumoylated species induced by herpes simplex virus type 1 (HSV-1) ubiquitin ligase ICP0. This activity correlates with relief from intrinsic immunity antiviral defence mechanisms. Previous work has shown that ICP0 is selective in substrate choice, with some sumoylated proteins such the promyelocytic leukemia protein PML being extremely sensitive, while RanGAP is completely resistant. Here we present a comprehensive proteomic analysis of changes in the cellular SUMO2 proteome during HSV-1 infection. Amongst the 877 potentially sumoylated species detected, we identified 124 whose abundance was decreased by a factor of 3 or more by the virus, several of which were validated by western blot and expression analysis. We found many previously undescribed substrates of ICP0 whose degradation occurs by a range of mechanisms, influenced or not by sumoylation and/or the SUMO2 interaction motif within ICP0. Many of these proteins are known or are predicted to be involved in the regulation of transcription, chromatin assembly or modification. These results present novel insights into mechanisms and host cell proteins that might influence the efficiency of HSV-1 infection.

PML suppresses IL-6-induced STAT3 activation by interfering with STAT3 and HDAC3 interaction

The promyelocytic leukemia protein PML acts as a tumor suppressor by forming transcription–regulatory complexes with a variety of repressor proteins. In the present study, we found that endogenous PML suppresses interleukin (IL)-6-induced gene expression as well as phosphorylation and transcriptional activation of STAT3 in hepatoma cells. We also found that PML-mediated suppression of IL-6-induced STAT3 activation by disrupting interactions between STAT3 and HDAC3. These results indicate that PML modulates IL-6-induced STAT3 activation and hepatoma cell growth by interacting with HDAC3.

Hematopoietic Stem Cells Burn Fat to Prevent Exhaustion

Ito et al. (2012) recently report in Nature Medicine that fatty acid oxidation (FAO) regulated by PPARδ controls asymmetric division in hematopoietic stem cells (HSCs). This metabolic mechanism prevents HSC exhaustion and is downstream of the promyelocytic leukemia protein PML, suggesting therapeutic implications for HSC function and disease.

Abstract 3952: New advances in regulation of senescence by PML and the PML nuclear bodies

Abstract Senescence is a cellular defense mechanism activated by short telomeres, DNA damage or expression of oncogenes. The program includes the expression of high levels of the promyelocytic leukemia protein PML that form nuclear spherical bodies, known as PML-nuclear bodies (PML-NB). The expression of PML in normal fibroblasts is sufficient to induce senescence while genetic inactivation of PML inhibits the process. These results suggest that PML is a critical component of the senescence tumor suppressor mechanism. Accordingly PML is poorly expressed in malignant human tumors but highly expressed in benign tumors. We recently discovered a new mechanism of regulation of RAS-induced senescence by PML, which implicates the recruitment of the RB/E2F complex to the PML-NB via RB-PML interaction. This leads to inhibition of cell cycle and DNA repair genes, DNA damage, p53 activation and ultimately to senescence. We show now that the cyclin dependent kinase CDK4 blocks the ability of PML to regulate E2F gene expression and senescence and that CDK inhibitors potentiate the ability of PML to restore the senescence program in tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3952. doi:1538-7445.AM2012-3952

Structural characterization of the Z RING-eIF4E complex reveals a distinct mode of control for eIF4E

The eukaryotic translation initiation factor eIF4E, a potent oncogene, is highly regulated. One class of eIF4E regulators, including eIF4G and the 4E-binding proteins (4E-BPs), interact with eIF4E using a conserved YXXXXLPhi-binding site. The structural basis of this interaction and its regulation are well established. Really Interesting New Gene (RING) domain containing proteins, such as the promyelocytic leukemia protein PML and the arenaviral protein Z, represent a second class of eIF4E regulators that inhibit eIF4E function by decreasing eIF4E's affinity for its m(7)G cap ligand. To elucidate the structural basis of this inhibition, we determined the structure of Z and studied the Z-eIF4E complex using NMR methods. We show that Z interacts with eIF4E via a novel binding site, which has no homology with that of eIF4G or the 4E-BPs, and is different from the RING recognition site used in the ubiquitin system. Z and eIF4G interact with distinct parts of eIF4E and differentially alter the conformation of the m(7)G cap-binding site. Our results provide a molecular basis for how PML and Z RINGs reduce the affinity of eIF4E for the m(7)G cap and thereby act as key inhibitors of eIF4E function. Furthermore, our findings provide unique insights into RING protein interactions.

Pml and TAp73 interacting at nuclear body mediate imatinib‐induced p53‐independent apoptosis of chronic myeloid leukemia cells

Bcr-abl signals for leukemogenesis of chronic myeloid leukemia (CML) and activates ras. Since the function of promyelocytic leukemia protein (pml) is provoked by ras to promote apoptosis and senescence in untransformed cells, the function is probably masked in CML. Imatinib specifically inhibits bcr-abl and induces apoptosis of CML cells. As reported previously, p53(wild) CML was more resistant to imatinib than that lacking p53. Here, we searched for an imatinib-induced p53 independent proapoptotic mechanism. We found imatinib up-regulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73; expression of pml and bax; formation of PML-nuclear body (NB); and co-localization of TAp73/PML-NB in p53-nonfunctioning K562 and p53(mutant) Meg-01 CML cells, but not in BCR-ABL(-) HL60 cells. In K562 cells, with short interfering RNAs (siRNAs), knockdown of pml led to dephosphorylation of TAp73. Knockdown of either pml or TAp73 abolished the imatinib-induced apoptosis. Inhibition of p38 MAPK with SB203580 led to dephosphorylation of TAp73, abolishment of TAp73/PML-NB co-localization, and the subsequent apoptosis. Conversely, interferon alpha-2a (IFNalpha), which increased phosphrylated TAp73 and TAp73/PML-NB co-localization, increased additively apoptosis with imatinib. The imatinib-induced TAp73/PML-NB co-localization was accompanied by co-immpunoprecipitation of TAp73 with pml. The imatinib-induced co-localization was also found in primary CML cells from 3 of 6 patients, including 2 with p53(mutant) and one with p53(wild). A novel p53-independent proapoptotic mechanism using p38 MAPK /pml/TAp73 axis with a step processing at PML-NB and probably with chk2 and bax being involved is hereby evident in some imatinib-treated CML cells.

Pml and TAp73 Interacting at Nuclear Body and Activated p38MAPK Mediate Imatinib-Induced p53-Independent Apoptosis of Chronic Myeloid Leukemia Cells

Imatinib induces apoptosis in chronic myeloid leukemic (CML) cells even with mutant p53. Ras provokes promyelocytic leukemia protein (pml), which promotes apoptosis and senescence in untransformed cells. In CML cells, ras is usually activated; however, the function of pml seems inadequate to induce apoptosis without imatinib. In both BCR-ABL+ p53mutant K562 and Meg-01 CML cells but not in BCR-ABL− HL60 cells, we found imatinib upregulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73, formation of PML-nuclear body (NB), co-localization of TAp73/PML-NB, and expression of bax. Co-immpunoprecipitation of TAp73 and pml was also consistent with the TAp73/PML-NB co-localization. The induced co-localization also occurred to primary CML cells from three out of six patients, including the two with p53mutant. In K562 cells, both inhibiting p38MAPK with SB203580 and silencing pml or TAp73 with short interfering RNAs (siRNAs) abolished the imatinib-induced apoptosis whereas interferon alpha-2a induced additively with imatinib the apoptosis. Notably, interferon alpha-2a increased additively while SB203580 hindered the imatinib-induced phosphorylation of TAp73 and the TAp73/PML-NB co-localization. Together, imatinib induced in some CML cells, especially with mutant p53, a p53-independent proapoptotic mechanism via a p38MAPK/chk2-pml/TAp73 signaling.

FoxO1 protects against pancreatic β cell failure through NeuroD and MafA induction

Diabetes causes pancreatic beta cell failure through hyperglycemia-induced oxidative stress, or "glucose toxicity." We show that the forkhead protein FoxO1 protects beta cells against oxidative stress by forming a complex with the promyelocytic leukemia protein Pml and the NAD-dependent deacetylase Sirt1 to activate expression of NeuroD and MafA, two Insulin2 (Ins2) gene transcription factors. Using acetylation-defective and acetylation-mimicking mutants, we demonstrate that acetylation targets FoxO1 to Pml and prevents ubiquitin-dependent degradation. We show that hyperglycemia suppresses MafA expression in vivo and that MafA inhibition can be prevented by transgenic expression of constitutively nuclear FoxO1 in beta cells. The findings provide a mechanism linking glucose- and growth factor receptor-activated pathways to protect beta cells against oxidative damage via FoxO proteins.

The human and African green monkey TRIM5alpha genes encode Ref1 and Lv1 retroviral restriction factor activities.

The rhesus macaque tripartite motif containing protein TRIM5alpha specifically restricts HIV-1 infection at an early post-entry step before reverse transcription [Stremlau, M., Owens, C. M., Perron, M. J., Kiessling, M., Autissier, P. & Sodroski, J. (2004) Nature 427, 848-853]. Here, we show that the human and African green monkey (AGM) TRIM5alpha genes encode Ref1 and Lv1 antiretroviral activities, respectively. Expression of TRIM5alpha in permissive cat cells renders them resistant to restriction-sensitive murine leukemia virus but not closely related insensitive virus. Disruption of TRIM5alpha expression in human and AGM cells with small interfering RNA rescues infectivity of restricted virus without affecting unrestricted virus. We also demonstrate that the activity of the murine restriction factor Fv1 depends on TRIM5alpha expression when Fv1 is expressed in human cells. Furthermore, a drug that modifies the behavior of the related promyelocytic leukemia protein PML specifically rescues infection by viruses restricted by human TRIM5alpha. Alignment of the TRIM5alpha proteins from rhesus macaque and AGM indicates an 18-aa insertion. We speculate that this insertion may contribute to the broader specificity of the AGM TRIM5alpha restriction as compared with the human and rhesus macaque proteins.

The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization.

The cap-binding eukaryotic initiation factor eIF4E is phosphorylated by the mitogen-activated protein (MAP) kinase-interacting kinases (Mnk's). Three forms of the Mnk's exist in human cells: Mnk1, Mnk2a, and Mnk2b. These last two are derived from the same gene by alternative splicing and differ only at their C termini. While Mnk2a contains a MAP kinase-binding site in this region, Mnk2b lacks such a sequence and is much less readily activated by MAP kinases in vitro. Expression of Mnk2b in mammalian cells leads to increased phosphorylation of eIF4E, showing that it acts as an eIF4E kinase in vivo. While Mnk2a is cytoplasmic, a substantial amount of Mnk2b is found in the nucleus. Both enzymes contain a stretch of basic residues in their N termini that plays a role in binding to eIF4G and functions as a nuclear localization signal. Binding of eIF4G or nuclear import appears to be regulated by the C terminus of Mnk2a. Furthermore, the MAP kinase-binding site of Mnk2a regulates nuclear entry. Within the nucleus, Mnk2b and certain variants of Mnk2a that are present in the nucleus colocalize with the promyelocytic leukemia protein PML, which also binds to eIF4E.

Association of hepatitis B virus polymerase with promyelocytic leukemia nuclear bodies mediated by the S100 family protein p11

Hepatitis B virus (HBV) polymerase (Pol) interacts with cellular chaperone proteins and thereby performs multiple functions necessary for viral replication. Yeast two-hybrid analysis was applied to identify additional cellular targets required for HBV Pol function. HBV Pol interacted with S100A10 (p11), a Ca 2+-modulated protein previously shown to bind to annexin II. The interaction between HBV Pol and p11 was confirmed by co-immunoprecipitation of the two proteins synthesized either in vitro or in transfected cells and by inhibition of the DNA polymerase activity of HBV Pol by p11. Immunofluorescence analysis of transfected human cell lines revealed that, although most HBV Pol and p11 was restricted to the cytoplasm, a small proportion of each protein colocalized as nuclear speckles; HBV Pol was not detected in the nucleus in the absence of p11. The HBV Pol–p11 nuclear speckles coincided with nuclear bodies containing the promyelocytic leukemia protein PML. Furthermore, the association of HBV Pol–p11 with PML was increased by exposure of cells to EGTA and inhibited by valinomycin. These results suggest a role for p11 in modulation of HBV Pol function and implicate PML nuclear bodies and intracellular Ca 2+ in viral replication.

Opposing effects of PML and PML/RARα on STAT3 activity

Promyelocytic leukemia protein PML acts as a tumor suppressor, whereas its chimeric mutant promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) causes acute promyelocytic leukemia (APL). Because PML has been shown to form transcription-regulatory complexes with various molecules, we speculated that PML and/or PML/RAR alpha might affect signal transducer and activator of transcription 3 (STAT3) activity, which plays a crucial role in granulocyte colony-stimulating factor (G-CSF)-induced growth and survival of myeloid cells. In luciferase assays, PML inhibited STAT3 activity in NIH3T3, 293T, HepG2, and 32D cells. PML formed a complex with STAT3 through B-box and COOH terminal regions in vitro and in vivo, thereby inhibiting its DNA binding activity. Although PML/RAR alpha did not interact with STAT3, it dissociated PML from STAT3 and restored its activity suppressed by PML. To assess the biologic significance of these findings, we introduced PML and PML/RAR alpha into interleukin-3 (IL-3)-dependent Ba/F3 cells expressing the chimeric receptor composed of extracellular domain of G-CSF-R and cytoplasmic domain of gp130, in which gp130-mediated growth is essentially dependent on STAT3 activity. Neither PML nor PML/RAR alpha affected IL-3-dependent growth of these clones. By contrast, gp130-mediated growth was abrogated by PML, whereas it was enhanced by PML/RAR alpha. These results reveal new functions of PML and PML/RAR alpha and suggest that dysregulated STAT3 activity by PML/RAR alpha may participate in the pathogenesis of APL.

Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions.

The promyelocytic leukemia protein PML is a tumor and growth suppressor and plays an important role in a multiple pathways of apoptosis and regulation of cell cycle progression. Our previous studies and others also documented a role of PML in transcriptional regulation through its association with transcription coactivator CBP and transcription corepressor HDAC. Here, we showed that PML is a potent transcriptional repressor of Nur77, an orphan receptor and a member of the steroid receptor superfamily of proteins. We found that PML represses Nur77-mediated transactivation through a physical and functional interaction between the two proteins. PML interacts with Nur-77 in vitro in a GST-pull down assay and in vivo by coimmunoprecipitation assay. PML/Nur77 colocalized in vivo in a double immunofluorescent staining and confocal microscopic analysis. Our study further showed that the coiled-coil domain of PML interacts with the DNA-binding domain of Nur77 (amino acids 267-332). Electrophoretic mobility shift assay demonstrated that PML interferes with Nur77 DNA binding in a dose-dependent manner. This study indicates that PML interacts with the DNA-binding domain of Nur77 and represses transcription by preventing it from binding to the target promoter. This study supports a role of PML/Nur77 interaction in regulating cell growth and apoptosis.

Perturbation of SUMOlation Enzyme Ubc9 by Distinct Domain within Nucleoporin RanBP2/Nup358

Ubc9, a conjugation enzyme for the ubiquitin-related modifier SUMO, is present predominantly in the nucleus and at the nuclear pore complex. The functional significance of its subcellular compartmentalization, however, remains to be elucidated. Here, we define a Pro-Glu-Asp-Ser-Thr-rich element containing 129 amino acid residues, designated IR1+2, on the human nucleoporin RanBP2/Nup358, which binds directly to Ubc9 with high affinity both in vitro and in vivo. When IR1+2 tagged with green fluorescence protein at its amino terminus (GFP-IR1+2) was transfected into COS-7 cells, we found that approximately 90% of the nuclear Ubc9 was sequestered in the cytoplasm. We also observed that both SUMO-1 and SUMO-2/3 were mislocalized, and promyelocytic leukemia protein PML formed an enlarged aggregate in the nucleus. Moreover, the homologous recombination protein Rad51 mislocalized to the cytoplasm, and Rad51 foci, a hallmark of functional association of Rad51 with damaged DNA, did not form efficiently even in the presence of a DNA strand breaker. These findings emphasize that the IR1+2 domain is a useful tool for manipulating the nuclear localization of Ubc9 and perturbing the subcellular localization of SUMOs and/or SUMOlated proteins, and they emphasize the important role of nuclear Ubc9 in the Rad51-mediated homologous recombination pathway, possibly by modulating intracellular trafficking of Rad51.

The RING domains of the promyelocytic leukemia protein PML and the arenaviral protein Z repress translation by directly inhibiting translation initiation factor eIF4E

The promyelocytic leukemia protein (PML) is a mammalian regulator of cell growth which is characteristically disrupted in acute promyelocytic leukemia and by a variety of viruses. PML contains a RING domain which is required for its growth-suppressive and antiviral properties. Although normally nuclear, in certain pathogenic conditions, including arenaviral infection, PML is relocated to the cytoplasm, where its functions are poorly understood. Here, we observe that PML and arenavirus protein Z use regions around the first zinc-binding site of their respective RING domains to directly interact, with sub-micromolar affinity, with the dorsal surface of translation initiation factor eIF4E, representing a novel mode of eIF4E recognition. PML and Z profoundly reduce the affinity of eIF4E for its substrate, the 5′ 7-methyl guanosine cap of mRNA, by over 100-fold. Association with the dorsal surface of eIF4E and direct antagonism of mRNA cap binding by PML and Z lead to direct inhibition of translation. These activities of the RING domains of PML and Z do not involve ubiquitin-mediated protein degradation, in contrast to many RINGs which have been observed to do so. Although PML and Z have well characterized physiological functions in regulation of growth and apoptosis, this work establishes the first discrete biochemical mechanism which underlies the biological activities of their RING domains. Thus, we establish PML and Z as translational repressors, with potential contributions to the pathogenesis of acute promyelocytic leukemia and variety of viral infections.