Cellular proteins localized at and interacting within ND10/PML nuclear bodies/PODs suggest functions of a nuclear depot

Negorev, Dmitri; Maul, Gerd G.

doi:10.1038/sj.onc.1204764

Cited by 242 publications

(187 citation statements)

References 87 publications

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“…The major components of PML-NBs are promyelocytic leukemia protein (PML) and Sp100, and the proapoptotic adaptor protein Daxx plays a crucial role in the assembly of PML-NBs by connecting sumoylated PML and Sp100. [9][10][11] These provide a scaffold to harbor several prominent regulatory factors including tumor suppressors, transcriptional regulators, and enzymes for signal transduction, and thereby PML-NBs contribute to multiple mechanisms of cellular control. 8,10,[12][13][14][15][16] While the functional interactions of these components remain unclear, the architecture of PML-NBs seems to be particularly important since its abrogation caused by a chromosomal translocation t(15;17) results in acute promyelocytic leukemia.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11] These provide a scaffold to harbor several prominent regulatory factors including tumor suppressors, transcriptional regulators, and enzymes for signal transduction, and thereby PML-NBs contribute to multiple mechanisms of cellular control. 8,10,[12][13][14][15][16] While the functional interactions of these components remain unclear, the architecture of PML-NBs seems to be particularly important since its abrogation caused by a chromosomal translocation t(15;17) results in acute promyelocytic leukemia. 8,14,16 In contrast, forced expression of PML, as well as the expression of oncogenic Ras, induces apparent hyperplasis (i.e.…”

Section: Introductionmentioning

confidence: 99%

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E2FBP1/hDril1 modulates cell growth through downregulation of promyelocytic leukemia bodies

et al. 2004

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Promyelocytic leukemia nuclear bodies (PML-NBs) comprise multiple regulatory factors and play crucial roles in the maintenance of cellular integrity, while unregulated activation of PML-NBs induces death and premature senescence. Hence, the function of PML-NBs must be directed properly; however, the mechanism that regulates PML-NBs remains unclear. In this paper, we show that PML-NBs are disintegrated by an AT-rich interaction domain family protein E2FBP1/hDril1 through specific desumoylation of promyelocytic leukemia protein (PML) in vivo and in vitro. RNA interference-mediated downregulation of E2FBP1/hDril1 results in hyperplasis of PML-NBs and consequent commitment to PML-dependent premature senescence. Thus, the function of E2FBP1/hDril1 is required for maintenance of survival potential of the cells. Our data suggest a novel mechanism to govern cellular integrity through the modulation of nuclear depots.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

E2FBP1/hDril1 modulates cell growth through downregulation of promyelocytic leukemia bodies

et al. 2004

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“…Interestingly, both proteins, PML and hDaxx, are components of a cellular subnuclear structure known as nuclear domain 10 (ND10) or PML nuclear bodies. ND10 structures represent multiprotein complexes of the cellular proteins PML, hDaxx, and Sp100 that assemble in distinct foci within the interchromosomal space of the nucleus (42). Previous studies identified the PML protein as the defining factor of ND10 structures since it functions as a kind of scaffold protein that is responsible for the assembly and maintenance of this domain and recruits other ND10-associated proteins like hDaxx to this subnuclear structure (25,53).…”

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confidence: 99%

Nuclear Domain 10 Components Promyelocytic Leukemia Protein and hDaxx Independently Contribute to an Intrinsic Antiviral Defense against Human Cytomegalovirus Infection

Tavalai

Papior

Rechter

et al. 2008

J Virol

114

142

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Infection with DNA viruses commonly results in the association of viral genomes with a cellular subnuclear structure known as nuclear domain 10 (ND10). Recent studies demonstrated that individual ND10 components, like hDaxx or promyelocytic leukemia protein (PML), mediate an intrinsic immune response against human cytomegalovirus (HCMV) infection, strengthening the assumption that ND10 components are part of a cellular antiviral defense mechanism. In order to further define the role of hDaxx and PML for HCMV replication, we generated either primary human fibroblasts with a stable, individual knockdown of PML or hDaxx (PML-kd and hDaxx-kd, respectively) or cells exhibiting a double knockdown. Comparative analysis of HCMV replication in PML-kd or hDaxx-kd cells revealed that immediate-early (IE) gene expression increased to a similar extent, regardless of which ND10 constituent was depleted. Since a loss of PML, the defining component of ND10, results in a dispersal of the entire nuclear substructure, the increased replication efficacy of HCMV in PML-kd cells could be a consequence of the dissociation of the repressor protein hDaxx from its optimal subnuclear localization. However, experiments using three different recombinant HCMVs revealed a differential growth complementation in PML-kd versus hDaxx-kd cells, strongly arguing for an independent involvement in suppressing HCMV replication. Furthermore, infection experiments using double-knockdown cells devoid of both PML and hDaxx illustrated an additional enhancement in the replication efficacy of HCMV compared to the single-knockdown cells. Taken together, our data indicate that both proteins, PML and hDaxx, mediate an intrinsic immune response against HCMV infection by contributing independently to the silencing of HCMV IE gene expression.

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“…Whereas Cajal bodies are often found associated to several different small nuclear RNA and small nucleolar RNA gene loci as well as histone gene loci (1)(2)(3)(4)(5), PML bodies are frequently located in the MHC gene region (6). For both nuclear bodies, different types of movements were described and assigned to distinct subgroups of Cajal and PML bodies (7)(8)(9)(10)(11)(12). The analysis of a baby hamster kidney cell line revealed that a fraction of PML bodies moved over longer distances and in an energy-dependent manner.…”

mentioning

confidence: 99%

Nuclear body movement is determined by chromatin accessibility and dynamics

Görisch

Wachsmuth

Ittrich

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

108

120

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Promyelocytic leukemia (PML) and Cajal bodies are mobile subnuclear organelles, which are involved in activities like RNA processing, transcriptional regulation, and antiviral defense. A key parameter in understanding their biological functions is their mobility. The diffusion properties of PML and Cajal bodies were compared with a biochemically inactive body formed by aggregates of murine Mx1 by using single-particle tracking methods. The artificial Mx1-yellow fluorescent protein body showed a very similar mobility compared with PML and Cajal bodies. The data are described quantitatively by a mechanism of nuclear body movement consisting of two components: diffusion of the body within a chromatin corral and its translocation resulting from chromatin diffusion. This finding suggests that the body mobility reflects the dynamics and accessibility of the chromatin environment, which might target bodies to specific nuclear subcompartments where they exert their biological function.C ajal and promyelocytic leukemia (PML) bodies are essential components of the nucleus that are thought to contain activities for RNA processing, transcriptional regulation, and antiviral defense. For understanding their biological functions, parameters have to be identified that characterize their mobility and lead to a localization of Cajal and PML bodies at their target sites in the nucleus. Whereas Cajal bodies are often found associated to several different small nuclear RNA and small nucleolar RNA gene loci as well as histone gene loci (1-5), PML bodies are frequently located in the MHC gene region (6). For both nuclear bodies, different types of movements were described and assigned to distinct subgroups of Cajal and PML bodies (7-12). The analysis of a baby hamster kidney cell line revealed that a fraction of PML bodies moved over longer distances and in an energy-dependent manner. These faster moving bodies were not observed in HeLa cells (8). In a detailed study of Cajal bodies in HeLa cells, an anomalous diffusion behavior and an ATP-and transcription-dependent association with chromatin was reported (7).Here, the mobility of PML and Cajal bodies has been compared with the nuclear body-like structures formed by Mx1 protein fused to yellow fluorescent protein (YFP). Mx proteins are IFN-induced GTPases of the dynamin super family involved in defense mechanisms against RNA viruses (13). The murine Mx1 protein, 72 kDa in size, has a natural nuclear localization sequence sequence and displays a nuclear body-like distribution (14,15). In contrast to the Mx1 WT protein, the Mx1-YFP construct studied has no antiviral activity as tested with influenza and Thogoto virus infection and formed crystals (S. Stertz and O. Haller, personal communication). The diffusion properties of this bona fide biologically inert body were used as a reference to identify principles determining the mobility of bodies within the nucleus. Cell Culture and Transfection. HeLa cells (ATCC CCL-2) were cultured on 12-mm glass coverslips for immunofluorescence or 35-...

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Cellular proteins localized at and interacting within ND10/PML nuclear bodies/PODs suggest functions of a nuclear depot

Cited by 242 publications

References 87 publications

E2FBP1/hDril1 modulates cell growth through downregulation of promyelocytic leukemia bodies

E2FBP1/hDril1 modulates cell growth through downregulation of promyelocytic leukemia bodies

Nuclear Domain 10 Components Promyelocytic Leukemia Protein and hDaxx Independently Contribute to an Intrinsic Antiviral Defense against Human Cytomegalovirus Infection

Nuclear body movement is determined by chromatin accessibility and dynamics

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