The puzzling multiple lives of PML and its role in the genesis of cancer

Ruggero, Davide; Wang, Zhugang; Pandolfi, Pier Paolo

doi:10.1002/1521-1878(200009)22:9<827::aid-bies8>3.0.co;2-1

Cited by 56 publications

(40 citation statements)

References 66 publications

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“…Although PML has emerged as a critical mediator of multiple apoptotic pathways (Wang et al, 1998b), the molecular mechanisms by which it exerts these effects remain largely unknown (Ruggero et al, 2000). It has been proposed that PML could exert its proapoptotic functions by actively recruiting to PML NBs, proapoptotic factors such as p53 and Daxx (Guo et al, 2000;Zhong et al, 2000c).…”

Section: Discussionmentioning

confidence: 99%

“…Promyelocytic leukemia (PML) nuclear bodies (PML NBs), also known as PODs (PML oncogenic domains), ND10 (nuclear domain 10) and Kr bodies, are discrete subnuclear domains that are specifically disrupted in cells from acute promyelocytic leukemia (APL), a distinct subtype of human myeloid leukemia (Ruggero et al, 2000;Zhong et al, 2000b;Negorev and Maul, 2001). Their name derives from their most intensively studied protein component, the PML protein, a RING finger IFN-inducible protein encoded by a gene originally cloned as the t(15; 17) chromosomal translocation partner of the retinoic acid receptor a (RARa) locus in APL (de The et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

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THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies

et al. 2003

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Promyelocytic leukemia (PML) nuclear bodies (PML NBs) are discrete subnuclear domains organized by the promyelocytic leukemia protein PML, a tumor suppressor essential for multiple apoptotic pathways. We have recently described a novel family of cellular factors, the THAP proteins, characterized by the presence at their amino-terminus of an evolutionary conserved putative DNA-binding motif, designated THAP domain. Here, we report that THAP1 is a novel nuclear proapoptotic factor associated with PML NBs, which potentiates both serum withdrawal-and TNFa-induced apoptosis, and interacts with prostate-apoptosis-response-4 (Par-4), a well characterized proapoptotic factor, previously linked to prostate cancer and neurodegenerative diseases. We show that endogenous Par-4 colocalizes with ectopic THAP1 within PML NBs in primary endothelial cells and fibroblasts. In addition, we found that Par-4 is a component of PML NBs in blood vessels, a major site of PML expression in vivo. Finally, we investigated the role of the THAP domain in THAP1 activities and found that this putative DNA-binding domain is not required for Par-4 binding and localization within PML NBs, but is essential for THAP1 proapoptotic activity. Together, our results provide an unexpected link between a nuclear factor of the THAP family, the proapoptotic protein Par-4 and PML nuclear bodies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies

et al. 2003

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“…PNBs are aggregates of PML and other proteins that are usually bound to the nuclear matrix. PNBs are the subject of many recent articles that are too numerous to cite here; the reader is referred to some of the many recent reviews (e.g., Hodges et al, 1998;Maul et al, 2000;Ruggero et al, 2000;Zhong et al, 2000). PNBs are present in many but not all tissues.…”

Section: Alt-associated Pml Bodiesmentioning

confidence: 99%

Alternative lengthening of telomeres in mammalian cells

et al. 2002

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Some immortalized mammalian cell lines and tumors maintain or increase the overall length of their telomeres in the absence of telomerase activity by one or more mechanisms referred to as alternative lengthening of telomeres (ALT). Characteristics of human ALT cells include great heterogeneity of telomere size (ranging from undetectable to abnormally long) within individual cells, and ALT-associated PML bodies (APBs) that contain extrachromosomal telomeric DNA, telomere-speci®c binding proteins, and proteins involved in DNA recombination and replication. Activation of ALT during immortalization involves recessive mutations in genes that are as yet unidenti®ed. Repressors of ALT activity are present in normal cells and some telomerase-positive cells. Telomere length dynamics in ALT cells suggest a recombinational mechanism. Inter-telomeric copying occurs, consistent with a mechanism in which singlestranded DNA at one telomere terminus invades another telomere and uses it as a copy template resulting in net increase in telomeric sequence. It is possible that t-loops, linear and/or circular extrachromosomal telomeric DNA, and the proteins found in APBs, may be involved in the mechanism. ALT and telomerase activity can co-exist within cultured cells, and within tumors. The existence of ALT adds some complexity to proposed uses of telomererelated parameters in cancer diagnosis and prognosis, and poses challenges for the design of anticancer therapeutics designed to inhibit telomere maintenance.

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“…This translocation involves the fusion of two genes, PML and the retinoic acid receptor ␣ (RAR␣), and leads to the disruption of PML-NBs (Ruggero et al 2000). Although the actual mechanistic function of the PML-NB has remained elusive, it has been implicated in many fundamental cellular processes, including transcription (Zhong et al 2000).…”

Section: Nuclear Bodiesmentioning

confidence: 99%

“…Although the actual mechanistic function of the PML-NB has remained elusive, it has been implicated in many fundamental cellular processes, including transcription (Zhong et al 2000). In support of a role in transcription, regulatory factors such as cyclic AMP response-binding protein (CBP) and retinoblastoma protein (pRB) have been shown to interact directly with PML (Ruggero et al 2000). A recent localization analysis of gene-dense domains in the human genome revealed that transcriptionally robust loci are associated with PML-NBs (Wang et al 2004).…”

Section: Nuclear Bodiesmentioning

confidence: 99%

Form follows function: the genomic organization of cellular differentiation

Kosak¹,

Groudine²

2004

Genes Dev.

218

179

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The extent to which the nucleus is functionally organized has broad biological implications. Evidence supports the idea that basic nuclear functions, such as transcription, are structurally integrated within the nucleus. Moreover, recent studies indicate that the linear arrangement of genes within eukaryotic genomes is nonrandom. We suggest that determining the relationship between nuclear organization and the linear arrangement of genes will lead to a greater understanding of how transcriptomes, dedicated to a particular cellular function or fate, are coordinately regulated. Current network theories may provide a useful framework for modeling the inherent complexity the functional organization of the nucleus.Louis Sullivan, whose early efforts helped pioneer the development of the skyscraper, is considered one of the most important architects of the last century. However, it is his dictum-"form ever follows function"-for which he is perhaps best known. Just as this imperative has influenced generations of architects, the idea that structure reflects function provides a useful perspective for a biologist's view of the cell. In many ways, the structure and function of cellular and subcellular organelles are inseparable; that is, disruptions in organelle function can lead to perturbations in its structure. Upon inhibition of rRNA transcription, for example, the nucleolus becomes disordered and ultimately disappears (Leung and Lamond 2003). This integration of structure and cellular function allows for conservation of resources and facilitates regulation at multiple levels.Although a completely sequenced genome may represent a genetic blueprint, molecular biologists currently lack a key with which to fully grasp how this sequence is related to the development and subsequent maintenance of a given organism. Following Sullivan's example, a comprehensive understanding of genomic sequence may require considering its arrangement in the nucleus; the form DNA takes in the nucleus reveals not only its higher-order structure, but it may impart information regarding its function. The current paradigm of gene regulation includes the binding of site-specific transcription factors, the recruitment of cofactors and general transcription factors, and the incorporation of multiple modifications to both the DNA and the histones that organize it (Felsenfeld and Groudine 2003). This description of transcription belies its enormous complexity, fueled by an ever-increasing catalog of proteins dedicated in one way or another to its regulation. Additionally, evidence supporting the role of nuclear localization in transcriptional regulation indicates that it is insufficient to know the components of transcription . Rather, a thorough understanding of the process requires knowing its functional organization within the nucleus. In this sense, transcription should not be viewed simply as a process that turns on a specific gene, but as a process that governs within the genome an entire network of genes (a transcriptome) that gives rise to a p...

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The puzzling multiple lives of PML and its role in the genesis of cancer

Cited by 56 publications

References 66 publications

THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies

THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies

Alternative lengthening of telomeres in mammalian cells

Form follows function: the genomic organization of cellular differentiation

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