SUMO: of branched proteins and nuclear bodies

Seeler, Jacob-S.; Dejean, Anne

doi:10.1038/sj.onc.1204758

Cited by 141 publications

(117 citation statements)

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“…PML is functionally regulated by post-translational modifications such as phosphorylation, sumoylation, ubiquitination, and acetylation. Sumoylation of PML is necessary for the proper formation of PML-NBs and the recruitment of NB-associated proteins, highlighting the importance of this modification in PML function (reviewed in Seeler and Dejean 25 ). To determine whether sumoylation of PML is also required for the PML regulation by SIRT1, MCF-7 cells were transfected with a plasmid encoding for PML4 or a PML sumoylation-defective mutant (PML4-TKO) together with Flag-SIRT1 or an empty vector and the levels of PML protein were analyzed by western blot.…”

Section: Resultsmentioning

confidence: 99%

SIRT1 stabilizes PML promoting its sumoylation

et al. 2010

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SIRT1, the closest mammalian homolog of yeast Sir2, is an NAD þ -dependent deacetylase with relevant functions in cancer, aging, and metabolism among other processes. SIRT1 has a diffuse nuclear localization but is recruited to the PML nuclear bodies (PML-NBs) after PML upregulation. However, the functions of SIRT1 in the PML-NBs are unknown. In this study we show that primary mouse embryo fibroblasts lacking SIRT1 contain reduced PML protein levels that are increased after reintroduction of SIRT1. In addition, overexpression of SIRT1 in HEK-293 cells increases the amount of PML protein whereas knockdown of SIRT1 reduces the size and number of PML-NBs and the levels of PML protein in HeLa cells. SIRT1 stimulates PML sumoylation in vitro and in vivo in a deacetylase-independent manner. Importantly, the absence of SIRT1 reduces the apoptotic response of vesicular stomatitis virus-infected cells and favors the extent of this PML-sensitive virus replication. These results show a novel function of SIRT1 in the control of PML and PML-NBs. The tumor suppressor PML is the main and essential component of the nuclear bodies (NBs), the dynamic compartments that participate in a number of cellular processes, including apoptosis, transcriptional regulation, DNA repair, and protection against viral infection. 1,2 PML acts as a tumor suppressor, antagonizing initiation, promotion, and progression of tumors of various histological origins. 3 PML is also implicated in the regulation of infection by a variety of RNA viruses, adenoviruses, and human cytomegalovirus. 4-7 Its function is regulated by post-translational modifications such as phosphorylation, sumoylation, ubiquitination, and acetylation. However, only the sumoylation of PML has been shown as essential for the formation of the PML-NBs and a crucial process for PML-dependent apoptosis and transcriptional regulation. 8 In addition to PML, PML-NBs contain several other proteins, such as SP100, SUMO-1, pRB, p53, and lately, the NAD þ -dependent, type III, histone/protein deacetylase SIRT1. 9,10 SIRT1 is the best-characterized class III histone deacetylase in mammalian cells and the closest homolog to yeast Sir2. However, although most of SIRT1 functions are related to its enzymatic activity, deacetylation-independent activities of SIRT1 have also been proposed. 11-14 SIRT1 is involved in a wide spectrum of biological processes through diverse substrates such as the tumor suppressor p53, 9,15-17 the transcription factor NF-kB, 18 and the FOXO family of transcription factors. 12,14,19,20 Although SIRT1 has a diffuse nuclear localization, it is recruited to the PML-NBs after PML upregulation. However, the functional significance of this PML-SIRT1 interaction has not been addressed.In this report, we show that there is a correlation between the levels of SIRT1 and PML present in both primary and transfected cells. This positive regulation of PML levels by SIRT1 is mediated by an increase in the sumoylation of PML by SIRT1, in a deacetylation-independent manner. Functional sign...

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Section: Resultsmentioning

confidence: 99%

SIRT1 stabilizes PML promoting its sumoylation

et al. 2010

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“…The repression of transcription factors by PIAS proteins often correlates with the subnuclear sequestration into speckles, such as promyelocytic leukemia nuclear bodies (3,20,21,23,34,41). This observation could account for the repression of transcription factor activity without changes in DNA binding.…”

Section: Piasy-deficient Mice Display Modest Defects In Ifn Andmentioning

confidence: 99%

PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling

Roth

Sustmann

Kieslinger

et al. 2004

The Journal of Immunology

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Protein inhibitors of activated STATs (PIAS) represent a small family of nuclear proteins that modulate the activity of many transcription factors and act as E3 ligases for covalent modification of proteins with the small ubiquitin-like modifier (SUMO). In particular, PIASy has been shown to inhibit the activation of gene expression by the IFN-responsive transcription factor STAT1 and the Wnt-responsive transcription factor LEF1. To assess the function of PIASy in vivo, we generated and analyzed mice carrying a targeted mutation of the Piasy gene. We find that homozygous mutant mice have no obvious morphological defects and have a normal distribution of lymphocyte populations. Molecular analysis of signaling in response to IFN-γ and Wnt agonists revealed a modest reduction in the activation of endogenous and transfected target genes. Two-dimensional analysis of total proteins and SUMO-modified proteins in transformed pre-B cells showed no significant differences between wild-type mice and homozygous mutant mice. Taken together, our data indicate that PIASy has a modest effect on cytokine and Wnt signaling, suggesting a redundancy with other members of the family of PIAS proteins.

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“…SUMO is believed to alter the interaction properties of its target, often affecting its localization within the cell (Seeler and Dejean, 2001). The functional relevance of class IIa HDAC sumoylation is still unclear, but sumoylation abolished HDAC4-associated HDAC activity (Kirsh et al, 2002).…”

Section: Other Posttranslational Modificationsmentioning

confidence: 99%