Sumo, ubiquitin's mysterious cousin

Müller, Stefan; Hoege, Carsten; Pyrowolakis, George; Jentsch, Stefan

doi:10.1038/35056591

Cited by 702 publications

(656 citation statements)

References 97 publications

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“…As ubiquitination occurs in the C-terminal region of pRb, which is heavily modified by other post-translational modifications (Figure 1), it is possible that interplay exists between ubiquitination and other modifications such as phosphorylation, acetylation and methylation. SUMO (small ubiquitin-related modifier) is a reversible post-translational modification, and many of its protein targets include transcriptional regulators (Muller et al, 2001(Muller et al, , 2004Wilkinson and Henley, 2010). pRb is SUMOylated in the B domain of the pocket region on K720 (Ledl et al, 2005) (Figure 1), within a cluster of lysine residues that are essential for the interaction with LXCXE motif-containing proteins (Chan et al, 2001b).…”

Section: Other Prb Post-translational Modificationsmentioning

confidence: 99%

Diversity within the pRb pathway: is there a code of conduct?

2012

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The failure of cell proliferation to be properly regulated is a hallmark of tumourigenesis. The retinoblastoma protein (pRb) pathway represents a key component in the regulation of the cell cycle and tumour suppression. Recent findings have revealed new levels of complexity reflecting a repertoire of post-translational modifications that occur on pRb together with its key effector E2F-1. Here we provide an overview of the modifications and consider the possibility of a 'code' that endows pRb with the ability to function in diverse physiological settings.

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Section: Other Prb Post-translational Modificationsmentioning

confidence: 99%

Diversity within the pRb pathway: is there a code of conduct?

2012

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“…1,2 A large number of sumoylated proteins, including RanGAP1, PML, homeodomain-interacting protein kinases (HIPKs), IkB, p53, c-Jun, Sp3, Elk-1, p300 histone acetyltransferase, histone deacetylase (HDAC), and many nuclear receptors, have been identified. [1][2][3] Sumoylation is a dynamic process that is mediated by activating, conjugating, and ligating enzymes and that is readily reversed by a family of SUMO-specific proteases. 4 Several members of SUMOspecific proteases have been reported in the mammalian system.…”

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confidence: 99%

SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis

Luo

et al. 2008

Cell Death Differ

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We have previously shown that tumor necrosis factor (TNF)-induced desumoylation and subsequent cytoplasmic translocation of HIPK1 are critical for ASK1-JNK activation. However, the mechanism by which TNF induces desumoylation of HIPK1 is unclear. Here, we show that SENP1, a SUMO-specific protease, specifically deconjugates SUMO from HIPK1 in vitro and in vivo. In resting endothelial cells (ECs), SENP1 is localized in the cytoplasm where it is complexed with an antioxidant protein thioredoxin. TNF induces the release of SENP1 from thioredoxin as well as nuclear translocation of SENP1. TNF-induced SENP1 nuclear translocation is specifically blocked by antioxidants such as N-acetyl-cysteine, suggesting that TNF-induced translocation of SENP1 is ROS dependent. TNF-induced nuclear import of SENP1 kinetically correlates with HIPK1 desumoylation and cytoplasmic translocation. Furthermore, the wild-type form of SENP1 enhances, whereas the catalyticinactive mutant form or siRNA of SENP1 blocks, TNF-induced desumoylation and cytoplasmic translocation of HIPK1 as well as TNF-induced ASK1-JNK activation. More importantly, these critical functions of SENP1 in TNF signaling were further confirmed in mouse embryonic fibroblast cells derived from SENP1-knockout mice. We conclude that SENP1 mediates TNF-induced desumoylation and translocation of HIPK1, leading to an enhanced ASK1-dependent apoptosis. The small ubiquitin-like modifier (SUMO) can be covalently attached to a large number of proteins through the formation of isopeptide bonds with specific lysine residues of target proteins. 1,2 A large number of sumoylated proteins, including RanGAP1, PML, homeodomain-interacting protein kinases (HIPKs), IkB, p53, c-Jun, Sp3, Elk-1, p300 histone acetyltransferase, histone deacetylase (HDAC), and many nuclear receptors, have been identified. 1-3 Sumoylation is a dynamic process that is mediated by activating, conjugating, and ligating enzymes and that is readily reversed by a family of SUMO-specific proteases. 4 Several members of SUMOspecific proteases have been reported in the mammalian system. 5-10 SENP1 is a protease that appears to deconjugate a large number of sumoylated proteins. 5 Different members of these SUMO-specific proteases appear to localize in different cellular compartments where they regulate protein function by modifying the protein stability, cellular localization, and protein-protein interactions. 5,6,[8][9][10][11][12] However, it is not known how these SUMO-specific proteases are regulated.HIPK1 is one of three closely related serine/threonine protein kinases that are primarily localized in the nucleus where it is sumoylated. 13,14 The HIPKs were originally identified as nuclear protein kinases that function as co-repressors for various homeodomain-containing transcription factors. 15 Recently, HIPKs have been shown to interact with other proteins involved in apoptosis and signal transduction in a cellular localization-dependent manner. In nucleus, HIPK2 phosphorylates p53 on Ser 46, resulting in the activatio...

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“…There are four mammalian SUMO proteins, SUMO-1, SUMO-2, SUMO-3, and SUMO-4 (Gill, 2004). SUMO is first activated for conjugation by the E1 enzymes Aos1/Uba2, subsequently transferred to the E2 conjugation enzyme Ubc9 and finally conjugated to target proteins by an E3 ligase (Hochstrasser, 2000;Yeh et al, 2000;Mü ller et al, 2001). Different classes of E3 ligase-proteins have been reported.…”

Section: Introductionmentioning

confidence: 99%

“…Posttranslational modification of proteins by the small ubiquitin-like modifier (SUMO) is an important regulatory mechanism that impinges on many cellular processes (Mü ller et al, 2001;Gill, 2003;Melchior et al, 2003;Seeler and Dejean, 2003;Verger et al, 2003;Johnson, 2004). SUMO conjugation regulates different protein functions including protein stability, subnuclear localization, DNA binding, and transcription (reviewed in Gill, 2003;Verger et al, 2003;Johnson, 2004;Hay, 2005).…”

Section: Introductionmentioning

confidence: 99%