Loss of SUMO1 in mice affects RanGAP1 localization and formation of PML nuclear bodies, but is not lethal as it can be compensated by SUMO2 or SUMO3

Evdokimov, Evgenij; Sharma, Prashant; Lockett, Stephen; Lualdi, Margaret; Kuehn, Michael R.

doi:10.1242/jcs.038570

Cited by 132 publications

(122 citation statements)

References 46 publications

(53 reference statements)

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“…The SUMO2 mRNA accounts for 80% of the entire SUMO mRNA pool in total mouse embryos at E7.5, whereas SUMO3 is only expressed at very low levels (2%) [18]. SUMO1 -/-mice are also viable and fertile and lack any obvious phenotype, indicating that the SUMO2 pool is able to compensate for the absence of SUMO1 [19,20]. Mating experiments between the different knockout mice further indicated that the different SUMO family members functionally compensated for each other [18].…”

Section: Twenty Years Of Sumo Research In Cell Cycle Controlmentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

234

211

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SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. KeywordsSUMO; mitosis; SUMOylation; cancer; cell cycle SUMO: a ubiquitin-like modifier that regulates nuclear processesThe complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of posttranslational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control. It is therefore not surprising that SUMO signal transduction has been implicated in the development of several different cancer types, which could potentially be exploited in anti-cancer therapies. In this review we will focus on the role of SUMO in cell cycle regulation, specifically highlighting its physiological relevance and its deregulation in cancer. Recent progress includes the identification of many novel SUMO substrates with important roles in cell cycle progression using proteomic approaches, and the demonstration that different mouse cancer models are dependent on a functioning SUMOylation system. Switching of SUMOylation in these cancer models caused a proliferation block of the cancer cells, showing that SUMO conjugating enzymes are potential drug targets. Europe PMC Funders Group Twenty years of SUMO research in cell cycle controlSUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO conjugating enzyme Ubc9 was first proposed to be a ubiquitin conjugating enzyme. Ubc9 was s...

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Section: Twenty Years Of Sumo Research In Cell Cycle Controlmentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

234

211

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“…Second, deficiency of UBC9 causes lethality and it is important for cell cycle progression and growth, probably by modulation of the degradation of mitotic cyclins (Nacerddine et al, 2005;Nowak and Hammerschmidt, 2006;Seufert et al, 1995). Yet, in contrast to the loss of UBC9 (Alkuraya et al, 2006), the loss of the UBC9 substrate SUMO1 has been shown to not cause any overt physiological and morphological phenotypes in the mouse (Evdokimov et al, 2008;Zhang et al, 2008), with the exception of a discordant study (Alkuraya et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress

Cho

Yi²,

Tserentsoodol³

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARYOxidative stress is a deleterious stressor associated with a plethora of disease and aging manifestations, including neurodegenerative disorders, yet very few factors and mechanisms promoting the neuroprotection of photoreceptor and other neurons against oxidative stress are known. Insufficiency of RAN-binding protein-2 (RANBP2), a large, mosaic protein with pleiotropic functions, suppresses apoptosis of photoreceptor neurons upon aging and light-elicited oxidative stress, and promotes age-dependent tumorigenesis by mechanisms that are not well understood. Here we show that, by downregulating selective partners of RANBP2, such as RAN GTPase, UBC9 and ErbB-2 (HER2; Neu), and blunting the upregulation of a set of orphan nuclear receptors and the light-dependent accumulation of ubiquitylated substrates, light-elicited oxidative stress and Ranbp2 haploinsufficiency have a selective effect on protein homeostasis in the retina. Among the nuclear orphan receptors affected by insufficiency of RANBP2, we identified an isoform of COUP-TFI (Nr2f1) as the only receptor stably co-associating in vivo with RANBP2 and distinct isoforms of UBC9. Strikingly, most changes in proteostasis caused by insufficiency of RANBP2 in the retina are not observed in the supporting tissue, the retinal pigment epithelium (RPE). Instead, insufficiency of RANBP2 in the RPE prominently suppresses the light-dependent accumulation of lipophilic deposits, and it has divergent effects on the accumulation of free cholesterol and free fatty acids despite the genotype-independent increase of light-elicited oxidative stress in this tissue. Thus, the data indicate that insufficiency of RANBP2 results in the cell-type-dependent downregulation of protein and lipid homeostasis, acting on functionally interconnected pathways in response to oxidative stress. These results provide a rationale for the neuroprotection from light damage of photosensory neurons by RANBP2 insufficiency and for the identification of novel therapeutic targets and approaches promoting neuroprotection.Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress

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“…RanGAP1 helps to accelerate the GTP hydrolysis function of Ran GTPase, converting Ran‐GTP to Ran‐GDP and promoting the activation of import carriers 21. The loss of SUMOylation of RanGAP1 likely results in the loss of localization at the nuclear pore complex and loss of function of RanGAP1 22, 23. We also found a decrease in nuclear TDP‐43 in the ALS8 fibroblasts.…”

Section: Discussionmentioning

confidence: 54%

Nucleocytoplasmic transport defect in a North American patient with ALS8

Guber

Schindler

Budron

et al. 2018

Ann Clin Transl Neurol

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Amyotrophic lateral sclerosis 8 (ALS8) is a rare progressive neurodegenerative disease resulting from mutation in the gene for vesicle‐associated membrane protein‐associated protein B. We evaluated a North American patient using exome sequencing, and identified a P56S mutation. The disease protein had similar subcellular localization and expression levels in the patient and control fibroblasts. Patient fibroblasts showed increased basal endoplasmic reticulum stress and dysfunction of nucleocytoplasmic transport as evidenced by impaired Ran trafficking. This finding extends the identification of ALS8 into North America, and indicates a cellular defect similar to other forms of hereditary motor neuron disease.

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Loss of SUMO1 in mice affects RanGAP1 localization and formation of PML nuclear bodies, but is not lethal as it can be compensated by SUMO2 or SUMO3

Cited by 132 publications

References 46 publications

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress

Nucleocytoplasmic transport defect in a North American patient with ALS8

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