Nucleotide Biosynthetic Enzyme GMP Synthase Is a TRIM21-Controlled Relay of p53 Stabilization

Reddy, B. Ashok; Knaap, Jan A. van der; Bot, A.; Mohd‐Sarip, Adone; Dekkers, Dick H. W.; Timmermans, Mieke; Martens, John W.M.; Demmers, Jeroen; Verrijzer, C. Peter

doi:10.1016/j.molcel.2013.12.017

Cited by 103 publications

(113 citation statements)

References 49 publications

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“…[21][22][23][24] However, the ability of exogenous guanosine to fully revert all phenotypes caused by GMPS depletion in vitro (Figure 1) strongly suggests that guanylate biosynthetic function has the most important role in GMPS-dependent maintenance of invasive and tumorigenic phenotypes of melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20] Mammalian GMPS has been the subject of several studies addressing its unconventional (GMP-unrelated) roles in the regulation of activity of ubiquitin-specific protease 7 (USP7). [21][22][23][24] However, because of the newly revealed importance of guanylate metabolism in control of melanoma cell invasion and tumorigenicity, 8 GMPS emerges as an attractive target for anti-cancer therapy.…”

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confidence: 99%

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Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

et al. 2015

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Malignant melanoma possesses one of the highest metastatic potentials among human cancers. Acquisition of invasive phenotypes is a prerequisite for melanoma metastases. Elucidation of the molecular mechanisms underlying melanoma invasion will greatly enhance the design of novel agents for melanoma therapeutic intervention. Here, we report that guanosine monophosphate synthase (GMPS), an enzyme required for the de novo biosynthesis of GMP, has a major role in invasion and tumorigenicity of cells derived from either BRAF V600E or NRAS Q61R human metastatic melanomas. Moreover, GMPS levels are increased in metastatic human melanoma specimens compared with primary melanomas arguing that GMPS is an attractive candidate for anti-melanoma therapy. Accordingly, for the first time we demonstrate that angustmycin A, a nucleoside-analog inhibitor of GMPS produced by Streptomyces hygroscopius efficiently suppresses melanoma cell invasion in vitro and tumorigenicity in immunocompromised mice. Our data identify GMPS as a powerful driver of melanoma cell invasion and warrant further investigation of angustmycin A as a novel anti-melanoma agent.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

et al. 2015

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“…Indeed, TRIM24 (Allton et al, 2009), TRIM39 (Zhang et al, 2012a,b) and TRIM59 (Zhou et al, 2014) help to degrade p53. In addition, TRIM8, TRIM13, TRIM19, TRIM21 and TRIM25 also affect p53 stability (Bernardi et al, 2004;Joo et al, 2011;Caratozzolo et al, 2012;Reddy et al, 2014;Zhang et al, 2015). TRIM28, TRIM29 and TRIM32 antagonize p53 function (Wang et al, 2005;Yuan et al, 2010;Liu et al, 2014).…”

Section: Role Of Trim-directed Precision Autophagy In Diseasementioning

confidence: 98%

Precision autophagy directed by receptor regulators – emerging examples within the TRIM family

Kimura

Mandell

Deretić

2016

Journal of Cell Science

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Selective autophagy entails cooperation between target recognition and assembly of the autophagic apparatus. Target recognition is conducted by receptors that often recognize tags, such as ubiquitin and galectins, although examples of selective autophagy independent of these tags are emerging. It is less known how receptors cooperate with the upstream autophagic regulators, beyond the well-characterized association of receptors with Atg8 or its homologs, such as LC3B (encoded by MAP1LC3B), on autophagic membranes. The molecular details of the emerging role in autophagy of the family of proteins called TRIMs shed light on the coordination between cargo recognition and the assembly and activation of the principal autophagy regulators. In their autophagy roles, TRIMs act both as receptors and as platforms ('receptor regulators') for the assembly of the core autophagy regulators, such as ULK1 and Beclin 1 in their activated state. As autophagic receptors, TRIMs can directly recognize endogenous or exogenous targets, obviating a need for intermediary autophagic tags, such as ubiquitin and galectins. The receptor and regulatory features embodied within the same entity allow TRIMs to govern cargo degradation in a highly exact process termed 'precision autophagy'.

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“…S7B). GMPS, which was detected with 145 PSMs, was reported to form a complex with USP7 to catalyze deubiquitylation of histone H2B and stabilize the expression of p53 (60,61). Other interactors include seven TFs, 25 CoRs, eight ubiquitin related proteins, five repair proteins, and two kinases.…”

Section: Uhrf2 Is Recruited To the Cdh1 Promoter For Epigeneticmentioning

confidence: 99%

Multidimensional Proteomics Reveals a Role of UHRF2 in the Regulation of Epithelial-Mesenchymal Transition (EMT)

Lai

Liang

Chen

et al. 2016

Molecular & Cellular Proteomics

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UHRF1 is best known for its positive role in the maintenance of DNMT1-mediated DNA methylation and is implicated in a variety of tumor processes. In this paper, we provided evidence to demonstrate a role of UHRF2 in cell motility and invasion through the regulation of the epithelial-mesenchymal transition (EMT) process by acting as a transcriptional co-regulator of the EMT-transcription factors (TFs). We ectopically expressed UHRF2 in gastric cancer cell lines and performed multidimensional proteomics analyses. Proteome profiling analysis suggested a role of UHRF2 in repression of cell-cell adhesion; analysis of proteome-wide TF DNA binding activities revealed the up-regulation of many EMT-TFs in UHRF2-overexpressing cells. These data suggest that UHRF2 is a regulator of cell motility and the EMT program. Indeed, cell invasion experiments demonstrated that silencing of UHRF2 in aggressive cells impaired their abilities of migration and invasion in vitro. Further ChIP-seq identified UHRF2 genomic binding motifs that coincide with several TF binding motifs including EMT-TFs, and the binding of UHRF2 to CDH1 promoter was validated by ChIP-qPCR. Moreover, the interactome analysis with IP-MS uncovered the interaction of UHRF2 with TFs including TCF7L2 and several protein complexes that regulate chromatin remodeling and histone modifications, suggesting that UHRF2 is a transcription co-regulator for TFs such as TCF7L2 to regulate the EMT process. Taken together, our study identified a role of UHRF2 in EMT and tumor metastasis and demonstrated an effective approach to obtain clues of UHRF2 function without prior knowledge through combining evidence from multidimensional proteomics analyses. Molecular & Cellular

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Nucleotide Biosynthetic Enzyme GMP Synthase Is a TRIM21-Controlled Relay of p53 Stabilization

Cited by 103 publications

References 49 publications

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

Precision autophagy directed by receptor regulators – emerging examples within the TRIM family

Multidimensional Proteomics Reveals a Role of UHRF2 in the Regulation of Epithelial-Mesenchymal Transition (EMT)

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