Role of Desumoylation in the Development of Prostate Cancer

Cheng, Jinke; Bawa, Tasneem; Lee, Peng; Gong, Limin; Yeh, Edward T.H.

doi:10.1593/neo.06445

Cited by 200 publications

(216 citation statements)

References 75 publications

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“…It was originally shown to be localized to the cytosol in NIH3T3 and HeLa cells (22). However, studies from other laboratories suggest that SENP6 is localized in the nucleoplasm (18,23). SENP6 also appears to prefer SUMO2/3 as substrates (23).…”

Section: Localization and Enzymatic Activity Of Sumo-specific Proteasesmentioning

confidence: 99%

“…SENP2 was reported to be tethered to the nuclear pore through binding to Nup153 nucleoporin (16,17). Furthermore, SENP2 is also localized in a yet undefined nuclear speckle that is distinct from the nuclear body (18). SENP2 has isopeptidase activity for all SUMOs.…”

Section: Localization and Enzymatic Activity Of Sumo-specific Proteasesmentioning

confidence: 99%

“…SENP6 also appears to prefer SUMO2/3 as substrates (23). SENP7 is the least characterized SENP that is localized in the nucleoplasm (18). However, its catalytic activity has not been convincingly demonstrated.…”

Section: Localization and Enzymatic Activity Of Sumo-specific Proteasesmentioning

confidence: 99%

“…SENP1 deconjugates SUMOylated HDAC1 (histone deacetylase 1) to reduce its deacetylase activity, allowing transcription to increase manyfold over background levels. This is biologically relevant because SENP1 is highly expressed in an early prostate cancer lesion called prostatic intraepithelial neoplasia and prostate cancer tissues but not in normal prostate tissues (18). Furthermore, the androgen receptor directly regulates SENP1 transcription by binding to an androgen-response element in the SENP1 promoter (38).…”

Section: Function Of Sumo-specific Proteasesmentioning

confidence: 99%

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SUMOylation and De-SUMOylation: Wrestling with Life's Processes

Yeh

2009

Journal of Biological Chemistry

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414

408

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The small ubiquitin-like modifier (SUMO) is a ubiquitinlike protein that covalently modifies a large number of cellular proteins. SUMO modification has emerged as an important regulatory mechanism for protein function and localization. SUMOylation is a dynamic process that is mediated by activating (E1), conjugating (E2), and ligating (E3) enzymes and readily reversed by a family of ubiquitin-like protein-specific proteases (Ulp) in yeast and sentrin/SUMO-specific proteases (SENP) in human. This review will focus on the de-SUMOylating enzymes with special attention to their biological function.Many biochemical pathways are reversible to create an on and off state that is essential for biological regulation. A reversible system allows for quick termination of a biological response that has to be precisely controlled. The SUMO 2 modification pathway is an example of a reversible system that is controlled by a series of on and off enzymes ( Fig. 1) (1). In contrast to the much more complex ubiquitin pathway (2), SUMOylation utilizes only a single conjugating enzyme, Ubc9 (3), and a limited number of ligases (4 -6). This simplicity also manifests in the off step because there are only two SUMO-deconjugating enzymes in yeast and six in human. One may assume that these limited numbers of on and off enzymes would sufficient to regulate only be a small number of substrates and biological pathways. However, the number of SUMO substrates continues to expand, and the varieties of systems that are known to be regulated by SUMO also proliferate quickly. Here, I will review only the enzymes that are involved in the de-SUMOylation pathways to provide insights into how these limited numbers of proteases are able to regulate a diverse array of biological responses. Localization and Enzymatic Activity of SUMO-specific ProteasesSUMO-specific proteases are C48 cysteine proteases that possess a conserved catalytic domain characterized by the catalytic triad (histidine, aspartate, and cysteine) and a conserved glutamine residue required for the formation of the oxyanion hole in the active site (7). Members of the C48 cysteine protease family have N-and C-terminal sequences that differ from each other. Homologs of these proteases are present in plant, yeast, and mammalian cells. In this review, I will focus on the two yeast ubiquitin-like protein-specific proteases (Ulp) and the six human sentrin/SUMO-specific proteases (SENP) ( Table 1).Yeast has a single SUMO-like modifier, Smt3, and two Smt3-specific proteases, Ulp1 and Ulp2. Both Smt3 and Ulp2 (Smt4) were identified from the same screen as suppressors of the Mif2 (a centromeric protein) mutation (8). Ulp1 is a protein of 621 amino acids that contains the catalytic domain at the C terminus and an N-terminal domain that attaches this protease to the nuclear pore (7). Ulp1 possesses the C-terminal hydrolase activity required for removing C-terminal amino acids from Smt3 to reveal the diglycine residues important for conjugation to Smt3 substrates. Ulp1 also has the isopeptidase activ...

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Section: Localization and Enzymatic Activity Of Sumo-specific Proteasesmentioning

confidence: 99%

Section: Localization and Enzymatic Activity Of Sumo-specific Proteasesmentioning

confidence: 99%

Section: Localization and Enzymatic Activity Of Sumo-specific Proteasesmentioning

confidence: 99%

Section: Function Of Sumo-specific Proteasesmentioning

confidence: 99%

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SUMOylation and De-SUMOylation: Wrestling with Life's Processes

Yeh

2009

Journal of Biological Chemistry

Self Cite

414

408

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“…SUMO is also conjugated to coregulators of ERa and ERb, thereby modulating their ability to interact with the nuclear receptor and to activate transcription. [11][12][13] In addition, various components of the SUMO-conjugating machinery are upregulated in several malignancies: UBC9 in melanomas, ovarian cancer and lung adenocarcinomas, [14][15][16] the SUMO isopeptidase SENP1 in prostate cancer 17 and PIAS3 in breast, lung, prostate, colorectal and brain tumors. 18 By using MCF-7 human breast cancer cells overexpressing a dominant-negative mutant of UBC9 or wild type UBC9 in a mouse xenograft model it was shown that tumors expressing the UBC9 mutant exhibited reduced growth, whereas wild type UBC9 enhanced tumor growth.…”

mentioning

confidence: 99%

Common variants in the UBC9 gene encoding the SUMO‐conjugating enzyme are associated with breast tumor grade

Dünnebier¹,

Bermejo²,

Haas³

et al. 2009

Intl Journal of Cancer

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UBC9 encodes a protein that conjugates small ubiquitin-related modifier (SUMO) to target proteins resulting in a change of their localization, activity or stability. Genetic variability may affect expression and activity of UBC9 and may have an impact on breast tumor progression. We investigated associations between UBC9 genotypes and histopathological parameters in 1,021 breast cancer cases of the GENICA collection using a single nucleotide polymorphism (SNP) tagging approach. Genotyping analyses were performed by TaqMan 1 allelic discrimination. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by ordinal logistic regression. Multiple imputation based on HapMap data was applied to boost the power of the study. The study revealed significant associations of three UBC9 SNPs with histological grade (rs7187167, p trend 5 0.001; rs11248866, p trend 5 0.009; rs8052688, p trend 5 0.008). Model selection identified a recessive penetrance model for rs7187167 as the best representation of tumor grade (global p 5 0.001). This model did not improve by inclusion of additional SNPs in linkage disequilibrium. Imputation of SNPs in a 300 kb region around the genotyped SNPs supported rs7187167 as a major contributor to tumor grade. Compared with common allele carriers, rare homozygotes presented less frequently with high grade tumors (G3 vs. G1: OR 0.26, 95% CI 0.11-0.62; G3 vs. G2: OR 0.45, 95% CI 0.23-0.86). In addition to tumor size, nodal status and estrogen receptor status, multivariate analyses confirmed an independent role of rs7187167 as predictor of tumor grade (p 5 0.0003). The present results underline the value of genetic variation in UBC9 for breast cancer prognosis. ' 2009 UICC Key words: UBC9 polymorphisms; SUMOylation; breast cancer progression; tumor grade; multiple imputation Rapid and reversible post-translational protein modifications including phosphorylation, methylation, acetylation, glycosylation and ubiquitination are key elements in the regulation of many cellular processes. Another recently identified type of modification is small ubiquitin-related modifier (SUMO) conjugation or SUMOylation. SUMO plays an important role in the regulation of physical interactions. 1,2 By masking or adding interaction surfaces or by inducing conformational changes, it governs proteinprotein and protein-DNA interactions and in consequence can lead to changes in protein localization, activity or stability. Substrates of SUMO participate in diverse cellular processes, including transcriptional regulation, nuclear transport, cell cycle control and maintenance of genome integrity. SUMOylation is a multistep process involving maturation, activation and conjugation. 3 The SUMO-conjugating enzyme UBC9 (UBE2I) is essential for SUMOylation and transfers the activated SUMO to the target protein. This transfer is facilitated by SUMO ligases such as the protein inhibitors of activated STAT (PIAS) family proteins that together with UBC9 confer substrate specificity. 2 Due to the existence of SUMO isopeptidases, SUM...

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Assays for Investigating deSUMOylation Enzymes

Madu

Chen

2012

CP Molecular Biology

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Post-translational modifications by the SUMO (Small Ubiquitin-like MOdifier) family of proteins are recently discovered essential regulatory mechanisms. All SUMO proteins are synthesized as larger precursors that are matured by SUMO-specific proteases, known as SENPs, which remove several C-terminal amino acids of SUMO to expose the Gly-Gly motif. SENPs also remove SUMO modifications from target proteins, making this modification highly dynamic. At least six deSUMOylation enzymes, all of which are encoded by essential genes, have been identified in mammals. SENP1 has been shown to play an important role in the development of prostate cancer and in angiogenesis. This unit describes and discusses methods for characterizing the deSUMOylation enzymes. These assays enable the identification of inhibitors of these enzymes and investigate their mechanism of inhibition in order to develop research tools and future therapeutics.

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Role of Desumoylation in the Development of Prostate Cancer

Cited by 200 publications

References 75 publications

SUMOylation and De-SUMOylation: Wrestling with Life's Processes

SUMOylation and De-SUMOylation: Wrestling with Life's Processes

Common variants in the UBC9 gene encoding the SUMO‐conjugating enzyme are associated with breast tumor grade

Assays for Investigating deSUMOylation Enzymes

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