Sumoylation: A new wrestler in the DNA repair ring

Aragón, Luís

doi:10.1073/pnas.0501342102

Cited by 9 publications

(3 citation statements)

References 23 publications

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“…Numerous targets of the sumoylation pathway have been identified downstream from Ube2I and PIAS1, specifically, STAT family members, p53 and c-Jun. 17,18 Importantly, we have recently shown that the tumor suppressor p53 is a major target of sumoylation in MMCLs after DNA damage and is also found sumoylated in MM patient samples but not in normal PCs (J.J.D., manuscript in preparation). Similarly, inhibitors of the 26S proteasome complex that is responsible for ATPϩUb-dependent proteolysis have demonstrated clinical benefit, although the precise substrates stabilized by bortezomib that ultimately lead to cell death remain unidentified.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16] Whereas ubiquitination generally leads to proteasome-mediated proteolysis, posttranslational covalent attachment of the small ubiquitin-like modifier (Sumo) to target substrates has been reported to have an additional function and may control subcellular localization, function, or binding of targets to other proteins. [17][18][19] In mammalian cells, 3 Sumo isoforms are expressed as precursors and are cleaved at the C-terminus by sumo-specific proteases. A complex that consists of SAE1 and SAE2 (E1) activates Sumo and transfers it to the conjugating enzyme Ubc9/Ube2I (E2).…”

Section: Introductionmentioning

confidence: 99%

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The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome

Driscoll

Pelluru

Lefkimmiatis

et al. 2010

Blood

105

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Multiple myeloma (MM) is a plasma cell neoplasm that proceeds through a premalignant state of monoclonal gammopathy of unknown significance; however, the molecular events responsible for myelomagenesis remain uncharacterized. To identify cellular pathways deregulated in MM, we addressed that sumoylation is homologous to ubiquitination and results in the attachment of the ubiquitin-like protein Sumo onto target proteins. Sumoylation was markedly enhanced in MM patient lysates compared with normal plasma cells and expression profiling indicated a relative induction of sumoylation pathway genes. The Sumoconjugating enzyme Ube2I, the Sumoligase PIAS1, and the Sumo-inducer ARF were elevated in MM patient samples and cell lines. Survival correlated with expression because 80% of patients with low UBE2I and PIAS1 were living 6 years after transplantation, whereas only 45% of patients with high expression survived 6 years. UBE2I encodes the sole Sumoconjugating enzyme in mammalian cells and cells transfected with a dominantnegative sumoylation-deficient UBE2I mutant exhibited decreased survival after radiation exposure, impaired adhesion to bone marrow stroma cell and decreased bone marrow stroma cell-induced proliferation. UBE2I confers cells with multiple advantages to promote tumorigenesis and predicts decreased survival when combined with PIAS1. The sumoylation pathway is a novel therapeutic target with implications for existing proteasomal- IntroductionMultiple myeloma (MM) is a neoplasia hallmarked by the clonal expansion of malignant plasma cells (PCs) and the accumulation of a monoclonal immunoglobulin (Ig) or Ig fragment detectable in the serum and/or urine. [1][2][3] MM is the second most commonly diagnosed hematologic malignancy in the Western world, accounts for nearly 20% of all hematologic malignancies, and despite conventional treatment or high-dose therapy with stem cell transplantation is generally considered incurable. 4,5 Recent advances in mechanistic understanding and treatment modalities have extended median survival to exceed 6 years, and 10% of MM patients survive beyond 10 years. [6][7][8] Although high-dose therapy and novel agents that include thalidomide, its analog lenalidomide, and proteasome inhibitors have significantly improved prognosis, patient survival remains highly variable and cannot be accurately predicted with current models in part because the cellular pathways that determine patient response to treatment remain unidentified.In eukaryotes, a highly conserved multienzyme system is used in a sequential process to covalently attach the polypeptide ubiquitin to proteins targeted for degradation. 9,10 Ubiquitination is an essential process that maintains cellular homeostasis through dynamic switches in protein functional states. Ubiquitin-protein conjugates are then degraded in by the ATP-dependent 26S proteasome complex. 11,12 Deregulation of ubiquitination in tumor models has resulted in malignant transformation and tumor progression. 13 In myeloma, proteasomal-dependent catabolis...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome

Driscoll

Pelluru

Lefkimmiatis

et al. 2010

Blood

105

View full text Add to dashboard Cite

show abstract

“…The ubiquitin proteasome pathway (UPP) is integral to the normal function of eukaryotic cells (Joazeiro and Weissman 2000; Tanaka et al, 2001; Pan et al, 2004; Dohmen, 2004; Pickard and Eddins 2004; Aragon, 2005; Mani and Gelmann, 2005; Denison et al, 2005). It is ATP dependent and involves the covalent attachment of chains of ubiquitin molecules to target substrates.…”

Section: Introductionmentioning

confidence: 99%

Protein degradation machinery is present broadly during early development in the sea urchin

Zazueta-Novoa

Wessel

2014

Gene Expression Patterns

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Ubiquitin-dependent proteosome-mediated proteolysis is an important pathway of degradation that controls the timed destruction of cellular proteins in all tissues. All intracellular proteins and many extracellular proteins are continually being hydrolyzed to their constituent amino acids as a result of their recognition by E3 ligases for specific targeting of ubiquitination. Gustavus is a member of an ECS-type E3 ligase which interacts with Vasa, a DEAD-box RNA helicase, to regulate its localization during sea urchin embryonic development, and Gustavus mRNA accumulation is highly localized and dynamic during development. We tested if the core complex for Gustavus function was present in the embryo and if other SOCS box proteins also had restricted expression profiles that would inform future research. Expression patterns of the key members of the proteasomal function, such as the E3 core complex which interacts with Gustavus, and other E3-SOCS box proteins, are widely spread and dynamic in early development of the embryo suggesting broad core complex availability in the proteasome degradation pathway and temporal/spatial enrichments of various E3 ligase dependent targeting mechanisms.

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BCA2 is differentially expressed in renal oncocytoma: an analysis of 158 renal neoplasms

et al. 2012

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The distinction between renal oncocytoma and renal cell carcinoma, especially chromophobe renal cell carcinoma and clear cell carcinoma with oncocytic features, is important due to the different biologic potentials of these tumors. RING E3 ligases have the subject of intense studies for their roles in many diseases including cancer and as potential therapeutic targets. All RING E3 ligases, including BCA2, contain a consensus protein sequence that would complex two or more zinc ions in the expressed protein. Identification of which ubiquitin ligases specifically affect distinct cellular processes is essential to the development of targeted therapeutics in these tumors. The ubiquitin-proteasome system regulates the turnover of proteins that have essential roles in the cell cycle, apoptosis, DNA damage repair, and in protein trafficking, which makes this pathway a target for oncogenic events. In this study, we investigated expression of BCA2 in renal oncocytoma and renal cell carcinoma. A total of 158 patients were included in the study. Our study has shown that 114/114 (100 %) cases of renal cell carcinoma were negative for BCA2. All 38 (100 %) cases of renal oncocytoma were positive for BCA2, and 6/6 (100 %) cases designated as oncocytic neoplasm which favor oncocytoma were also positive for BCA2. This is the first study to date evaluating the expression of BCA2 in renal oncocytoma. BCA2 could serve as a marker that may be utilized in the distinction between renal oncocytoma and its mimickers.

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Sumoylation: A new wrestler in the DNA repair ring

Cited by 9 publications

References 23 publications

The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome

The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome

Protein degradation machinery is present broadly during early development in the sea urchin

BCA2 is differentially expressed in renal oncocytoma: an analysis of 158 renal neoplasms

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