The ubiquitin-proteasome system

Nandi, Dipankar; Tahiliani, P; Kumar, Anujith; Chandu, Dilip

doi:10.1007/bf02705243

Cited by 581 publications

(420 citation statements)

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“…Although no specific UBE2C inhibitors are currently available for clinical use, proteasome inhibitors form a novel class of chemotherapeutic agents that lead to cell cycle arrest and cell death. Bortezomib is a specific reversible inhibitor of proteasome function that is crucial for protein degradation 17 and has been approved by the US Food and Drug Administration for therapy for multiple myeloma. 18 Earlier studies by other groups, including our laboratory, have shown that SCF-SKP2 ubiquitin proteasome pathway alterations in tumors is a ubiquitous phenomenon and is present in various tumors, such as CRC, ovarian carcinomas, and diffuse large Bcell lymphomas.…”

mentioning

confidence: 99%

Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma

Bavi

Uddin

Ahmed

et al. 2011

The American Journal of Pathology

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Substantial evidence implicates the ubiquitin-conjugating enzyme E2C (UBE2C) gene, in several human cancers, including colorectal carcinoma (CRC). We therefore investigated the prognostic value of UBE2C alterations in CRC and UBE2C signaling in CRC cell lines. UBE2C protein expression and UBE2C gene copy number were evaluated on clinical samples by immunohistochemistry and fluorescence in situ hybridization in a TMA format. The effect of the proteasome inhibitor bortezomib and small-interfering RNA knockdown was assessed by apoptotic assays and immunoblotting. UBE2C dysregulation was associated with proliferative marker Ki-67, accumulation of cyclin A and B1, and a poor overall survival. UBE2C expression was an independent prognostic marker in early-stage (I and II) CRC. UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1. In vitro, bortezomib treatment of CRC cells caused inhibition of cell viability via down-regulation of UBE2C. UBE2C knockdown by bortezomib or transfection with specific small-interfering RNA against UBE2C also caused cells to be arrested at the G2/M level, leading to accumulation of cyclin A and cyclin B1. In vivo, a significant reduction in tumor volume and weight was noted in mice treated with a combination of subtoxic doses of oxaliplatin and bortezomib compared with treatment with oxaliplatin or bortezomib alone. Altogether, our results suggest that UBE2C and the ubiq- Although colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide, various therapeutic modalities followed in clinical practice are not life saving. More recently, advances in understanding of tumor biology have led to the development of targeted therapies, 1 allowing progress in the treatment of CRC. 2 The ubiquitin proteasome system is important for the orchestration of several important cell cycle events, such as proteolysis of cyclin-dependent kinase and their inhibitors. 3,4 Proper cell cycle progression is orchestrated by the controlled oscillation of a series of cell cycle events. Deregulation of appropriate cell cycle control often results in chromosomal instability, which is a potential trigger for the initiation of cancer. 5 In this system, substrate molecules are regulated for degradation by ubiquitinactivating enzyme (E1), ubiquitin-conjugating enzyme (E2), and E3 ligase. The ubiquitin-conjugating enzyme E2C (UBE2C), also known as UBCH10, along with the E3 ligase of the anaphase-promoting complex catalyze the ubiquitination of mitotic cyclins A and B1, as well as securin. 3,6 UBE2C is essential for cell cycle progression, and mutation of its active site cysteine confers a dominant-negative phenotype. 3,6 Overexpression of UBE2C at the mRNA level has been reported in a number of cancer cell lines and primary tumors, whereas only low levels were found in normal tissues. 7 The oncogenic role of UBE2C is also reported in thyroid, 8 ovarian, 9 esopha-

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confidence: 99%

Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma

Bavi

Uddin

Ahmed

et al. 2011

The American Journal of Pathology

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“…It is this active site that can be targeted by some proteasome inhibitors (such as Bortezomib) (Figure 1) through nucleophilic attack (67,70). Additionally, the 19S regulatory particle (700 kDa) contains six ATPase and at least eight non-ATPase subunits, which are required for recognition, deubiquitination, unfolding, and translocation of tagged proteins prior to degradation by the 20S proteasome (71)(72).…”

Section: Ubiquitin-proteasome Pathwaymentioning

confidence: 99%

New applications of old metal-binding drugs in the treatment of human cancer

Dou¹

2012

Front Biosci

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Significant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition to platinum-based complexes, the anticancer properties of other metals such as ruthenium have been realized, and ruthenium-based compounds are currently being investigated in clinical trials. Since the process of drug development can be expensive and cumbersome, finding new applications of existing drugs may provide effective means to expedite the regulatory process in bringing new drugs to the clinical setting. Encouraging findings from laboratory studies reveal significant anticancer activity from different classes of metal-chelating compounds, such as disulfiram, clioquinol, and dithiocarbamate derivatives that are currently approved for the treatment of various pathological disorders. Their use as coordination complexes with metals such as copper, zinc, and gold that target the ubiquitin-proteasome pathway have shown significant promise as potential anticancer agents. This review discusses the unique role of several selected metals in relation to their anti-cancer properties as well as the new therapeutic potential of several previously approved metal-chelating drugs. In vitro and in vivo experimental evidence along with mechanisms of action (e.g., via targeting the tumor proteasome) will also be discussed with anticipation of strengthening this exciting new concept. KeywordsDisulfiram; Clioquinol; Dithiocarbamates; Copper; Zinc; Ubiquitin-Proteasome Pathway; Proteasome Inhibitor; Chymotrypsin-Like Activity; Review INTRODUCTION The use of metal complexes for cancer treatmentThe development of metal-based complexes for the treatment of cancer began with the discovery of the anti-cancer properties of cisplatin in the early 1960s (Figure 1). Over 90% of testicular cancer cases have been cured by cisplatin, and it has also been important in the treatment of several other types of cancer, including ovarian, cervical, bladder, head and neck, melanoma, and lymphomas (1). Cisplatin interacts with DNA and forms adducts which interfere with the replication and transcription processes, and ultimately triggers apoptosis (2). These cisplatin-DNA interactions have been extensively studied, and it has been clearly shown that a (Pt)-GG intrastrand cross-link is responsible for the cytotoxicity of Send correspondence to: Qing Ping Dou, The Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA, doup@karmanos.org. NIH Public Access Author ManuscriptFront Biosci (Schol Ed). Author manuscript; available in PMC 2013 May 07. Published in final edited form as:Front Biosci (Schol Ed). ; 4: 375-391. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cisplatin (3). However, the toxicities associated with cisplatin, coupled with intrinsic and acquired drug resistance, ha...

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“…On the activation by E1 enzyme and the conjugation to E2 enzyme, ubiquitin moieties is transferred to the E3 ligase-recognized substrates, leading to polyubiquitination of the substrate protein, which will be destined for destruction by the 26S proteasome (Nandi et al, 2006;von Mikecz, 2006). The selectivity of the ubiquitinproteasome pathway for a particular substrate protein relies on E3 ligases.…”

Section: Introductionmentioning

confidence: 99%

The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

et al. 2009

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The inhibitor of growth family member 3 (ING3) has been shown to modulate transcription, cell cycle control and apoptosis. We previously reported that nuclear ING3 expression was remarkably reduced in melanomas, which correlated with a poorer patient survival, suggesting that decreased ING3 expression may be associated with melanoma progression. However, the mechanism of diminished ING3 expression in melanoma is not clear. Here we show that ING3 level was decreased in metastatic melanoma cells because of a rapid degradation. Furthermore, we showed that ING3 undergoes degradation through the ubiquitinproteasome pathway. ING3 physically interacts with subunits of E3 ligase Skp1-Cullin-F-box protein complex (SCF complex). Knockdown of F-box protein S-phase kinaseassociated protein 2 (Skp2) reduces the ubiquitination of ING3 and significantly stabilizes ING3 in melanoma cells. In addition, lysine 96 residue is essential for ING3 ubiquitination as its mutation to arginine dramatically abrogated ING3 degradation. Disruption of ING3 degradation stimulated ING3-induced G1 cell-cycle arrest and enhanced ultravioletinduced apoptosis. Taken together, our data show that ING3 is degraded by the ubiquitin-proteasome pathway through the SCF Skp2 complex and interruption of ING3 degradation enhances the tumor-suppressive function of ING3, which provides a potential cancer therapeutic approach by interfering ING3 degradation.

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The ubiquitin-proteasome system

Cited by 581 publications

References 155 publications

Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma

Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma

New applications of old metal-binding drugs in the treatment of human cancer

The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

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