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Simins, Almut B.; Weighardt, Heike; Weidner, K. Michael; Weidle, Ulrich H.; Holzmann, Bernhard

doi:10.1023/a:1006790912877

Cited by 29 publications

(6 citation statements)

References 29 publications

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“…In ADRM1 knock-out mice, the most notable phenotype is a defect in oogenesis, suggesting that ADRM1 normally plays a critical role in ovarian development [7]. The role ADRM1 plays in ovarian cancer is unknown but it has been shown to be upregulated in metastatic tumor cells, and its overexpression increased the propensity of cells to engage in cell-cell interactions [2,8]. A study of commonly overexpressed genes in solid tumors by microarray analysis shows that ADRM1 is consistently over-expressed in multiple tumor types, including lung adenocarcinoma, lung squamous cell carcinoma, bladder, colon, liver, kidney, and stomach cancer in addition to ovarian cancer [9], suggesting that this gene may be a potential target in many tumor types.…”

Section: Introductionmentioning

confidence: 99%

Amplification Target ADRM1: Role as an Oncogene and Therapeutic Target for Ovarian Cancer

Fejzo

Anderson

Euw

et al. 2013

IJMS

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Approximately 25,000 ovarian cancers are diagnosed in the U.S. annually, and 75% are in the advanced stage and largely incurable. There is critical need for early detection tools and novel treatments. Proteasomal ubiquitin receptor ADRM1 is a protein that is encoded by the ADRM1 gene. Recently, we showed that among 20q13-amplified genes in ovarian cancer, ADRM1 overexpression was the most highly correlated with amplification and was significantly upregulated with respect to stage, recurrence, and metastasis. Its overexpression correlated significantly with shorter time to recurrence and overall survival. Array-CGH and microarray expression of ovarian cancer cell lines provided evidence consistent with primary tumor data that ADRM1 is a 20q13 amplification target. Herein, we confirm the ADRM1 amplicon in a second ovarian cancer cohort and define a minimally amplified region of 262 KB encompassing seven genes. Additionally, using RNAi knock-down of ADRM1 in naturally amplified cell line OAW42 and overexpression of ADRM1 via transfection in ES2, we show that (1) ADRM1 overexpression increases proliferation, migration, and growth in soft agar, and (2) knock-down of ADRM1 results in apoptosis. Proteomic analysis of cells with ADRM1 knock-down reveals dysregulation of proteins including CDK-activating kinase assembly factor MAT1. Taken together, the results indicate that amplified ADRM1 is involved in cell proliferation, migration and survival in ovarian cancer cells, supporting a role as an oncogene and novel therapeutic target for ovarian cancer.

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Section: Introductionmentioning

confidence: 99%

Amplification Target ADRM1: Role as an Oncogene and Therapeutic Target for Ovarian Cancer

Fejzo

Anderson

Euw

et al. 2013

IJMS

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“…ADRM1 was originally identified as ADhesion Regulating Molecule-1 in metastatic tumor cells [ 28 ]. Several observations have driven interest in RPN13 ’s role in cancer biology; 1) early studies suggested that ADRM1 transcript levels commonly upregulated in diverse tumor types [ 29 ], 2) ADRM1 was identified as a recurrent amplification target in ovarian cancer [ 30 – 32 ], colorectal carcinoma [ 33 , 34 ], gastric cancer [ 35 , 36 ], 3) knockdown of ADRM1 transcripts suppressed proliferation, growth in soft agar and migration of diverse cancer lines but not normal cells [ 31 , 34 – 39 ], 4) over-expression of RPN13 via ectopic expression of ADRM1 enhanced proliferation [ 32 , 35 ], 5) ADRM1 -encoded RPN13 is required for cell cycle progression [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma

et al. 2017

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BackgroundOvarian carcinoma is highly dependent on the ubiquitin proteasome system (UPS), but its clinical response to treatment with the proteasome inhibitor bortezomib has been disappointing. This has driven exploration of alternate approaches to target the UPS in ovarian cancer. Recently, proteasome inhibitors targeting the 19S regulatory particle-associated RPN13 protein have been described, such as RA190. RPN13, which is encoded by ADRM1, facilitates the recognition by the proteasome of its polyubiquinated substrates. Inhibition of RPN13 produces a rapid, toxic accumulation of polyubiquitinated proteins in ovarian and other cancer cells, triggering apoptosis.Here, we sought to determine if RPN13 is available as a target in precursors of ovarian/fallopian tube cancer as well as all advanced cases, and the impact of increased ADRM1 gene copy number on sensitivity of ovarian cancer to RA190.Methods ADRM1 mRNA was quantified by RNAscope in situ hybridization and RPN13 protein detected by immunohistochemistry in high grade serous carcinoma (HGSC) of the ovary and serous tubal intraepithelial carcinoma (STIC). Amplification of ADRM1 and sensitivity to RA190 were determined in ovarian cancer cell lines.ResultsHere, we demonstrate that expression of ADRM1mRNA is significantly elevated in STIC and HGSC as compared to normal fallopian tube epithelium. ADRM1 mRNA and RPN13 were ubiquitously and robustly expressed in ovarian carcinoma tissue and cell lines. No correlation was found between ADRM1 amplification and sensitivity of ovarian cancer cell lines to RA190, but all were susceptible.ConclusionsRPN13 can potentially be targeted by RA190 in both in situ and metastatic ovarian carcinoma. Ovarian cancer cell lines are sensitive to RA190 regardless of whether the ADRM1 gene is amplified.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-017-0347-y) contains supplementary material, which is available to authorized users.

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“…The Rpn13 protein, previously termed adhesion-regulating protein 1 or GP110, has been identified as a tumor-associated gene product [1], [2], [3], [4], [5], [6], and more recently as an amplification target in ovarian cancer [7]. Initially, Rpn13 was suggested to regulate cell adhesion as a membrane-associated protein [2], but further examination revealed that it is primarily a cytosolic protein associated with proteasomes [8].…”

Section: Introductionmentioning

confidence: 99%

“…Initially, Rpn13 was suggested to regulate cell adhesion as a membrane-associated protein [2], but further examination revealed that it is primarily a cytosolic protein associated with proteasomes [8]. Proteasomes are central molecular complexes of the non-lysosomal, ubiquitin-ATP-dependent protein degradation pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Viability of the human HeLa cell line, was also unaffected by knocking down expression of Rpn13 [15] or Uch37 [16]. Overexpression of Rpn13 was reported to increase the adherence of 293T cells [2], as well as human natural killer (NK) and T cells [8], to endothelial cells. However, one study found that overexpression of the C-terminal domain of Rpn13 that modifies Uch37 function, led to cell death in the 293T cell line [10].…”

Section: Introductionmentioning

confidence: 99%

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Regulators of the Proteasome Pathway, Uch37 and Rpn13, Play Distinct Roles in Mouse Development

et al. 2010

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Rpn13 is a novel mammalian proteasomal receptor that has recently been identified as an amplification target in ovarian cancer. It can interact with ubiquitin and activate the deubiquitinating enzyme Uch37 at the 26S proteasome. Since neither Rpn13 nor Uch37 is an integral proteasomal subunit, we explored whether either protein is essential for mammalian development and survival. Deletion of Uch37 resulted in prenatal lethality in mice associated with severe defect in embryonic brain development. In contrast, the majority of Rpn13-deficient mice survived to adulthood, although they were smaller at birth and fewer in number than wild-type littermates. Absence of Rpn13 produced tissue-specific effects on proteasomal function: increased proteasome activity in adrenal gland and lymphoid organs, and decreased activity in testes and brain. Adult Rpn13−/− mice reached normal body weight but had increased body fat content and were infertile due to defective gametogenesis. Additionally, Rpn13−/− mice showed increased T-cell numbers, resembling growth hormone-mediated effects. Indeed, serum growth hormone and follicular stimulating hormone levels were significantly increased in Rpn13−/− mice, while growth hormone receptor expression was reduced in the testes. In conclusion, this is the first report characterizing the physiological roles of Uch37 and Rpn13 in murine development and implicating a non-ATPase proteasomal protein, Rpn13, in the process of gametogenesis.

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Cited by 29 publications

References 29 publications

Amplification Target ADRM1: Role as an Oncogene and Therapeutic Target for Ovarian Cancer

Amplification Target ADRM1: Role as an Oncogene and Therapeutic Target for Ovarian Cancer

Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma

Regulators of the Proteasome Pathway, Uch37 and Rpn13, Play Distinct Roles in Mouse Development

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