A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance

Chauhan, Dharminder; Tian, Ze; Nicholson, Benjamin; Kumar, Krishna; Zhou, Bin; Carrasco, Ruben D.; McDermott, Jeffrey L.; Leach, Craig A.; Fulcinniti, Mariaterresa; Kodrasov, Matthew P.; Weinstock, Joseph; Kingsbury, William D.; Hideshima, Teru; Shah, Parantu K.; Minvielle, Stéphane; Altun, Mikael; Kessler, Benedikt M.; Orłowski, Robert Z.; Richardson, Paul G.; Munshi, Nikhil C.; Anderson, Kenneth C.

doi:10.1016/j.ccr.2012.08.007

Cited by 488 publications

(514 citation statements)

References 38 publications

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“…To address the in vivo function of USP28 in intestinal homeostasis, we vidual USPs using small-molecule inhibitors (32,33), which suggests that targeting USP28 may be therapeutically feasible. However, whether USP28 has a role in intestinal tumorigenesis is not known.…”

Section: Mice Harboring a Usp28 Deletion Show Normal Intestinal Morphmentioning

confidence: 99%

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Diefenbacher¹,

Popov

Blake³

et al. 2014

J. Clin. Invest.

123

136

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R e s e a R c h a R t i c l e3 4 0 7 jci.org Volume 124 Number 8 August 2014 IntroductionThe intestine is made up of repetitive units that consist of a differentiated compartment (the villus) and a proliferative compartment (the crypt). Intestinal stem cells are located in the crypt (1, 2) and produce rapidly proliferating daughter cells, the transit amplifying cells, which subsequently differentiate into 2 main epithelial lineages. The absorptive lineage is composed of all enterocytes, while the secretory lineage is composed of goblet cells (secreting protective mucins), enteroendocrine cells (secreting hormones like serotonin or secretin), and Paneth cells (3, 4). Whether transit amplifying cells differentiate along an absorptive or a secretory lineage is regulated by the Notch pathway (5). Engagement of Notch receptors by Notch ligands, such as Delta or Jagged, induces proteolytic cleavage of the receptor by γ-secretase. The cleaved NOTCH1 receptor (NICD1) translocates into the nucleus, resulting in the formation of an active transcriptional complex composed of RBPJκ (also known as CSL or CBF1) and NICD1. Notch signal activation induces hairy/enhancer of split (Hes) gene expression. Ablation of Notch signaling via genetic deletion of Rbpj results in secretory cell expansion (6). Conversely, in transgenic mice overexpressing NICD1, goblet cells are absent, and the proliferative compartment is expanded (7).The Wnt signaling pathway is a key regulator of intestinal stem cell homeostasis (8), and 2 of the target genes induced by Wnt signaling, c-MYC and c-JUN, encode transcription factors that have oncogenic potential (9, 10). Consequently, aberrant activation of the adenomatous polyposis coli/β-catenin/T cell factor (APC/ β-catenin/TCF) pathway is an initiating event in the majority of human colorectal cancers (11).c-MYC is a transcription factor with key functions in cell differentiation and cancer development (12)(13)(14). In the intestine, c-MYC is required for the altered proliferation and differentiation induced by APC inactivation (15-18). c-MYC is a highly labile protein, and at least 2 ubiquitin ligases, SKP2 and FBW7, can target it for proteasomal degradation (19-21). c-MYC ubiquitination is antagonized by the deubiquitinase USP28, which "piggybacks" on FBW7 and stabilizes c-MYC protein (22). Thus, an E3 ubiquitin ligase and a deubiquitinase, FBW7 and USP28, are together recruited to substrates (22), and a cycle of deubiquitination and ubiquitination controls c-MYC stability.Genomic data from human cancers suggest that most colorectal cancer mutations converge on c-MYC misregulation (23). Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24-29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17). Transgenic expression of a dominant-negative allele of Myc, OmoMyc, has provided proof of principle that targeting ...

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Section: Mice Harboring a Usp28 Deletion Show Normal Intestinal Morphmentioning

confidence: 99%

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Diefenbacher¹,

Popov

Blake³

et al. 2014

J. Clin. Invest.

123

136

View full text Add to dashboard Cite

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“…The tumor-inoculated nude xenograft model was performed as previously described (LeBlanc et al, 2002;Chauhan et al, 2012). Twenty mice were randomized to two groups, each group was subcutaneously at the right armpit with 5.0×10 6 A2780 or A2780/Taxol cells in 200 μl of PBS/matrigel (1:1) respectively.…”

Section: Nude Mouse Xenograft Modelmentioning

confidence: 99%

Mechanistic Analysis of Taxol-induced Multidrug Resistance in an Ovarian Cancer Cell Line

Wang¹,

Zhao²,

Wu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…One recently described Usp7 inhibitor has demonstrated anti-MM activity in preclinical animal models. 3 Other inhibitors targeting two DUBs that are components of the 19S proteasome have been shown to have activity against several tumors, including myeloma. 4 Usp9x has received considerable attention as a potential therapeutic target for several cancers after it was reported to regulate the ubiquitination and half-life of Mcl-1, a key antiapoptotic protein detected in many tumors.…”

Section: Introductionmentioning

confidence: 99%

Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

Peterson

Sun

Liu

et al. 2015

Blood

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A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance

Cited by 488 publications

References 38 publications

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Mechanistic Analysis of Taxol-induced Multidrug Resistance in an Ovarian Cancer Cell Line

Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

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