FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination

Dupont, Sirio; Mamidi, Anant; Cordenonsi, Michelangelo; Montagner, Marco; Zacchigna, Luca; Adorno, Maddalena; Martello, Graziano; Stinchfield, Michael J.; Soligo, Sandra; Morsut, Leonardo; Inui, Masafumi; Moro, Stefano; Modena, Nicola; Argenton, Francesco; Newfeld, Stuart J.; Piccolo, Stefano

doi:10.1016/j.cell.2008.10.051

Cited by 446 publications

(470 citation statements)

References 36 publications

(52 reference statements)

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“…In recent years, more and more studies have revealed the involvement of deubiquitinating enzymes in cancers as well as in other diseases (8,48). USP9X, a ubiquitin-specific protease family member, is shown to regulate ubiquitination of different signal transduction pathway proteins, including AMPK (48), TGFb (8), ErbB2/HER2 (49), and ASK1 (7).…”

Section: Discussionmentioning

confidence: 99%

“…5,6). USP9X has been shown to regulate multiple cellular functions (7)(8)(9)(10), and increased expression of USP9X in tumors is significantly associated with poor prognosis for patients with multiple myeloma (4). USP9X does not affect all apoptosis signaling pathways but specifically modulates those regulated by Mcl-1: USP9X binds to Mcl-1 and removes the Lys48-linked polyubiquitin chain that normally marks Mcl-1 for proteasomal degradation.…”

Section: Introductionmentioning

confidence: 99%

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Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Zhang

Cai

Zhu

et al. 2011

Molecular Cancer Therapeutics

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The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL, but not Mcl-1, which may confer resistance to this agent in various cancers with high levels of Mcl-1. Here, we showed that the combination of gemcitabine and ABT-737 exhibited synergistic cytotoxicity and induced significant apoptosis in multiple cancer types, including lung, renal, bladder, and prostate cancers. The enhanced apoptosis induced by gemcitabine plus ABT-737 was accompanied by the greater extent of mitochondrial depolarization, caspases-3 activation, and PARP cleavage in 95-D and 5637 cell lines. Importantly, in ABT-737-resistant cancer cells, the interaction between USP9X and Mcl-1, which was increased by ABT-737 treatment, could be disrupted by gemcitabine, thus resulting in enhanced ubiquitination and the subsequent degradation of Mcl-1 and ultimately in the synergism of these two drugs. Moreover, the increased anticancer efficacy of gemcitabine combined with ABT-737 was further validated in a human lung cancer 95-D xenograft model in nude mice. Taken together, our data first showed the synergistic anticancer capabilities achieved by combining gemcitabine and ABT-737 and, second, opened new opportunities to use antiapoptotic Bcl-2 family members, which drive tumor cell resistance in current anticancer therapies, therapeutically. Mol Cancer Ther; 10(7); 1264-75. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Zhang

Cai

Zhu

et al. 2011

Molecular Cancer Therapeutics

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“…A third posttranslational modification that negatively regulates DNA binding is monoubiquitylation, which again induces disruption of DNA-bound SMAD complexes. Monoubiquitylation at Lys519 and, to a lesser extent, Lys507 in the MH2 domain of SMAD4 by the E3 ubiquitin ligase TIF1g (transcriptional intermediary factor 1g, also known as TRIM33 or ectodermin) disrupts the formation of SMAD2/3 -SMAD4 complexes and as a result their ability to bind DNA (Dupont et al 2009). This mechanism will be discussed in more detail below.…”

Section: Dna Binding Of Smad Complexes and Its Regulation By Posttranmentioning

confidence: 99%

Transcriptional Control by the SMADs

Hill

2016

Cold Spring Harb Perspect Biol

282

256

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The transforming growth factor-b (TGF-b) family of ligands elicit their biological effects by initiating new programs of gene expression. The best understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications. The SMAD complexes have weak affinity for DNA and limited specificity and, thus, they cooperate with other site-specific transcription factors that act either to actively recruit the SMAD complexes or to stabilize their DNA binding. In some situations, these cooperating transcription factors function to integrate the signals from TGF-b family ligands with environmental cues or with information about cell lineage. Activated SMAD complexes regulate transcription via remodeling of the chromatin template. Consistent with this, they recruit a variety of coactivators and corepressors to the chromatin, which either directly or indirectly modify histones and/or modulate chromatin structure.

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“…So far, three DUBs have been reported to be involved in the regulation of this pathway: USP9X, AMSH-LP and UCHL5. USP9X positively regulates TGF-b signaling by deubiquitylating SMAD4 and promoting its association with SMAD2 (Dupont et al, 2009). USP9X also deubiquitylates the AMPK-related kinases NUAK1 and MARK4, implicated in the regulation of cell polarity and proliferation, and modulates their phosphorylation and activation by LKB1 (Al-Hakim et al, 2008).…”

Section: Signaling Pathwaysmentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination

Cited by 446 publications

References 36 publications

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Transcriptional Control by the SMADs

Deubiquitinases in cancer: new functions and therapeutic options

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