Fbw7 and Usp28 – enemies and allies

Taranets, Lyudmyla; Zhu, Jing; Xu, Wen-Shan; Popov, Nikita

doi:10.4161/23723556.2014.995041

Cited by 7 publications

(6 citation statements)

References 10 publications

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“…In this model, USP28 may serve as either a tumor promotor or suppressor depending on the status of autocatalytic ubiquitination of FBW7. In the intestine, USP28 deletion does not affect FBW7 stability and attenuates tumorigenesis, while in tissues where FBW7 autocatalytic turnover is favored, deletion of USP28 resembles FBW7 loss-of-function, thus exhibiting a tumor-promoting effect 20 . It is also worth noting that, in addition to the aforementioned oncogenic proteins, other substrates that are known not be associated with FBW7, are also subject to deubiquitination and stabilization by USP28, including Claspin, CHK2, and LSD1 [21][22][23] .…”

Section: Disrupting Physiological Homeostasis Of Ubiquitination Processmentioning

confidence: 99%

Targeting deubiquitinase USP28 for cancer therapy

et al. 2018

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As one of the most important post-translational modifications, ubiquitination plays versatile roles in cancer-related pathways, and is involved in protein metabolism, cell-cycle progression, apoptosis, and transcription. Counteracting the activities of the E3 ligases, the deubiquitylating enzymes have been suggested as another important mechanism to modulate the ubiquitination process, and are implicated in cancer as well. In this article, we review the emerging roles of USP28 in cancer pathways as revealed by recent studies. We discuss the major mechanisms by which USP28 is involved in the cancer-related pathways, whereby USP28 regulates physiological homeostasis of ubiquitination process, DNA-damage response, and cell cycle during genotoxic stress. We further review the studies where USP28 was targeted for treating multiples cancers including non-small cell lung cancer, breast cancer, intestinal cancers, gliomas, and bladder cancer. As a result, the clinical significance of targeting USP28 for cancer therapy merits further exploration and demonstration.

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Section: Disrupting Physiological Homeostasis Of Ubiquitination Processmentioning

confidence: 99%

Targeting deubiquitinase USP28 for cancer therapy

et al. 2018

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“…Ub chains exist in a dynamic equilibrium of E3-mediated assembly and DUB-mediated disassembly. DUBs may be in the same complex as E3s (Sowa et al, 2009) and can work as an Ub chain editing module (Engel et al, 2016;Iyengar et al, 2015;Taranets et al, 2015;Wertz et al, 2004). Recent evidence suggests this may be the case for LUBAC.…”

Section: Regulation Of Lubac By Deubiquitinasesmentioning

confidence: 99%

The Met1-Linked Ubiquitin Machinery: Emerging Themes of (De)regulation

2017

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The linear ubiquitin chain assembly complex, LUBAC, is the only known mammalian ubiquitin ligase that makes methionine 1 (Met1)-linked polyubiquitin (also referred to as linear ubiquitin). A decade after LUBAC was discovered as a cellular activity of unknown function, there are now many lines of evidence connecting Met1-linked polyubiquitin to NF-κB signaling, cell death, inflammation, immunity, and cancer. We now know that Met1-linked polyubiquitin has potent signaling functions and that its deregulation is connected to disease. Indeed, mutations and deficiencies in several factors involved in conjugation and deconjugation of Met1-linked polyubiquitin have been implicated in immune-related disorders. Here, we discuss current knowledge and recent insights into the role and regulation of Met1-linked polyubiquitin, with an emphasis on the mechanisms controlling the function of LUBAC.

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“…In line with previous observations the decrease of USP28 was accompanied by a reduction in HIF-1α (Flügel et al , 2012), p53 (Richter et al , 2018), and c-MYC levels. (Richter et al , 2018; Zhang et al , 2006; Popov et al , 2007; Fong et al , 2016)(Taranets et al , 2015) Knockdown of DTX3L using two different DTX3L shRNAs raised USP28 protein levels up to two-fold and induced HIF-1α levels under hypoxia, and p53, and c-MYC levels under both normoxia and hypoxia ( Fig. 3A,B ).…”

Section: Resultsmentioning

confidence: 99%

DTX3L and USP28 fine-tune DNA double strand repair through mutual regulation of their protein levels

Ashok

Mennerich

Vela-Rodríguez

et al. 2023

Preprint

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The DNA damage response involves a complex protein network with members mediating different post-translational modifications such as ubiquitination and deubiquitination. Thereby the E3 ubiquitin ligase DTX3L as well as the deubiquitinase USP28 are recruited especially to DNA double strand breaks (DSBs) suggesting mutual functional interactions. Here we present evidence for the existence of such crosstalk. Mechanistically we show that DTX3L interacts directly with USP28 and ubiquitinates it, which leads to its proteasomal degradation. Vice versa, USP28 can remove those polyubiquitin chains from itself as well as from autoubiquitinated DTX3L. Consequently, these mutual regulatory interactions between DTX3L and USP28 affected DSB repair activities. Analysis of distinct DSB repair pathways reveals synthetic dysfunction of canonical non-homologues end joining (NHEJ) and homologous recombination (HR), upon USP28 and DTX3L double knockdown, suggesting cooperation between these proteins. Conversely, error-prone microhomology-mediated end joining (MMEJ) requires USP28 to counterbalance the antagonistic DTX3L effect. Together, the present data indicate that DTX3L and USP28 are under mutual control to fine-tune the capacity and quality of the cellular responses to stresses such as DNA damage.

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Fbw7 and Usp28 – enemies and allies

Cited by 7 publications

References 10 publications

Targeting deubiquitinase USP28 for cancer therapy

Targeting deubiquitinase USP28 for cancer therapy

The Met1-Linked Ubiquitin Machinery: Emerging Themes of (De)regulation

DTX3L and USP28 fine-tune DNA double strand repair through mutual regulation of their protein levels

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