Molecular mechanisms and functions of cytokine-inducible deubiquitinating enzymes

Lim, Key Hwan; Ramakrishna, Suresh; Baek, Kwang‐Hyun

doi:10.1016/j.cytogfr.2013.05.007

Cited by 28 publications

(18 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A number of recent studies suggest that DUBs are responsible for deubiquitinating of a number of cell cycle regulators and consequent regulation of their steady state levels [ 35 ]. For instance, DUBs have been proposed to play a critical role in regulating NF-κB pathway [ 36 ], TGFβ signaling [ 37 ] as well as p53 and MDM2 [ 38 ] levels and activity suggesting that DUB dysregulation is a frequent event in cancer.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells

et al. 2015

View full text Add to dashboard Cite

Breast cancer is one of the leading causes of cancer death among women in the United States. Patients expressing the estrogen and progesterone receptor (ER and PR) and human epidermal growth factor 2 (HER-2) tumor markers have favorable prognosis and efficacious therapeutic options. In contrast, tumors that are negative for these markers (triple-negative) have a disproportionate share of morbidity and mortality due to lack of a validated molecular target.Deubiquitinating enzymes (DUBs) are a critical component of ubiquitin-proteasome-system degradation and have been shown to be differentially expressed and activated in a number of cancers, including breast, with their aberrant activity linked to cancer prognosis and clinical outcome. We evaluated the effect of the DUB inhibitors b-AP15 and RA-9 alone and in combination with early- and late-stage lysosomal inhibitors on cell viability in a panel of triple negative breast cancer (TNBC) cell lines.Our results indicate small-molecule DUB inhibitors have a profound effect on TNBC viability and lead to activation of autophagy as a cellular mechanism to compensate for ubiquitin-proteasome-system stress. Treatment with sub-optimal doses of DUB and lysosome inhibitors synergistically kills TNBC cells. This supports the evaluation of DUB inhibition, in combination with lysosomal inhibition, as a therapeutic approach for the treatment of TNBC.

show abstract

Section: Discussionmentioning

confidence: 99%

Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells

et al. 2015

View full text Add to dashboard Cite

show abstract

“…DUB1 is specifically induced by IL-3, IL-5, and GM-CSF, while DUB2 is stimulated by IL-2. USP17 (DUB3) is involved in the regulation of cell growth and survival and it is regulated by the cytokines IL-4 and IL-6 [4]. Ovarian tumour domain containing 6B (OTUD-6B) is a DUB, whose expression in B lymphocytes is induced by secretion of IL-3, IL-4, IL-13, or GM-CSF.…”

Section: Mechanisms Of Regulation Of Dubsmentioning

confidence: 99%

Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

López-Castejón

Edelmann

2016

Mediators of Inflammation

View full text Add to dashboard Cite

Inflammation is a protective response of the organism to tissue injury or infection. It occurs when the immune system recognizes Pathogen-Associated Molecular Patterns (PAMPs) or Damage-Associated Molecular Pattern (DAMPs) through the activation of Pattern Recognition Receptors. This initiates a variety of signalling events that conclude in the upregulation of proinflammatory molecules, which initiate an appropriate immune response. This response is tightly regulated since any aberrant activation of immune responses would have severe pathological consequences such as sepsis or chronic inflammatory and autoimmune diseases. Accumulative evidence shows that the ubiquitin system, and in particular ubiquitin-specific isopeptidases also known as deubiquitinases (DUBs), plays crucial roles in the control of these immune pathways. In this review we will give an up-to-date overview on the role of DUBs in the NF-κB pathway and inflammasome activation, two intrinsically related events triggered by activation of the membrane TLRs as well as the cytosolic NOD and NLR receptors. Modulation of DUB activity by small molecules has been proposed as a way to control dysregulation or overactivation of these key players of the inflammatory response. We will also discuss the advances and challenges of a potential use of DUBs as therapeutic targets in inflammatory pathologies.

show abstract

“…The DUBs which have been identifi ed so far are listed in Table 15.1 . Except for JAMMs, which are zinc metalloproteases, all DUBs have conserved domains including Cys, Asp/Asn, and His domains, which are associated with their catalytic activity [ 3 ]. …”

Section: Dub and Its Familymentioning

confidence: 99%

Deubiquitinating Enzymes as Novel Targets for Cancer Therapies

Baek

Lim

Park

2014

Resistance to Targeted Anti-Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Most ubiquitinated proteins can be recognized and degraded by the 26S proteasome. In the meantime, protein deubiquitination by various deubiquitinating enzymes (DUBs) regulates protein stability within cells, and it can counterbalance intracellular homeostasis mediated by ubiquitination. Numerous reports have demonstrated that an aberrant process of the ubiquitin-proteasome pathway (UPP) regulated by the ubiquitination and deubiquitination systems results in failure of balancing between protein stability and degradation, and this failure can lead to tumorigenesis in various organs and tissues of mammals. The identifi cation of molecular properties for various DUBs is very critical to understand cancer development and tumorigenesis. Therefore, knowledge of DUBs and their association with cancer and diseases is indispensible for developing effective inhibitors for DUBs. This chapter describes various features and functions of cancer-related DUBs. In addition, we summarize several inhibitors that specifi cally target certain DUBs in cancer and suggest that DUBs may be one of the most ideal and attractive therapeutic targets.

show abstract

Molecular mechanisms and functions of cytokine-inducible deubiquitinating enzymes

Cited by 28 publications

References 41 publications

Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells

Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells

Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

Deubiquitinating Enzymes as Novel Targets for Cancer Therapies

Contact Info

Product

Resources

About