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Brooke–Spiegler Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Mapped to chromosome 16q12.1, the CYLD gene spans 56 kb and contains 20 exons, of which the first three are untranslated, exon 3 (in the 5-prime untranslated region) and the 9-bp exon 7 (which is coding) show alternative splicing, and exon 4 contains the ATG start codon. The encoded protein CYLD is a 956 aa, 120 kDa deubiquitinating enzyme while a splice variant lacking exon 7 produces a 953 aa protein.
The mitotic phase of spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
In the mitotic division of spermatogonia, it has been proposed that both symmetric and asymmetric division occurs. Symmetric division allows the stem cell to become two stem cells or two committed progenies while asymmetric division allows the stem cell to give rise to a stem cell and a committed progeny.9 The asymmetric segregation of cell fate determinant could be one plausible mechanism for determining the identity of progenies.9 The deubiquitinating enzyme UCH-L1 is expressed in spermatogonia and asymmetrically distributed to the two progenies in the asymmetric division of spermatogonia. A higher level of UCH-L1 is observed in Plzf+ Aundiff spermatogonia whereas c-Kit+ differentiating spermatogonia inherit low/undetectable level of UCH-L1.77 This result suggests that UCH-L1 may be involved in regulating the self-renewal and differentiation of spermatogonia.
Hereditary Spastic Paraparesis and Other Hereditary Myelopathies
Published in Anand D. Pandyan, Hermie J. Hermens, Bernard A. Conway, Neurological Rehabilitation, 2018
Jon Marsden, Lisa Bunn, Amanda Denton, Krishnan Padmakumari Sivaraman Nair
Depending on ethnicity, SCA3 accounts for between 21 and 56% of SCA cases.107 Prevalence varies according to founder effects. It is a polyglutamate (polyQ) disease caused by a CAG repeated expansion of the ATXN3 gene on chromosome 14q. The protein encoded by ATXN3, ataxin-3, is a deubiquitinating enzyme that cleaves ubiquitin off substrates. It is felt that this enzyme’s function, and thus biochemical pathways dependent upon ubiquitin, are affected in SCA3.108 The age of onset varies from childhood to late adult life and there is an inverse correlation between the number of CAG repeats and the age of onset and disease severity.109
Role of bromodomain and extraterminal (BET) proteins in prostate cancer
Published in Expert Opinion on Investigational Drugs, 2023
Adel Mandl, Mark C. Markowski, Michael A. Carducci, Emmanuel S. Antonarakis
Preclinical studies also demonstrated that prostate cancer-specific mutations in SPOP (speckle-type POZ protein), an E3 ubiquitin ligase substrate binding protein commonly mutated in prostate cancer, resulted in impaired degradation of BETs and promoted intrinsic resistance to BET inhibitors both in vitro and in vivo prostate cancer models [64–67]. Another resistance mechanism may be related to deubiquitinating enzyme 3 (DUB3), which binds to BRD4 and promotes its deubiquitination and stabilization. The nuclear receptor corepressor 2 (NCOR2)–histone deacetylase 10 (HDAC10) complex transcriptionally represses the expression of DUB3 [68]. The NCOR2 gene is frequently deleted in CRPC patient specimens, and loss of NCOR2 induces the elevation of DUB3 and BRD4 proteins in PC cells [69]. DUB3-proficient PC cells are resistant to the BET inhibitor JQ1 in vitro and in vivo, but this effect is diminished by DUB3 inhibitory agents [68]. This suggests that DUB3 could be a viable therapeutic target to overcome BET inhibitor resistance.
Incorporating molecular biomarkers into clinical practice for gastric cancer
Published in Expert Review of Anticancer Therapy, 2019
Shunsuke Nakamura, Mitsuro Kanda, Yasuhiro Kodera
Ubiquitin-specific protease 3 (USP3) encodes a deubiquitinating enzyme that that plays important roles in tumorigenesis [25]. To date, the expression of USP3 in various cancers, including GC, is still unknown. Fang et al [25] . evaluated the possibility of using USP3 as a prognostic biomarker for GC and its role in GC tumorigenesis. The expression of USP3 increases in GC vs normal tissues, and overexpression of USP3 significantly correlates with the Lauren classification, depth of invasion, nodal status, distant metastasis, stage, differentiation, vascular invasion, and shorter DFS. Silencing USP3 suppresses GC cell proliferation and migration in vitro as well as proliferation and metastasis in vivo. The expression of USP3 in GC cells positively correlates with the enzymatic activity of matrix metalloproteinase-2 (MMP-2), which is involved in the degradation of the extracellular matrix associated with metastasis as well as with components of the cell cycle machinery such as cyclins D and E that mediate the G1 phase [25]. These findings indicate that USP3 can serve as a prognostic biomarker and a potential therapeutic target for GC.
Burning controversies in NETs and autoimmunity: The mysteries of cell death and autoimmune disease
Published in Autoimmunity, 2018
In contrast to apoptosis, necrosis is a consequence of sudden, accidental or extreme physiochemical stress resulting in the disruption of cellular structures. Cell death by excessive heat, osmotic shock and freeze-thawing are examples of this uncontrolled and accidental cellular injury. In necrosis, there is sudden loss of membrane integrity and thus, necrosis is associated with uncontrolled and excessive dispersal of proinflammatory DAMPs such as HMGB1, IL-1α, uric acid, ATP, etc. Induction of necrosis can leave open avenues for cells to regulate it, albeit in incomplete and unsuccessful manner. Such a hybrid outcome is called “necroptosis” and may limit the overtly harmful proinflammatory effects of necrosis [29]. Necroptosis, similar to apoptosis, is a well-regulated event that requires complex signalling. TNFa-triggered necroptosis can also be induced de novo following the inhibition of caspase 8, in contrast to its activation during TNFa-induced apoptosis. Necroptosis requires assembly of receptor-activated protein kinases (RIPK1, RIPK3), and mixed lineage kinase domain like (MLKL) into a unique “necrosome” complex [30]. Necroptosis can be inhibited by RIP1 kinase inhibitor necrostatin-1, suggesting involvement of a unique signalling pathway. The formation of necrosome complex IIb also requires the deubiquitination of RIPK1 by a K63-specific deubiquitinating enzyme, CYLD [31,32]. Recently, it was shown that ANCA mediated NET formation involves RIPK1/3 and MLKL, the key mediators of necroptosis [33], whereas E. Coli or PMA-induced NET formation seemed to bypass necrosome complex formation [34] indicating a partial overlap between necroptosis and NETs, depending on the respective triggers.