CYLD mutations in familial skin appendage tumours

Saggar, S; Chernoff, Karen A.; Lodha, Sailesh; Horev, Liran; Kohl, Stefan; Honjo, Rachel Sayuri; Brandt, Heidrun; Hartmann, Karin; Çelebi, J. Tok

doi:10.1136/jmg.2007.056127

Cited by 78 publications

(75 citation statements)

References 27 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mutations in CYLD have been associated with cylindromatosis, Brooke-Spiegler syndrome, and familial trichoepithelioma, all of which are predisposed to multiple skin tumors of the head and neck (13). Additionally, downregulation of USP7 has been linked with non-small cell lung carcinoma, and in conjunction with p53 status, USP7 was shown to be a prognostic marker for adenocarcinoma patients (14).…”

Section: Introductionmentioning

confidence: 99%

The Deubiquitinating Enzyme USP17 Is Highly Expressed in Tumor Biopsies, Is Cell Cycle Regulated, and Is Required for G1-S Progression

et al. 2010

View full text Add to dashboard Cite

Ubiquitination is a reversible posttranslational modification that is essential for cell cycle control, and it is becoming increasingly clear that the removal of ubiquitin from proteins by deubiquitinating enzymes (DUB) is equally important. In this study, we have identified high levels of the DUB USP17 in several tumor-derived cell lines and primary lung, colon, esophagus, and cervix tumor biopsies. We also report that USP17 is tightly regulated during the cell cycle in all the cells examined, being abundantly evident in G 1 and absent in S phase. Moreover, regulated USP17 expression was necessary for cell cycle progression because its depletion significantly impaired G 1 -S transition and blocked cell proliferation. Previously, we have shown that USP17 regulates the intracellular translocation and activation of the GTPase Ras by controlling Ras-converting enzyme 1 (RCE1) activation. RCE1 also regulates the processing of other proteins with a CAAX motif, including Rho family GTPases. We now show that USP17 depletion blocks Ras and RhoA localization and activation. Moreover, our results confirm that USP17-depleted cells have constitutively elevated levels of the cyclin-dependent kinase inhibitors p21 cip1 and p27 kip1 , known downstream targets of Ras and RhoA signaling. These observations clearly show that USP17 is tightly regulated during cell division and that its expression is necessary to coordinate cell cycle progression, and thus, it may be considered a promising novel cancer therapeutic target.

show abstract

Section: Introductionmentioning

confidence: 99%

The Deubiquitinating Enzyme USP17 Is Highly Expressed in Tumor Biopsies, Is Cell Cycle Regulated, and Is Required for G1-S Progression

et al. 2010

View full text Add to dashboard Cite

show abstract

“…BSS, FC and MFT1 were originally described as distinct clinical entities, but due to their overlapping clinical symptoms and their manifestation within the same families, they are now considered as a clinical variants that represent a phenotypic spectrum of a single entity Welch et al, 1968;Young et al, 2006;Oranje et al, 2008]. [Bignell et al, 2000;Bowen et al, 2005;Grossmann et al, 2013;Linos et al, 2011;Lv et al, 2008;Kacerovska et al, 2013;Saggar et al, 2008;Van den Ouweland et al, 2011;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;Kazakov et al, 2011;Nagy et al, 2013]. Therefore, it has been hypothesized that BSS, FC and MFT1 are not different disease entities, but represent a phenotypic spectrum of the same disease.…”

mentioning

confidence: 99%

Phenotype–genotype correlations for clinical variants caused by CYLD mutations

Nagy

Farkas

Kemény

et al. 2015

European Journal of Medical Genetics

View full text Add to dashboard Cite

Brooke-Spiegler syndrome (BSS; OMIM 605041) is an autosomal dominant condition characterized by skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. In 1996, the gene locus for BSS was mapped to 16q12-13, and, in 2000, mutations in the cylindromatosis (CYLD) gene were determined to cause BSS, familial cylindromatosis (FC; OMIM 132700) and multiple familial trichoepithelioma type 1 (MFT1; OMIM 601606). The CYLD gene encodes an enzyme with deubiquitinase activity. To date, a total of 95 different diseases-causing mutations have been published for the CYLD gene. A summary of mutations identified in Hungarian patients and a review of previously published mutations are presented in this update. The majority of the sequence changes are frameshift (48%), nonsense (27%), missense (12%) and splice-site (11%) mutations; however, two in-frame deletions have also been reported Most mutations are located in exons 9-20. Analysis of the identified CYLD gene mutations and the observed BSS, FC and MFT1 clinical phenotypes of the patients revealed significant genotype-phenotype correlations. Elucidation of these genotype-phenotype correlations is critical for the diagnosis of these rare monogenic skin diseases. In addition, characterized correlations may promote the understanding of their mechanisms and may hopefully contribute to the development of future therapeutic modalities.

show abstract

“…Mutations in CYLD have been described in familiar cylindromatosis, in which patients show a predisposition to develop multiple head and neck skin tumors (Saggar et al, 2008). The generation of mutant mice deficient in CYLD has confirmed the tumor-suppressor role of this DUB because of its ability to enhance NK-kB activity (Zhang et al, 2006b).…”

Section: Genetic or Functional Alterations Of Dubs In Cancermentioning

confidence: 95%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

CYLD mutations in familial skin appendage tumours

Cited by 78 publications

References 27 publications

The Deubiquitinating Enzyme USP17 Is Highly Expressed in Tumor Biopsies, Is Cell Cycle Regulated, and Is Required for G1-S Progression

The Deubiquitinating Enzyme USP17 Is Highly Expressed in Tumor Biopsies, Is Cell Cycle Regulated, and Is Required for G1-S Progression

Phenotype–genotype correlations for clinical variants caused by CYLD mutations

Deubiquitinases in cancer: new functions and therapeutic options

Contact Info

Product

Resources

About