TY  - JOUR
A1  - Williams, Richard D.
A1  - Chagtai, Tasnim
A1  - Alcaide-German, Marisa
A1  - Apps, John
A1  - Wegert, Jenny
A1  - Popov, Sergey
A1  - Vujanic, Gordan
A1  - Van Tinteren, Harm
A1  - Van den Heuvel-Eibrink, Marry M
A1  - Kool, Marcel
A1  - De Kraker, Jan
A1  - Gisselsson, David
A1  - Graf, Norbert
A1  - Gessler, Manfred
A1  - Pritchard-Jones, Kathy
T1  - Multiple mechanisms of MYCN dysregulation in Wilms tumour
JF  - Oncotarget
N2  - Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation.
KW  - integrative genomics viewer
KW  - oncogene amplification
KW  - sequencing data
KW  - gene
KW  - gain
KW  - copy number
KW  - somatic mutations
KW  - beta-catenin
KW  - histology
KW  - reveals
KW  - Wilms tumour
KW  - MYCN
KW  - DNA methylation
KW  - prognostic marker
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143471
VL  - 6
IS  - 9
ER  - 
TY  - JOUR
A1  - Salat, Daniela
A1  - Winkler, Anja
A1  - Urlaub, Henning
A1  - Gessler, Manfred
T1  - Hey bHLH Proteins Interact with a FBXO45 Containing SCF Ubiquitin Ligase Complex and Induce Its Translocation into the Nucleus
JF  - PLoS One
N2  - The Hey protein family, comprising Hey1, Hey2 and HeyL in mammals, conveys Notch signals in many cell types. The helix-loop-helix (HLH) domain as well as the Orange domain, mediate homo- and heterodimerization of these transcription factors. Although distinct interaction partners have been identified so far, their physiological relevance for Hey functions is still largely unclear. Using a tandem affinity purification approach and mass spectrometry analysis we identified members of an ubiquitin E3-ligase complex consisting of FBXO45, PAM and SKP1 as novel Hey1 associated proteins. There is a direct interaction between Hey1 and FBXO45, whereas FBXO45 is needed to mediate indirect Hey1 binding to SKP1. Expression of Hey1 induces translocation of FBXO45 and PAM into the nucleus. Hey1 is a short-lived protein that is degraded by the proteasome, but there is no evidence for FBXO45-dependent ubiquitination of Hey1. On the contrary, Hey1 mediated nuclear translocation of FBXO45 and its associated ubiquitin ligase complex may extend its spectrum to additional nuclear targets triggering their ubiquitination. This suggests a novel mechanism of action for Hey bHLH factors.
KW  - ubiquitination
KW  - glycerol
KW  - transcription factors
KW  - DNA-binding proteins
KW  - immunoprecipitation
KW  - protein interactions
KW  - protein domains
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125769
VL  - 10
IS  - 6
ER  -