TY  - JOUR
AU  - Dietachmayr, Michael
AU  - Rathakrishnan, Abirami
AU  - Karpiuk, Oleksandra
AU  - von Zweydorf, Felix
AU  - Engleitner, Thomas
AU  - Fernández-Sáiz, Vanesa
AU  - Schenk, Petra
AU  - Ueffing, Marius
AU  - Rad, Roland
AU  - Eilers, Martin
AU  - Gloeckner, Christian Johannes
AU  - Clemm von Hohenberg, Katharina
AU  - Bassermann, Florian
TI  - Antagonistic activities of CDC14B and CDK1 on USP9X regulate WT1-dependent mitotic transcription and survival.
JO  - Nature Communications
VL  - 11
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2020-01409
SP  - 1268
PY  - 2020
AB  - Regulation of mitosis secures cellular integrity and its failure critically contributes to the development, maintenance, and treatment resistance of cancer. In yeast, the dual phosphatase Cdc14 controls mitotic progression by antagonizing Cdk1-mediated protein phosphorylation. By contrast, specific mitotic functions of the mammalian Cdc14 orthologue CDC14B have remained largely elusive. Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. We further demonstrate that WT1 functions as a mitotic transcription factor and specify CXCL8/IL-8 as a target gene of WT1 that conveys mitotic survival. Together, we describe a ubiquitin-dependent signaling pathway that directs a mitosis-specific transcription program to regulate mitotic survival.
KW  - A549 Cells
KW  - Apoptosis
KW  - CDC2 Protein Kinase: antagonists & inhibitors
KW  - Dual-Specificity Phosphatases: antagonists & inhibitors
KW  - Gene Knockdown Techniques
KW  - HEK293 Cells
KW  - HeLa Cells
KW  - Humans
KW  - Interleukin-8: metabolism
KW  - Mitosis: physiology
KW  - Phosphorylation
KW  - Transcription Factors
KW  - Ubiquitin Thiolesterase: drug effects
KW  - Ubiquitin Thiolesterase: genetics
KW  - Ubiquitin Thiolesterase: metabolism
KW  - WT1 Proteins: genetics
KW  - WT1 Proteins: metabolism
KW  - CXCL8 protein, human (NLM Chemicals)
KW  - Interleukin-8 (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - USP9X protein, human (NLM Chemicals)
KW  - WT1 Proteins (NLM Chemicals)
KW  - WT1 protein, human (NLM Chemicals)
KW  - CDC2 Protein Kinase (NLM Chemicals)
KW  - CDK1 protein, human (NLM Chemicals)
KW  - CDC14B protein, human (NLM Chemicals)
KW  - Dual-Specificity Phosphatases (NLM Chemicals)
KW  - Ubiquitin Thiolesterase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:32152317
C2  - pmc:PMC7063047
DO  - DOI:10.1038/s41467-020-15059-5
UR  - https://pub.dzne.de/record/153412
ER  -