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USP11 regulates PML stability to control Notch-induced malignancy in brain tumours.


ABSTRACT: The promyelocytic leukaemia (PML) protein controls multiple tumour suppressive functions and is downregulated in diverse types of human cancers through incompletely characterized post-translational mechanisms. Here we identify USP11 as a PML regulator by RNAi screening. USP11 deubiquitinates and stabilizes PML, thereby counteracting the functions of PML ubiquitin ligases RNF4 and the KLHL20-Cul3 (Cullin 3)-Roc1 complex. We find that USP11 is transcriptionally repressed through a Notch/Hey1-dependent mechanism, leading to PML destabilization. In human glioma, Hey1 upregulation correlates with USP11 and PML downregulation and with high-grade malignancy. The Notch/Hey1-induced downregulation of USP11 and PML not only confers multiple malignant characteristics of aggressive glioma, including proliferation, invasiveness and tumour growth in an orthotopic mouse model, but also potentiates self-renewal, tumour-forming capacity and therapeutic resistance of patient-derived glioma-initiating cells. Our study uncovers a PML degradation mechanism through Notch/Hey1-induced repression of the PML deubiquitinase USP11 and suggests an important role for this pathway in brain tumour pathogenesis.

SUBMITTER: Wu HC 

PROVIDER: S-EPMC5645609 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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USP11 regulates PML stability to control Notch-induced malignancy in brain tumours.

Wu Hsin-Chieh HC   Wu Hsin-Chieh HC   Lin Yu-Ching YC   Liu Cheng-Hsin CH   Chung Hsiang-Ching HC   Wang Ya-Ting YT   Lin Ya-Wen YW   Ma Hsin-I HI   Tu Pang-Hsien PH   Lawler Sean E SE   Chen Ruey-Hwa RH  

Nature communications 20140101


The promyelocytic leukaemia (PML) protein controls multiple tumour suppressive functions and is downregulated in diverse types of human cancers through incompletely characterized post-translational mechanisms. Here we identify USP11 as a PML regulator by RNAi screening. USP11 deubiquitinates and stabilizes PML, thereby counteracting the functions of PML ubiquitin ligases RNF4 and the KLHL20-Cul3 (Cullin 3)-Roc1 complex. We find that USP11 is transcriptionally repressed through a Notch/Hey1-depen  ...[more]

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