STIP is a critical nuclear scaffolding protein linking USP7 to p53-Mdm2 pathway regulation

Ye, Mao; Tang, YH; Tang, Shijun; Liu, Jing; Wu, Kuangpei; Yao, Shanshan; Sun, Yang; Zhou, Lei; Deng, Tanggang; Chen, Ying; Huang, Cheng‐Han; Tan, Weihong

doi:10.18632/oncotarget.5303

Cited by 12 publications

(12 citation statements)

References 32 publications

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“…USP7 encodes a ubiquitin-specific protease that stabilizes MDM2 and TP53. 67 The majority of mutations (76.5%) were heterozygous out-of-frame indel (N=25) or nonsense (N=1) mutations in or proximal to the catalytic domain indicating the mutations result in loss-of-function ( Supplementary Figure 2 ). Additional associations between mutations and T-ALL subtypes included CTCF (56.0% of 25 mutations) and KDM6A (42.9% of 21 mutations) in TLX3 cases, and KMT2A (77.8% of 18 mutations) in HOXA cases ( Supplementary Table 19 ).…”

Section: Patterns Of Epigenetic Mutation In T-allmentioning

confidence: 99%

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

et al. 2017

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Genetic alterations activating NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors are hallmarks of T-ALL, but detailed genome-wide sequencing of large T-ALL cohorts has not been performed. Using integrated genomic analysis of 264 T-ALL cases, we identify 106 putative driver genes, half of which were not previously described in childhood T-ALL (e.g. CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We described new mechanisms of coding and non-coding alteration, and identify 10 recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOX1 deregulated ALL, PTPN2 mutations in TLX1 T-ALL, and PIK3R1/PTEN mutations in TAL1 ALL, suggesting that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.

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Section: Patterns Of Epigenetic Mutation In T-allmentioning

confidence: 99%

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

et al. 2017

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“…Inhibition of USP7 provided an efficient means to target PRC1.1. Of course it is evident that USP7 can function in several pathways, often through regulating protein stability of tumor suppressors or epigenetic regulators [66][67][68] and it is particularly the TP53 pathway that is strongly controlled by USP7 [49,[69][70][71]. Various USP7 inhibitors have been developed, and most recently selective USP7 inhibitors were generated that destabilize USP7 substrates including MDM2 and thereby increase TP53-mediated apoptosis of cancer cells [40,72].…”

Section: Discussionmentioning

confidence: 99%

USP7 as part of non-canonical PRC1.1 is a druggable target in leukemia

Maat

Jaques

López

et al. 2017

Preprint

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Acute myeloid leukemia (AML) is a highly heterogeneous disease in which genetic and epigenetic changes disturb regulatory mechanisms controlling stem cell fate and maintenance. AML still remains difficult to treat, in particular in poor risk AML patients carrying TP53 mutations. Here, we identify the deubiquitinase USP7 as an integral member of non-canonical PRC1.1 and show that targeting of USP7 provides an alternative therapeutic approach for AML. USP7 inhibitors effectively induced apoptosis in (primary) AML cells, also independent of the USP7-MDM2-TP53 axis, whereby survival of both the cycling as well as quiescent populations was affected. MLL-AF9-induced leukemia was significantly delayed in vivo in human leukemia xenografts. We previously showed that non-canonical PRC1.1 is critically important for leukemic stem cell self-renewal, and that genetic knockdown of the PRC1.1 chromatin binding component KDM2B abrogated leukemia development in vitro and in vivo [1]. Here, by performing KDM2B interactome studies in TP53mut cells we identify that USP7 is an essential component of PRC1.1 and is required for its stability and function. USP7 inhibition results in disassembly of the PRC1.1 complex and consequently loss of binding to its target loci. Loss of PRC1.1 binding coincided with reduced H2AK119ub and H3K27ac levels and diminished gene transcription, whereas H3K4me3 levels remained unaffected. Our studies highlight the diverse functions of USP7 and link it to Polycomb-mediated epigenetic control. USP7 inhibition provides an efficient therapeutic approach for AML, also in the most aggressive subtypes with mutations in TP53.Key pointsUSP7 is a therapeutic target in leukemia, including poor risk TP53mut AML.USP7 is an essential component of non-canonical PRC1.1 and is required for its stability and function.

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“… 96 Another HAUSP-interacting nuclear factor, Sip1/Tuftelin-interacting protein (STIP), may act as a scaffold to regulate p53-MDM2 dynamics. 97 …”

Section: Hausp In Oncogenesismentioning

confidence: 99%

Emerging insights into HAUSP (USP7) in physiology, cancer and other diseases

Bhattacharya

Chakraborty

Basu³

et al. 2018

Sig Transduct Target Ther

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129

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Herpesvirus-associated ubiquitin-specific protease (HAUSP) is a USP family deubiquitinase. HAUSP is a protein of immense biological importance as it is involved in several cellular processes, including host-virus interactions, oncogenesis and tumor suppression, DNA damage and repair processes, DNA dynamics and epigenetic modulations, regulation of gene expression and protein function, spatio-temporal distribution, and immune functions. Since its discovery in the late 1990s as a protein interacting with a herpes virus regulatory protein, extensive studies have assessed its complex roles in p53-MDM2-related networks, identified numerous additional interacting partners, and elucidated the different roles of HAUSP in the context of cancer, development, and metabolic and neurological pathologies. Recent analyses have provided new insights into its biochemical and functional dynamics. In this review, we provide a comprehensive account of our current knowledge about emerging insights into HAUSP in physiology and diseases, which shed light on fundamental biological questions and promise to provide a potential target for therapeutic intervention.

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STIP is a critical nuclear scaffolding protein linking USP7 to p53-Mdm2 pathway regulation

Cited by 12 publications

References 32 publications

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

USP7 as part of non-canonical PRC1.1 is a druggable target in leukemia

Emerging insights into HAUSP (USP7) in physiology, cancer and other diseases

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