The ubiquitin ligase Huwe1 regulates the maintenance and lymphoid commitment of hematopoietic stem cells

King, Bryan; Boccalatte, Francesco; Moran-Crusio, Kelly; Wolf, Elmar; Wang, Jingjing; Kayembe, Clarisse; Lazaris, Charalampos; Yu, Xiaofeng; Aranda-Orgillés, Beatriz; Lasorella, Anna; Aifantis, Iannis

doi:10.1038/ni.3559

Cited by 63 publications

(60 citation statements)

References 60 publications

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“…This study further showed that N-MYC is expressed in self-renewing, quiescent stem cells that switch to higher C-MYC expression in transit-amplifying progenitors that further differentiate. Data from this study suggest that N-MYC's role in HSCs appears to be in the activation of stem-like properties and is dependent on the ubiquitin ligase HUWE1 (43). Consistent with this idea, transduction of mouse bone marrow cells with N-MYC but not C-MYC stimulated the proliferation and self-renewal of myeloid cells in vitro and rapidly caused AML in vivo (44).…”

Section: Hematologic Malignanciessupporting

confidence: 73%

“…This suggests that both MYC proteins are coexpressed in the most immature populations of HSCs. Most recently, data from an elegant study involving fluorescent fusion alleles of Mycn and Myc in mouse models showed that N-MYC is expressed in the most primitive stem and progenitor compartments and is mutually exclusive to C-MYC expression (43). This study further showed that N-MYC is expressed in self-renewing, quiescent stem cells that switch to higher C-MYC expression in transit-amplifying progenitors that further differentiate.…”

Section: Hematologic Malignanciesmentioning

confidence: 85%

“…In vitro, the complex recognizes E-box sequences with a core CACA/GTG sequence ("consensus E-box"). Chromatin immunoprecipitation sequencing studies show that N-MYC binds to thousands of active promoters transcribed by RNAPII and to enhancers with an open chromatin structure in embryonic stem cells and in N-MYC-driven neuroblastoma, medulloblastoma, and AML cells (43,94). This pattern is essentially identical to that of C-MYC.…”

Section: N-myc-dependent Transcriptionmentioning

confidence: 92%

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The Expanding World of N-MYC–Driven Tumors

2018

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Enhanced and deregulated expression of N-MYC, a member of the MYC family of transcription factors, drives the development of multiple tumors, including tumors of the nervous and hematologic systems and neuroendocrine tumors in other organs. This review summarizes the cell-of-origin, biological features, associated signaling pathways, and current treatment strategies for N-MYC-driven tumors. We also highlight biological differences within specifi c tumor types that are driven by the different MYC proteins.Signifi cance: N-MYC is a driver of multiple tumor types that are derived through a mechanism that involves direct differentiation within the same lineage (e.g., in the case of neuroblastoma, medulloblastoma, and acute myeloid leukemia) and is often associated with a poor prognosis. Emerging data suggest that N-MYC also drives other tumor types through a mechanism that promotes a lineage switch and that this switch may be exploited for therapeutic purposes. Cancer Discov; 8(2);

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Section: Hematologic Malignanciessupporting

confidence: 73%

Section: Hematologic Malignanciesmentioning

confidence: 85%

Section: N-myc-dependent Transcriptionmentioning

confidence: 92%

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The Expanding World of N-MYC–Driven Tumors

2018

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“…For these reasons, the role of Mule in various tissues, whether at steady state or in disease, had been elusive. During the last year, we and others have exploited different Mule knockout mouse models to demonstrate that Mule is involved in the regulation of intestinal, hematopoietic, and neural stem cells (8,15,16). Significantly, the developmental programs of all these tissues are driven by the Wnt pathway (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

Dominguez-Brauer

Khatun

Elia

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell selfrenewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates β-catenin levels. Stabilization and nuclear localization of β-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/ Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule's influence on oncogenesis by showing that Mule interacts directly with β-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to finetune the Wnt pathway and provides multiple safeguards against tumorigenesis.β-catenin | Mule | Wnt signaling | stem cells | colorectal cancer A ctivation of the Wnt pathway, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays a critical role in stem cell self-renewal, and thus the homeostasis of normal mammalian tissues. However, constitutive activation of Wnt signaling has been implicated in a broad range of cancers, including melanoma, hepatocellular carcinoma, and cancers of the prostate, thyroid, ovary, and breast (1-3). Perhaps the best-studied malignancy arising from the loss of regulation of the Wnt signaling pathway is colorectal cancer, which develops through a multistage process driven by the progressive accumulation of genetic mutations (4). The key initial activating mutation occurs in components of the Wnt pathway, but most commonly in APC.Canonical Wnt signaling involves a relay of protein interactions that serve to transmit a signal from the extracellular space to the plasma membrane. This signal is amplified in the cytoplasm and then directed to the nucleus to culminate in the activation of the Wnt target gene program. In molecular terms, when the glycoprotein Wnt is secreted into the extracellular space, it binds to a cell's Frizzled receptors in conjunction with the low-density lipoprotein receptorrelated proteins 5 and 6 (LRP5/6). The engagement of these receptors recruits the scaffolding protein Dishevelled (Dvl), leading to LRP5/6 phosphorylation and consequent recruitment of the scaffolding protein, Axin2 and glycogen synthase kinase 3 beta (GSK-3β). This recruitment results in disruption of the "destruction complex" that contains APC and normally binds to the signal transduction protein β-catenin to trigger its degradation. On Wn...

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“…The 482 kDa HECT ligase HUWE1 functions in diverse cellular pathways, including protein quality control, transcription, DNA repair, apoptosis, neuronal differentiation, and mitophagy . It has been recognized as an important player in tumor biology; its precise functions, however, are complex and likely to depend on tumor stage and/or entity.…”

Section: Case Studies On Hect Ligase‐directed Ligand Discoverymentioning

confidence: 99%

Developing Small‐Molecule Inhibitors of HECT‐Type Ubiquitin Ligases for Therapeutic Applications: Challenges and Opportunities

2018

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The ubiquitin system regulates countless physiological and disease-associated processes and has emerged as an attractive entryway for therapeutic efforts. With over 600 members in the human proteome, ubiquitin ligases are the most diverse class of ubiquitylation enzymes and pivotal in encoding specificity in ubiquitin signaling. Although considerable progress has been made in the identification of small molecules targeting RING ligases, relatively little is known about the "druggability" of HECT (homologous to E6AP C terminus) ligases, many of which are critically implicated in human pathologies. A major obstacle to optimizing the few available ligands is our incomplete understanding of their inhibitory mechanisms and the structural basis of catalysis in HECT ligases. Here, we survey recent approaches to manipulate the activities of HECT ligases with small molecules to showcase the particular challenges and opportunities these enzymes hold as therapeutic targets.

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The ubiquitin ligase Huwe1 regulates the maintenance and lymphoid commitment of hematopoietic stem cells

Cited by 63 publications

References 60 publications

The Expanding World of N-MYC–Driven Tumors

The Expanding World of N-MYC–Driven Tumors

E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

Developing Small‐Molecule Inhibitors of HECT‐Type Ubiquitin Ligases for Therapeutic Applications: Challenges and Opportunities

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