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The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE85833 | GEO | 2016/08/20

SECONDARY ACCESSION(S): PRJNA339518

REPOSITORIES: GEO

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The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-08-20 | E-GEOD-85833 | biostudies-arrayexpress

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

Project description:Hematopoietic stem cells (HSCs) are dormant in the bone marrow and can be activated in response to diverse stresses to replenish all blood cell types. We identified the ubiquitin ligase Huwe1 as a crucial regulator of HSC function via its post-translational control of the oncoprotein N-myc (encoded by Mycn). We found Huwe1 to be essential for HSC self-renewal, quiescence and lymphoid-fate specification in mice. Through the use of a fluorescent fusion allele (MycnM), we observed that N-myc expression was restricted to the most immature, multipotent stem and progenitor populations. N-myc expression was upregulated in response to stress or following loss of Huwe1, which led to increased proliferation and stem-cell exhaustion. Mycn depletion reversed most of these phenotypes in vivo, which suggested that the attenuation of N-myc by Huwe1 is essential for reestablishing homeostasis following stress.

| S-EPMC5117833 | biostudies-literature

The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [microarray]

Project description:We identified the ubiquitin ligase Huwe1 as a crucial regulator of hematopoietic stem cell (HSC) functions. We generated Huwe1 conditional knock-out mice and discovered that the loss of this ligase causes an increased proliferation and stem cell exhaustion, together with a decreased lymphoid specification in vivo. We observed that the ubiquitin ligase Huwe1 is controlling the expression of N-myc at the level of the most immature stem and progenitor hematopoietic populations, mediating the described effects. Hematopoietic stem cells (HSC) from the bone marrow of transgenic animals carrying a N-myc/mCherry fusion gene were sorted according to N-myc expression (defined by mCherry) into N-myc high and low subpopulations. Each of these 2 populations was subjected to microarray gene expression profiling.

2016-08-20 | E-GEOD-85832 | biostudies-arrayexpress

The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [microarray]

2016-08-20 | GSE85832 | GEO

The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [high-throughput sequencing]

2016-08-17 | GSE85723 | GEO

The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment

Project description:The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment

| PRJNA339518 | ENA

Regulation of stem cell maintenance and lymphoid specification by the ubiquitin ligase Huwe1

Project description:The ubiquitin ligase Huwe1 regulates stem cell quiescence, maintenance and lymphoid specification by controlling the expression of N-Myc.

2016-08-18 | GSE85488 | GEO

A conformational switch regulates the ubiquitin ligase HUWE1.

Project description:The human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1 that counteracts dimer formation by associating with the dimerization region intramolecularly. Our studies reveal, intriguingly, that the tumor suppressor p14ARF binds to this segment and may thus shift the conformational equilibrium of HUWE1 toward the inactive state. We propose a model, in which the activity of HUWE1 underlies conformational control in response to physiological cues-a mechanism that may be exploited for cancer therapy.

| S-EPMC5308896 | biostudies-literature

Drosophila HUWE1 Ubiquitin Ligase Regulates Endoreplication and Antagonizes JNK Signaling During Salivary Gland Development.

Project description:The HECT-type ubiquitin ligase HECT, UBA and WWE Domain Containing 1, (HUWE1) regulates key cancer-related pathways, including the Myc oncogene. It affects cell proliferation, stress and immune signaling, mitochondria homeostasis, and cell death. HUWE1 is evolutionarily conserved from Caenorhabditis elegance to Drosophila melanogaster and Humans. Here, we report that the Drosophila ortholog, dHUWE1 (CG8184), is an essential gene whose loss results in embryonic lethality and whose tissue-specific disruption establishes its regulatory role in larval salivary gland development. dHUWE1 is essential for endoreplication of salivary gland cells and its knockdown results in the inability of these cells to replicate DNA. Remarkably, dHUWE1 is a survival factor that prevents premature activation of JNK signaling, thus preventing the disintegration of the salivary gland, which occurs physiologically during pupal stages. This function of dHUWE1 is general, as its inhibitory effect is observed also during eye development and at the organismal level. Epistatic studies revealed that the loss of dHUWE1 is compensated by dMyc proeitn expression or the loss of dmP53. dHUWE1 is therefore a conserved survival factor that regulates organ formation during Drosophila development.

| S-EPMC6210797 | biostudies-other

Ubiquitin ligase HUWE1 regulates axon branching through the Wnt/?-catenin pathway in a Drosophila model for intellectual disability.

Project description:We recently reported that duplication of the E3 ubiquitin ligase HUWE1 results in intellectual disability (ID) in male patients. However, the underlying molecular mechanism remains unknown. We used Drosophila melanogaster as a model to investigate the effect of increased HUWE1 levels on the developing nervous system. Similar to the observed levels in patients we overexpressed the HUWE1 mRNA about 2-fold in the fly. The development of the mushroom body and neuromuscular junctions were not altered, and basal neurotransmission was unaffected. These data are in agreement with normal learning and memory in the courtship conditioning paradigm. However, a disturbed branching phenotype at the axon terminals of the dorsal cluster neurons (DCN) was detected. Interestingly, overexpression of HUWE1 was found to decrease the protein levels of dishevelled (dsh) by 50%. As dsh as well as Fz2 mutant flies showed the same disturbed DCN branching phenotype, and the constitutive active homolog of ?-catenin, armadillo, could partially rescue this phenotype, our data strongly suggest that increased dosage of HUWE1 compromises the Wnt/?-catenin pathway possibly by enhancing the degradation of dsh.

| S-EPMC3841167 | biostudies-literature

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