CUL4B ubiquitin ligase in mouse development: A model for human X-linked mental retardation syndrome?

Zhao, Yongchao; Sun, Yi

doi:10.1038/cr.2012.79

Cited by 11 publications

(13 citation statements)

References 16 publications

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“…CUL4, a member of the cullin-RING ubiquitin ligase family, is expressed in mammals as two paralogs, CUL4A and CUL4B (Zhao and Sun 2012). CUL4B is encoded on the X Chromosome, and deficiency in males is associated with intellectual disability, seizures, aggressive outbursts, central obesity, muscle wasting, short stature, macrocephaly, and dysmorphic features including brachydactyly, macroglossia, pes cavus, and prominent upper lip (Tarpey et al 2007; Zhao and Sun 2012).…”

Section: Discussionmentioning

confidence: 99%

“…CUL4B is encoded on the X Chromosome, and deficiency in males is associated with intellectual disability, seizures, aggressive outbursts, central obesity, muscle wasting, short stature, macrocephaly, and dysmorphic features including brachydactyly, macroglossia, pes cavus, and prominent upper lip (Tarpey et al 2007; Zhao and Sun 2012). The phenotype of patients with CUL4B mutations overlaps with the phenotype of our patients.…”

Section: Discussionmentioning

confidence: 99%

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De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features

Webster

Cho²,

Alexander³

et al. 2016

Cold Spring Harb Mol Case Stud

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Using whole-exome sequencing, we have identified novel de novo heterozygous pleckstrin homology domain-interacting protein (PHIP) variants that are predicted to be deleterious, including a frameshift deletion, in two unrelated patients with common clinical features of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features. A nonsense mutation in PHIP has previously been associated with similar clinical features. Patients with microdeletions of 6q14.1, including PHIP, have a similar phenotype of developmental delay, intellectual disability, hypotonia, and obesity, suggesting that the phenotype of our patients is a result of loss-of-function mutations. PHIP produces multiple protein products, such as PHIP1 (also known as DCAF14), PHIP, and NDRP. PHIP1 is one of the multiple substrate receptors of the proteolytic CUL4-DDB1 ubiquitin ligase complex. CUL4B deficiency has been associated with intellectual disability, central obesity, muscle wasting, and dysmorphic features. The overlapping phenotype associated with CUL4B deficiency suggests that PHIP mutations cause disease through disruption of the ubiquitin ligase pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features

Webster

Cho²,

Alexander³

et al. 2016

Cold Spring Harb Mol Case Stud

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“…Interestingly, a recent study shows that Cul4b, a Cul domain E3 ubiquitin ligase mediated the degradation of HUWE120. Cul4b, an X-linked mental retardation protein, was also shown to be critical for extra-embryonic tissue development, while dispensable for embryo proper development2122. Since both Cul4b and HUWE1 are involved in the X-linked mental retardation, it would be interesting to generate embryo specific and extra-embryonic tissue specific knock out mice and check whether they have neuron specific phenotype2614.…”

Section: Discussionmentioning

confidence: 99%

HUWE1 plays important role in mouse preimplantation embryo development and the dysregulation is associated with poor embryo development in humans

Chen¹,

Xu²,

Yang³

et al. 2016

Sci Rep

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HUWE1 is a HECT domain containing ubiquitin ligase implicated in neurogenesis, spermatogenesis and cancer development. The purpose of the current study is to investigate the role of HUWE1 in early embryo development. Here we demonstrate that Huwe1 is expressed in both nucleus and cytoplasm of preimplantation mouse embryos as well as gametes. Hypoxia (5% O2) treatment could significantly increase Huwe1 expression during mouse embryo development process. HUWE1 knockdown inhibited normal embryonic development and reduced blastocyst formation, and increased apoptotic cell numbers were observed in the embryos of HUWE1 knockdown group. Human embryo staining result showed that reduced HUWE1 staining was observed in the poor-quality embryos. Furthermore, Western blot result showed that significantly reduced expression of HUWE1 was observed in the villi of miscarriage embryos compared with the normal control, indicating that reduced expression of HUWE1 is related to poor embryo development. Oxidative reagent, H2O2 inhibited HUWE1 expression in human sperm, indicating that HUWE1 expression in sperm is regulated by oxidative stress. In conclusion, these results suggest that HUWE1 protein could contribute to preimplantation embryo development and dysregulated expression of HUWE1 could be related to poor embryo development and miscarriage in IVF clinic.

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“…Thus, Cul-4b is essential for the development of extra-embryonic tissues, which lack Cul-4a expression, but is dispensable for embryogenesis itself 71 . Given the fact that the Cul-4A gene is amplified or overexpressed in a number of human cancers (for review see 61,72 ), which is associated with poor prognosis for cancer patients 73 , whereas Cul-4B mutations are associated with human X-linked mental retardation (XLMR) syndrome 74,75 , these Cul-4 conditional mouse models will be very useful for cancer research ( Cul-4a) as well as for the study of neuronal and behavioral deficiencies seen in human Cul-4B XLMR patients ( Cul-4b) 76 . Along this line, a conditional Cre-dependent gain-of-function Cul-4a Tg mouse model has been established 77 , which can be particularly useful for determining a potential causal role of Cul-4a overexpression in diseases, as seen in many human cancers 61,72 , especially in organ-specific tumorigenesis.…”

Section: Cullinsmentioning

confidence: 99%

Genetically engineered mouse models for functional studies of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases

2013

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The SCF (SKP1 (S-phase-kinase-associated protein 1), Cullin-1, F-box protein) E3 ubiquitin ligases, the founding member of Cullin-RING ligases (CRLs), are the largest family of E3 ubiquitin ligases in mammals. Each individual SCF E3 ligase consists of one adaptor protein SKP1, one scaffold protein cullin-1 (the first family member of the eight cullins), one F-box protein out of 69 family members, and one out of two RING (Really Interesting New Gene) family proteins RBX1/ROC1 or RBX2/ROC2/SAG/RNF7. Various combinations of these four components construct a large number of SCF E3s that promote the degradation of many key regulatory proteins in cell-context, temporally, and spatially dependent manners, thus controlling precisely numerous important cellular processes, including cell cycle progression, apoptosis, gene transcription, signal transduction, DNA replication, maintenance of genome integrity, and tumorigenesis. To understand how the SCF E3 ligases regulate these cellular processes and embryonic development under in vivo physiological conditions, a number of mouse models with transgenic (Tg) expression or targeted deletion of components of SCF have been established and characterized. In this review, we will provide a brief introduction to the ubiquitin-proteasome system (UPS) and the SCF E3 ubiquitin ligases, followed by a comprehensive overview on the existing Tg and knockout (KO) mouse models of the SCF E3s, and discuss the role of each component in mouse embryogenesis, cell proliferation, apoptosis, carcinogenesis, as well as other pathogenic processes associated with human diseases. We will end with a brief discussion on the future directions of this research area and the potential applications of the knowledge gained to more effective therapeutic interventions of human diseases.

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CUL4B ubiquitin ligase in mouse development: A model for human X-linked mental retardation syndrome?

Cited by 11 publications

References 16 publications

De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features

De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features

HUWE1 plays important role in mouse preimplantation embryo development and the dysregulation is associated with poor embryo development in humans

Genetically engineered mouse models for functional studies of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases

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