CUL3 and protein kinases: Insights from PLK1/KLHL22 interaction

Metzger, Thibaud; Kleiss, Charlotte; Sumara, Izabela

doi:10.4161/cc.25369

Cited by 19 publications

(13 citation statements)

References 36 publications

(57 reference statements)

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“…In addition, exome sequencing detected a mutation in the VCAM1 gene, which has been reported to function as a tumor suppressor gene in HCC . Notably, our exome analysis identified mutations in four additional genes, SPOP , KLHL22 , TRPC4AP , and RNF169 , which have been reported to play a role in the ubiquitin pathway . For example, a heterozygous missense mutation altering Ser119 within the SPOP gene was identified in a single HB case (Table ).…”

Section: Resultsmentioning

confidence: 79%

Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex

et al. 2014

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Hepatoblastoma (HB) is the most common primary liver tumor in children. Mutations in the b-catenin gene that lead to constitutive activation of the Wnt pathway have been detected in a large proportion of HB tumors. To identify novel mutations in HB, we performed whole-exome sequencing of six paired HB tumors and their corresponding lymphocytes. This identified 24 somatic nonsynonymous mutations in 21 genes, many of which were novel, including three novel mutations targeting the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) genes in the Wnt pathway, and genes previously shown to be involved in the ubiquitin ligase complex (SPOP, KLHL22, TRPC4AP, and RNF169). Functionally, both the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) were observed to be gain-of-functional mutations, and the CAPRIN2 (R968H/S969C) was also shown to activate the Wnt pathway in HB cells. These findings suggested the activation of the Wnt pathway in HB, which was confirmed by immunohistochemical staining of the b-catenin in 42 HB tumors. We further used short hairpin RNA (shRNA)-mediated interference to assess the effect of 21 mutated genes on HB cell survival. The results suggested that one novel oncogene (CAPRIN2) and three tumor suppressors (SPOP, OR5I1, and CDC20B) influence HB cell growth. Moreover, we found that SPOP S119N is a loss-of-function mutation in HB cells. We finally demonstrated that one of the mechanisms by which SPOP inhibits HB cell proliferation is through regulating CDKN2B expression. Conclusion: These results extend the landscape of genetic alterations in HB and highlight the dysregulation of Wnt and ubiquitin pathways in HB tumorigenesis.

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Section: Resultsmentioning

confidence: 79%

Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex

et al. 2014

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“…p.R659Q in ZDHH8 is present in the ExAC data set; rs781662370. ZDHH8 has been reported to be associated with susceptibility to schizophrenia (Mukai et al 2004), ZNF74 has been also reported o be associated with age-at-onset of schizophrenia (Takase et al 2001), and KLHL22 plays a role in ubiquitination (Metzger et al 2013). The WW domaincontaining oxidoreductase (WWOX), a likely tumor suppressor gene, is linked to neuronal development (Chang 2015).…”

Section: Discussionmentioning

confidence: 98%

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

et al. 2016

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Intellectual disability is a heterogeneous disease with many genes and mutations influencing the phenotype. Consanguineous families constitute a rich resource for the identification of rare variants causing autosomal recessive disease, due to the effects of inbreeding. Here, we examine three consanguineous Arab families, recruited in a quest to identify novel genes/mutations. All the families had multiple offspring with non-specific intellectual disability. We identified homozygosity (autozygosity) intervals in those families through SNP genotyping and whole exome sequencing, with variants filtered using Ingenuity Variant Analysis (IVA) software. The families showed heterogeneity and novel mutations in three different genes known to be associated with intellectual disability. These mutations were not found in 514 ethnically matched control chromosomes. p.G410C in WWOX, p.H530Y in RARS2, and p.I69F in C10orf2 are novel changes that affect protein function and could give new insights into the development and function of the central nervous system.

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“…E3 ligase Chfr ubiquitination of Plk1 results in a delay of cells entering mitosis in the presence of mitotic stress through negative regulation of Cdc2 activation (47). Ubiquitination of Plk1 by Cullin 3 ligase complex with the BTB adaptor KLHL22 directs Plk1 dissociation from the kinetochore without affecting Plk1 stability (48, 49). Although CHIP depletion did not affect cell cycle progression during non-stress condition (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

Chen

Farah

et al. 2016

Molecular Cancer Therapeutics

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Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer (PCa) when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) re-activation is responsible for the recurrence of PCa after ADT. Thus targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSPs) are chaperones that modify stability and activity of their client proteins. HSP90, a major player of the HSP family, regulates stabilities of many proteins, including AR and Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events. Further, HSP90 is overexpressed in different cancers, including PCa. Herein, we show that co-treatment of PCa with AR antagonist enzalutamide and HSP90 inhibitor leads to more severe cell death due to a synergistic reduction of AR protein. Interestingly, we show that overexpression of Plk1 rescued the synergistic effect and that co-targeting HSP90 and Plk1 also leads to more severe cell death. Mechanistically, we show that E3 ligase CHIP, in addition to targeting AR, is responsible for the degradation of Plk1 as well. These findings suggest that co-targeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC.

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CUL3 and protein kinases: Insights from PLK1/KLHL22 interaction

Cited by 19 publications

References 36 publications

Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex

Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

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