Knockdown of Cyclin-dependent Kinase 10 (cdk10) Gene Impairs Neural Progenitor Survival via Modulation of raf1a Gene Expression

Yeh, Chi-Wei; Kao, Shoa-Hsuan; Cheng, Yi-Chuan; Hsu, Li‐Sung

doi:10.1074/jbc.m112.420265

Cited by 17 publications

(18 citation statements)

References 47 publications

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“…We injected mRNA of the normal ATX-3 and ATX-3 exp (80Q) into wild-type and p53 mutant fish one-cell embryos. In zebrafish, otx2 is expressed in the prospective forebrain/midbrain in mid/gastrulae [36–38], and neurogenin 1 ( ngn1 ) is reported to be a determinant of zebrafish basal forebrain dopaminergic neurons [39,40]. We performed the whole-mount in situ hybridization using otx2 and ngn1 as two neural markers to evaluate the neural loss upon the normal ATX-3 and ATX-3 exp (80Q) expression in zebrafish.…”

Section: Resultsmentioning

confidence: 99%

The Machado–Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53

Guan

et al. 2016

PLoS Biol

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As a deubiquitinating enzyme (DUB), the physiological substrates of ataxin-3 (ATX-3) remain elusive, which limits our understanding of its normal cellular function and that of pathogenic mechanism of spinocerebellar ataxia type 3 (SCA3). Here, we identify p53 to be a novel substrate of ATX-3. ATX-3 binds to native and polyubiquitinated p53 and deubiquitinates and stabilizes p53 by repressing its degradation through the ubiquitin (Ub)-proteasome pathway. ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription/expression of p53 target genes and promotes p53-dependent apoptosis in both mammalian cells and the central nervous system of zebrafish. Furthermore, the polyglutamine (polyQ)-expanded ATX-3 retains enhanced interaction and deubiquitination catalytic activity to p53 and causes more severe p53-dependent neurodegeneration in zebrafish brains and in the substantia nigra pars compacta (SNpc) or striatum of a transgenic SCA3 mouse model. Our findings identify a novel molecular link between ATX-3 and p53-mediated cell death and provide an explanation for the direct involvement of p53 in SCA3 disease pathogenesis.

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Section: Resultsmentioning

confidence: 99%

The Machado–Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53

Guan

et al. 2016

PLoS Biol

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“…Chromatin immunoprecipitation experiments established that CDK10 and ETS2 bind to a putative ETS2-binding site in the c-RAF gene promoter, and that CDK10 silencing increases binding of ETS2 to this site [ 10 ]. The upregulation of c-RAF in response to inhibition of CDK10 expression has also been observed in biliary tract cancer cell lines [ 22 ] and in zebrafish embryos [ 23 ].…”

Section: Cdk10 Regulates Transcription and Developmentmentioning

confidence: 99%

“…Inhibiting CDK10 expression by morpholinos hindered the development of the central nervous system by triggering apoptosis in the brain and dorsal neurons. The control exerted by CDK10 on neural progenitor cells was shown to be mediated by the Raf-MEK-ERK1/2 pathway [ 23 ]. The developmental functions of CDK10 were also investigated in the lepidopteran Helicoverpa armigera, which poses a severe threat to crop production worldwide.…”

Section: Cdk10 Regulates Transcription and Developmentmentioning

confidence: 99%

The awakening of the CDK10/Cyclin M protein kinase

et al. 2017

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Cyclin-dependent kinases (CDKs) play important roles in the control of fundamental cellular processes. Some of the most characterized CDKs are considered to be pertinent therapeutic targets for cancers and other diseases, and first clinical successes have recently been obtained with CDK inhibitors. Although discovered in the pre-genomic era, CDK10 attracted little attention until it was identified as a major determinant of resistance to endocrine therapy for breast cancer. In some studies, CDK10 has been shown to promote cell proliferation whereas other studies have revealed a tumor suppressor function. The recent discovery of Cyclin M as a CDK10 activating partner has allowed the unveiling of a protein kinase activity against the ETS2 oncoprotein, whose degradation is activated by CDK10/Cyclin M-mediated phosphorylation. CDK10/Cyclin M has also been shown to repress ciliogenesis and to maintain actin network architecture, through the phoshorylation of the PKN2 protein kinase and the control of RhoA stability. These findings shed light on the molecular mechanisms underlying STAR syndrome, a severe human developmental genetic disorder caused by mutations in the Cyclin M coding gene. They also pave the way to a better understanding of the role of CDK10/Cyclin M in cancer.

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“…Thus, the deletion of MC1R in our patients could potentially be contributing to their red hair color and light complexion that distinguishes both girls from their parents. To our knowledge, none of the remaining genes have been associated with disease, although CDK10, a cyclin‐dependent kinase, has been shown to have a critical role in neurogenesis in the developing zebrafish [Yeh et al, ].…”

Section: Discussionmentioning

confidence: 99%

Monozygotic twins with a de novo 0.32 Mb 16q24.3 deletion, including TUBB3 presenting with developmental delay and mild facial dysmorphism but without overt brain malformation

Grønborg

Kjærgaard

Hove

et al. 2015

American J of Med Genetics Pt A

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Nervous system development is highly dependent on the function of microtubules, which are assembled from tubulin heterodimers containing several α- and β-tubulin isotypes encoded by separate genes. A spectrum of neurological disorders with malformations of the central nervous system has recently been associated with missense mutations in this group of genes. Here, we report two patients, monozygotic twins, carrying a de novo 0.32 Mb deletion of chromosome 16q24.3 including the TUBB3 gene. The patients presented with global developmental delay, mild facial dysmorphism, secondary microcephaly, and mild spastic diplegia. Cerebral magnetic resonance imaging of the patients did not reveal cortical malformations, malformations of the corticospinal tracts, basal ganglia, corpus callosum, or optic nerves. This observation is in contrast to the group of neurological disorders that are associated with heterozygous missense mutations in genes encoding different neuronal α- and β-tubulin isotypes, termed tubulinopathies. On the background of current knowledge regarding the function and genotype-phenotype correlations of mutations in the neuronal tubulin isotypes, the clinical and diagnostic findings in these patients are discussed. To our knowledge, this is the first report of patients with a de novo deletion of the TUBB3 gene. The lack of cortical or other cerebral malformations supports the current hypothesis that TUBB3-related tubulinopathies are caused by altered protein function.

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Knockdown of Cyclin-dependent Kinase 10 (cdk10) Gene Impairs Neural Progenitor Survival via Modulation of raf1a Gene Expression

Cited by 17 publications

References 47 publications

The Machado–Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53

The Machado–Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53

The awakening of the CDK10/Cyclin M protein kinase

Monozygotic twins with a de novo 0.32 Mb 16q24.3 deletion, including TUBB3 presenting with developmental delay and mild facial dysmorphism but without overt brain malformation

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