Cell cycle‐dependent ubiquitylation and destruction of <scp>NDE</scp>1 by <scp>CDK</scp>5‐<scp>FBW</scp>7 regulates ciliary length

Maskey, Dipak; Marlin, M. Caleb; Kim, Seokho; Kim, Sehyun; Ong, E-Ching; Li, Guangpu; Tsiokas, Leonidas

doi:10.15252/embj.201490831

Cited by 71 publications

(88 citation statements)

References 69 publications

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“…Sequence of CDK5 siRNAs are as follow: UAUGACAGAAUCCCAGCCCTT, GGGCUGGGAUUCUGUCAUATT42. For efficient gene silencing, siRNAs were transfected twice.…”

Section: Methodsmentioning

confidence: 99%

Cyclin I-like (CCNI2) is a cyclin-dependent kinase 5 (CDK5) activator and is involved in cell cycle regulation

Liu

Zhai

Zhao

et al. 2017

Sci Rep

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In contrast to conventional cyclin-dependent kinases that are important for mitotic cell division, cyclin-dependent kinase 5 (CDK5) is predominantly activated in post-mitotic cells and is involved in various cellular events. The kinase activity of CDK5 is tightly regulated by specific activators including p35, p39, and cyclin I (CCNI). Here we show that cyclin I-like (CCNI2), a homolog of CCNI, interacts with CDK5 and activates the kinase activity of CDK5. Different from CCNI, which colocalizes with CDK5 in the nuclei in transfected cells, CCNI2 mainly retains CDK5 in the cytoplasm as well as on the cell membrane. Furthermore, although the expression level of CCNI2 mRNA and CCNI2 protein do not change significantly during cell cycle, depletion of CCNI2 with siRNA affects cell cycle progression as well as cell proliferation. In conclusion, our data strongly suggest that CCNI2 is a novel CDK5 activator and is involved in cell cycle regulation.

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“…Sequence of CDK5 siRNAs are as follow: UAUGACAGAAUCCCAGCCCTT, GGGCUGGGAUUCUGUCAUATT42. For efficient gene silencing, siRNAs were transfected twice.…”

Section: Methodsmentioning

confidence: 99%

Cyclin I-like (CCNI2) is a cyclin-dependent kinase 5 (CDK5) activator and is involved in cell cycle regulation

Liu

Zhai

Zhao

et al. 2017

Sci Rep

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“…We showed that total CRMP2 and p-CRMP2 (Ser522) are increased in cystic disease and that the reduction of CDK5 leads to decreased level of both total CRMP2 and p-CRMP2. Interestingly, very recent findings by Maskey et al described intriguing involvement of CDK5 in regulating the FBW7-NDE1 pathway and its presumptive modulation of cilia length in a cell cycle-dependent manner, at least in vitro (54). It is possible that CDK5 may act through multiple downstream targets and therefore, its function in kidneys needs to be further investigated in subsequent studies in multiple disease settings.…”

Section: Discussionmentioning

confidence: 99%

Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis

Husson¹,

Moreno²,

Smith³

et al. 2016

Hum. Mol. Genet.

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Polycystic kidney diseases (PKDs) comprise a subgroup of ciliopathies characterized by the formation of fluid-filled kidney cysts and progression to end-stage renal disease. A mechanistic understanding of cystogenesis is crucial for the development of viable therapeutic options. Here, we identify CDK5, a kinase active in post mitotic cells, as a new and important mediator of PKD progression. We show that long-lasting attenuation of PKD in the juvenile cystic kidneys (jck) mouse model of nephronophthisis by pharmacological inhibition of CDK5 using either R-roscovitine or S-CR8 is accompanied by sustained shortening of cilia and a more normal epithelial phenotype, suggesting this treatment results in a reprogramming of cellular differentiation. Also, a knock down of Cdk5 in jck cells using small interfering RNA results in significant shortening of ciliary length, similar to what we observed with R-roscovitine. Finally, conditional inactivation of Cdk5 in the jck mice significantly attenuates cystic disease progression and is associated with shortening of ciliary length as well as restoration of cellular differentiation. Our results suggest that CDK5 may regulate ciliary length by affecting tubulin dynamics via its substrate collapsin response mediator protein 2. Taken together, our data support therapeutic approaches aimed at restoration of ciliogenesis and cellular differentiation as a promising strategy for the treatment of renal cystic diseases.

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“…Nde1, a paralogue of Ndel1, is highly expressed in mitotic cells but depleted during quiescence, and silencing of Nde1 in cultured cells and zebrafish leads to marked enhancement of cilium length and a delay in S phase entry 77 . Nde1 levels are controlled by CDK5 phosphorylation in G0/G1 cells, which targets Nde1 for ubiquitylation (and subsequent destruction) by the F-box protein Fbw7, a tumour suppressor 78 . Ablation of Nde1 in mice leads to microcephaly, possibly due to proliferative delays provoked by the persistence of cilia in progenitor neurons 77,79 .…”

Section: Cilium Disassemblymentioning

confidence: 99%

Cilium assembly and disassembly

2016

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The primary cilium is an antenna-like, immotile organelle present on most types of mammalian cells, which interprets extracellular signals that regulate growth and development. Although once considered a vestigial organelle, the primary cilium is now the focus of considerable interest. We now know that ciliary defects lead to a panoply of human diseases, termed ciliopathies, and the loss of this organelle may be an early signature event during oncogenic transformation. Ciliopathies include numerous seemingly unrelated developmental syndromes, with involvement of the retina, kidney, liver, pancreas, skeletal system and brain. Recent studies have begun to clarify the key mechanisms that link cilium assembly and disassembly to the cell cycle, and suggest new possibilities for therapeutic intervention.

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Cell cycle‐dependent ubiquitylation and destruction of NDE1 by CDK5‐FBW7 regulates ciliary length

Cited by 71 publications

References 69 publications

Cyclin I-like (CCNI2) is a cyclin-dependent kinase 5 (CDK5) activator and is involved in cell cycle regulation

Cyclin I-like (CCNI2) is a cyclin-dependent kinase 5 (CDK5) activator and is involved in cell cycle regulation

Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis

Cilium assembly and disassembly

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