Functional Versatility of the CDK Inhibitor p57Kip2

Creff, Justine; Besson, Arnaud

doi:10.3389/fcell.2020.584590

Cited by 51 publications

(43 citation statements)

References 172 publications

(266 reference statements)

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“…p57 is expressed at high levels during embryogenesis and its expression decreases, becoming much more restricted at E13.5 and only being expressed in a limited number of adult tissues. 60 This is unlike p21 and p27 which are more ubiquitously expressed. Together with our data suggesting that p57 may be a poor inhibitor of CyclinD/Cdk4, this suggests that in tissues where both p27 and p57 are expressed, phosphorylation of p27 would be the rate-limiting factor in promoting cell cycle entry.…”

Section: Discussionmentioning

confidence: 96%

Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation

Warnecke

et al. 2021

Preprint

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Balanced proliferation-quiescence decisions are vital during normal development and in tissue homeostasis and their dysregulation underlies tumorigenesis. Entry into proliferative cycles is driven by Cyclin/Cyclin-dependent kinases (Cdks). Conserved Cdk inhibitors (CKIs), p21(Cip1/Waf1), p27(Kip1) and p57(Kip2), bind to Cyclin/Cdks and inhibit Cdk activity. p27 tyrosine phosphorylation, in response to mitogenic signalling, promotes activation of CyclinD/Cdk4 and CyclinA/Cdk2. Tyrosine phosphorylation is conserved in p21 and p57, although the number of sites differs. We use molecular dynamics simulations to compare the structural changes in Cyclin/Cdk/CKI trimers induced by single and multiple tyrosine phosphorylation in CKIs and their impact on CyclinD/Cdk4 and CyclinA/Cdk2 activity. Despite shared structural features, CKI binding induces distinct structural responses in Cyclin/Cdks and the predicted effects of CKI tyrosine phosphorylation on Cdk activity are not conserved across CKIs. Our analyses suggest how CKIs may have evolved to be sensitive to different inputs to give context-dependent control of Cdk activity.

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Section: Discussionmentioning

confidence: 96%

Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation

Warnecke

et al. 2021

Preprint

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“…The severe developmental phenotype of p57 knock-out mice could be mostly reverted by introducing p27 into the p57 locus revealing the prominent role of the cyclin/CDK-inhibitory function of p57 ( Susaki et al, 2009 ; Duquesnes et al, 2016 ). However, some phenotypes remained which indicated that p57 might have important non-canonical functions independent of cyclin/CDK-inhibition ( Creff and Besson, 2020 ). One novel non-canonical function of p57 is the regulation of transcription through interaction with transcription factors ( Joseph et al, 2009 ; Creff and Besson, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…The biological significance of c-Jun-activation by p57 remains to be investigated. Both, p57 and c-Jun are important for embryonic development ( Eferl and Wagner, 2003 ; Creff and Besson, 2020 ; Papavassiliou and Musti, 2020 ). A total of 10% of p57 knockout mice die between E13 and E16 ( Yan et al, 1997 ; Zhang et al, 1997 , 57) and c-jun −/− mice die around E13 ( Hilberg et al, 1993 ).…”

Section: Discussionmentioning

confidence: 99%

“…Not all of the observed defects in p57 knock-out mice can be explained by impaired cyclin/CDK- and cell cycle regulation ( Susaki et al, 2009 ; Duquesnes et al, 2016 ). During the last years, novel roles for Cip/Kip proteins in transcription regulation have emerged ( Perkins, 2002 ; Bachs et al, 2018 ; Creff and Besson, 2020 ). p57 is known to regulate transcription by direct but also by indirect mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of c-Jun/AP-1-Activity by the Cell Cycle Inhibitor p57Kip2

Kullmann

Pegka

Ploner

et al. 2021

Front. Cell Dev. Biol.

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p57 is a member of the Cip/Kip family of cell cycle inhibitors which restrict the eukaryotic cell cycle by binding to and inhibiting cyclin/CDK complexes. They are considered as tumor suppressors and inactivating genomic mutations of p57 are associated with human overgrowth disorders. Increasing evidence suggests that p57 controls additional cellular processes beyond cell cycle control such as apoptosis, cell migration or transcription. Here we report that p57 can stimulate AP-1 promotor activity. While transactivation by c-Jun is strongly activated by p57, it did not enhance c-Fos induced transcription. This indicates that c-Jun is the target of p57 in the canonical AP-1 heterodimeric transcription factor. We could detect endogenous p57/c-Jun containing complexes in cells by co-immunoprecipitation. The strong stimulation of c-Jun activity is not the consequence of activating phosphorylation in the transactivation domain (TAD) of c-Jun, but rather due to negative interference with c-Jun repressors and positive interference with c-Jun activators. In contrast to full-length p57, the amino- and carboxy-terminal domains of p57 are insufficient for a significant activation of c-Jun induced transcription. When expressed in presence of full length p57, the p57 C-terminus abrogated and the N-terminus enhanced c-Jun activation. This indicates that the C-terminus may bind and sequester a putative activator of c-Jun, whereas the N-terminus may sequester a c-Jun repressor. Interestingly, the p57 aminoterminus is sufficient for binding to the two c-Jun repressors HDAC1 and HDAC3. These data are consistent with a model of c-Jun activation where p57 is a part of large nuclear remodeling/transcription complexes. p57 might stimulate transcription by inhibiting transcription repressor proteins like HDACs via its N-terminus and/or attracting transcription activators through its C-terminus. These data suggest that in addition to its role as a CDK inhibitor and tumor suppressor, p57 may also exert tumor promoting functions by activation of the proto-oncoprotein c-Jun.

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“…2c-d'). Therefore, we hypothesised that the initial stage of the neurons was induced by Sox14, and investigated the expression of p57 KIP2 , which appears immediately after neuronal birth [21,22], using in situ hybridisation. As a result, we found the expressing area expanded into the progenitor regions, as well as the upregulated expression level ( Fig. 2e-f'; n=5 for control and n=6/8 for Sox14).…”

Section: Sox14 Inhibits Neural Progenitor Cells and Promotes Transitimentioning

confidence: 99%

Sox14 is essential for initiation of interneuron differentiation in the chick spinal cord

Katsuyama

Kadoya

Shirai

et al. 2021

Preprint

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The neural tube comprises several different types of progenitors and postmitotic neurons that coordinately act with each other to play integrated functions. Its development consists of two phases: proliferation of progenitor cells and differentiation into postmitotic neurons. How progenitor cells differentiate into each corresponding neuron is an important question for understanding the mechanisms of neuronal development. Here we introduce one of the Sox transcription factors, Sox14, which plays an essential role in the promotion of neuronal differentiation. Sox14 belongs to the SoxB subclass and its expression starts in the progenitor regions before neuronal differentiation is initiated at the trunk level of the neural tube. After neuronal differentiation is initiated, Sox14 expression gradually becomes confined to the V2a region of the neural tube, where Chx10 is co-expressed. Overexpression of Sox14 restricts progenitor cell proliferation. Conversely, the blockade of Sox14 expression by the RNAi strategy inhibits V2a neuron differentiation and causes expansion of the progenitor domain. We further found that Sox14 acted as a transcriptional activator. Taken together, Sox14 acts as a modulator of cell proliferation and an initiator protein for neuronal differentiation in the intermediate region of the neural tube.

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Functional Versatility of the CDK Inhibitor p57Kip2

Cited by 51 publications

References 172 publications

Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation

Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation

Stimulation of c-Jun/AP-1-Activity by the Cell Cycle Inhibitor p57Kip2

Sox14 is essential for initiation of interneuron differentiation in the chick spinal cord

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