p57KIP2: “Kip”ing the Cell under Control

Pateras, Ioannis S.; Apostolopoulou, Kalliopi; Niforou, Katerina; Kotsinas, Athanassios; Gorgoulis, Vassilis G.

doi:10.1158/1541-7786.mcr-09-0317

Cited by 143 publications

(171 citation statements)

References 253 publications

(324 reference statements)

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“…This result seems consistent with the expression pattern of p57, which is more restricted than the distribution of p21 and p27. (31) We concluded that, as was described for the induction of differentiation by bone morphogenetic protein 4 (BMP-4), (32) in hMSCs the regulation by RUNX2 of the G 0 /G 1 cell cycle arrest and hence differentiation in osteoblastic cells was preferentially mediated by the increase in p21 and p27.…”

Section: Discussionmentioning

confidence: 66%

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Ghali

Chauveau

Hardouin

et al. 2010

Journal of Bone and Mineral Research

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RUNX2 is a bone-specific transcription factor that plays a critical role in prenatal bone formation and postnatal bone development. It regulates the expression of genes that are important in committing cells into the osteoblast lineage. There is increasing evidence that RUNX2 is involved in osteoblast proliferation. RUNX2 expression increases during osteoblast differentiation, and recent data even suggest that it acts as a proapoptotic factor. The cytokine tumor necrosis factor a (TNF-a) is known to modulate osteoblast functions in a manner that depends on the differentiation stage. TNF-a affects the rate at which mesenchymal precursor cells differentiate into osteoblasts and induces apoptosis in mature osteoblasts. Thus we sought to establish whether or not the effects of TNF-a and fetal calf serum on proliferation and apoptosis in human mesenchymal stem cells (hMSCs) were dependent on RUNX2 level and activity. We transfected hMSCs with small interfering RNAs (siRNAs) directed against RUNX2 and found that they proliferated more quickly than control hMSCs transfected with a nonspecific siRNA. This increase in proliferation was accompanied by a rise in cyclin A1, B1, and E1 expression and a decrease in levels of the cyclin inhibitor p21. Moreover, we observed that RUNX2 silencing protected hMSCs from TNF-a's antiproliferative and apoptotic effects. This protection was accompanied by the inhibition of caspase-3 activity and Bax expression. Our results confirmed that RUNX2 is a critical link between cell fate, proliferation, and growth control. This study also suggested that, depending on the osteoblasts' differentiation stage, RUNX2 may control cell growth by regulating the expression of elements involved in hormone and cytokine sensitivity. ß

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Section: Discussionmentioning

confidence: 66%

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Ghali

Chauveau

Hardouin

et al. 2010

Journal of Bone and Mineral Research

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“…Down-regulation of p57 Kip2 , both transcriptionally and translationally, has been frequent demonstrated in many human cancers (Pateras et al, 2009), indicating that the level of p57 Kip2 might be important to control cell-cycle progression (Besson et al, 2008). Signaling through the PI3K-Akt-mTOR pathway was necessary and sufficient for the increase in p57Kip2, whereas MEK-ERK activity suppressed this increase (Worster et al, 2012).…”

Section: Pak4 Suppresses P57mentioning

confidence: 99%

P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57^Kip2 in Human Breast Cancer

Wang

Zhang

et al. 2013

The Anatomical Record

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The p21-activated kinases have been implicated in the control of cell cycle progression. However, the biological mechanism underlying the role of p21-activated kinase 4 (PAK4) in cell cycle control remains unknown. Here, by using quantitative RT-PCR and immunoblot analyses, we discovered that over-expression of PAK4 could suppress cyclin-dependent kinase inhibitor 1C ( p57 Kip2 ) expression in the MCF-7 human breast cancer cell line, whereas lentiviral vector-mediated small interfering RNA (siRNA) knockdown of PAK4 markedly promoted p57Kip2 expression in MCF-7 cells. Furthermore, PAK4-mediated down-regulation of p57Kip2 was reversed by MG132, a specific proteasome inhibitor. The ubiquitination assay confirmed that the activity of PAK4 attenuated p57Kip2 protein stability through the ubiquitin-proteasome pathway in MCF-7 cells. Moreover, a significant inverse correlation between PAK4 and p57Kip2 protein levels was observed in breast cancer tissues by immunohistochemical analysis. Taken together, our data demonstrate a novel function for PAK4 in regulating the stability of p57 Kip2, possibly through the ubiquitin-proteasome pathway, leading to increased proliferation of breast cancer cells. Thus, PAK4 may be used as a potential diagnostic and therapeutic target for human breast cancer. Anat Rec, 296:1561Rec, 296: -1567Rec, 296: , 2013. V C 2013 Wiley Periodicals, Inc.

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“…23 Cdkn1c silencing has been observed in several cancer cell types and has been found to contribute to their malignant phenotype. 1 A number of studies, addressing the molecular mechanisms underlying Cdkn1c repression, focused on the gain of repressive epigenetic modifications at the promoter or on the loss of KvDMR1 function resulting in maternal expression of Kcnq1ot1 and biallelic silencing of Cdkn1c. In contrast, the possible role of the accumulation of repressive modifications at KvDMR1 in the cancer cell context has never been considered.…”

Section: Differential H3k9me2 Enrichment Marks Kvdmr1 In Cancer Cellsmentioning

confidence: 99%

“…1 Compared to the other Cip/Kip CKIs p21 cip1 and p27 kip1 , p57 kip2 exerts unique functions not compensated by the other family members, as suggested by the lethal phenotype of knockout mice 2,3 and by the developmental anomalies associated with Cdkn1c loss or misexpression in humans. 4 The unique role of the Cdkn1c protein has been ascribed both to the presence of specific biochemical features of the protein, not shared by the other family members, 5,6 and to the specific expression pattern of the gene.…”

mentioning

confidence: 99%

“…8 The levels of Cdkn1c protein are fine-tuned by multiple regulatory mechanisms, ranging from epigenetic to posttranslational control, in different cell types. 1 Moreover, Cdkn1c is a paternally imprinted gene, expressed exclusively from the maternal allele, in both human and mouse. 9,10 Paternal Cdkn1c is regulated by an imprinting control region, called Kv-differentially methylated region 1 (KvDMR1), which controls the imprinting of the Kcnq1 domain, a cluster of imprinted genes including Cdkn1c.…”

mentioning

confidence: 99%

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A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells

et al. 2016

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The cdk inhibitor p57 kip2 , encoded by the Cdkn1c gene, plays a critical role in mammalian development and in the differentiation of several tissues. Cdkn1c protein levels are carefully regulated via imprinting and other epigenetic mechanisms affecting both the promoter and distant regulatory elements, which restrict its expression to particular developmental phases or specific cell types. Inappropriate activation of these regulatory mechanisms leads to Cdkn1c silencing, causing growth disorders and cancer. We have previously reported that, in skeletal muscle cells, induction of Cdkn1c expression requires the binding of the bHLH myogenic factor MyoD to a long-distance regulatory element within the imprinting control region KvDMR1. Interestingly, MyoD binding to KvDMR1 is prevented in myogenic cell types refractory to the induction of Cdkn1c. In the present work, we took advantage of this model system to investigate the epigenetic determinants of the differential interaction of MyoD with KvDMR1. We show that treatment with the DNA demethylating agent 5-azacytidine restores the binding of MyoD to KvDMR1 in cells unresponsive to Cdkn1c induction. This, in turn, promotes the release of a repressive chromatin loop between KvDMR1 and Cdkn1c promoter and, thus, the upregulation of the gene. Analysis of the chromatin status of Cdkn1c promoter and KvDMR1 in unresponsive compared to responsive cell types showed that their differential responsiveness to the MyoD-dependent induction of the gene does not involve just their methylation status but, rather, the differential H3 lysine 9 dimethylation at KvDMR1. Finally, we report that the same histone modification also marks the KvDMR1 region of human cancer cells in which Cdkn1c is silenced. On the basis of these results, we suggest that the epigenetic status of KvDMR1 represents a critical determinant of the cell type-restricted expression of Cdkn1c and, possibly, of its aberrant silencing in some pathological conditions.

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p57KIP2: “Kip”ing the Cell under Control

Abstract: , on gene and protein structure, its transcriptional and translational regulation, and its role in human physiology and pathology, focusing on cancer development.

Cited by 143 publications

References 253 publications

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57^Kip2 in Human Breast Cancer

A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells

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p57KIP2: “Kip”ing the Cell under Control

Abstract: , on gene and protein structure, its transcriptional and translational regulation, and its role in human physiology and pathology, focusing on cancer development.

Cited by 143 publications

References 253 publications

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57Kip2 in Human Breast Cancer

A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells

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P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57^Kip2 in Human Breast Cancer