Regulation of p57KIP2 during Muscle Differentiation: Role of Egr1, Sp1 and DNA Hypomethylation

Figliola, Rocco; Busanello, Anna; Vaccarello, Giovanna; Maione, Rossella

doi:10.1016/j.jmb.2008.05.004

Cited by 41 publications

(61 citation statements)

References 55 publications

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“…It was during the examination of a number of different fibroblast cell types, showing comparable abilities to undergo apparently normal differentiation in response to MyoD, that we found the occurrence of their differential responsiveness to the induction of Cdkn1c. 19,21,22 In the present work, we employed immortalized mouse C57BL/6 as responsive and C3H10T1/2 as unresponsive fibroblasts, the 2 cell types in which we had previously examined in most detail the role of MyoD in regulating the long-range interaction between KvDMR1 and Cdkn1c promoter. 23,24 Comparison of the promoter 21 and KvDMR1 ( Supplementary Fig.…”

Section: -Aza Treatment Restores the Functional Interaction Of Myod mentioning

confidence: 99%

“…19,21,22 In the present work, we employed immortalized mouse C57BL/6 as responsive and C3H10T1/2 as unresponsive fibroblasts, the 2 cell types in which we had previously examined in most detail the role of MyoD in regulating the long-range interaction between KvDMR1 and Cdkn1c promoter. 23,24 Comparison of the promoter 21 and KvDMR1 ( Supplementary Fig. 1) sequences between the 2 cell types revealed a complete identity, thus suggesting the existence of some epigenetic restriction in unresponsive cells.…”

Section: -Aza Treatment Restores the Functional Interaction Of Myod mentioning

confidence: 99%

“…In this regard, the use of pharmacological inhibitors of DNA methylation or genetic ablation of individual DNA methyltransferases suggested that the DNA methylation status of the 2 regulatory elements exert opposite effects on Cdkn1c expression. In fact, while promoter and gene body hypermethylation have been implicated in Cdkn1c silencing during imprinting, 36 prior to differentiation, 21 and in tumor cells. [37][38][39][40] KvDMR1 hypermethylation, present on the maternal allele, is believed to support maternal-specific Cdkn1c expression.…”

Section: -Aza Treatment Restores the Functional Interaction Of Myod mentioning

confidence: 99%

“…We found that Cdkn1c is a target of the muscle-specific basic helix-loop helix (bHLH) factor MyoD. 19 MyoD is the prototypical master regulator of differentiation 20 and induces Cdkn1c expression through a complex mechanism involving, on one hand, the mediation of MyoD-induced factors, which interact with Cdkn1c promoter 21,22 and, on the other hand, the direct interaction of MyoD with KvDMR1. 23,24 In particular, we found that, in undifferentiated myoblasts, KvDMR1 is involved in a repressive long-range chromatin interaction with Cdkn1c promoter, mediated by CTCF.…”

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confidence: 99%

“…These cell types, that we termed unresponsive in comparison with the normally responsive cells, represented a very useful experimental tool to highlight the existence of cis-acting constraints preventing Cdkn1c expression 21,22 and to reveal the functional importance of the MyoD binding to KvDMR1. 23,24 In particular, we found that, in unresponsive cells, MyoD is unable to interact with KvDMR1-chromatin and promote the release of the CTCFmediated loop.…”

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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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Section: -Aza Treatment Restores the Functional Interaction Of Myod mentioning

confidence: 99%

Section: -Aza Treatment Restores the Functional Interaction Of Myod mentioning

confidence: 99%

Section: -Aza Treatment Restores the Functional Interaction Of Myod mentioning

confidence: 99%

mentioning

confidence: 99%

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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Changes on chromosome 11p15.5 as specific marker for embryonal rhabdomyosarcoma?

Vicha,

Jencova,

Novakova‐Kodetova

et al. 2023

Genes Chromosomes & Cancer

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Rhabdomyosarcomas (RMS) constitute a heterogeneous spectrum of tumors with respect to clinical behavior and tumor morphology. The paternal uniparental disomy (pUPD) of 11p15.5 is a molecular change described mainly in embryonal RMS. In addition to LOH, UPD, the MLPA technique (ME030kit) also determines copy number variants and methylation of H19 and KCNQ1OT1 genes, which have not been systematically investigated in RMS. All 127 RMS tumors were divided by histology and PAX status into four groups, pleomorphic histology (n = 2); alveolar RMS PAX fusion‐positive (PAX+; n = 39); embryonal RMS (n = 70) and fusion‐negative RMS with alveolar pattern (PAX‐RMS‐AP; n = 16). The following changes were detected; negative (n = 21), pUPD (n = 75), gain of paternal allele (n = 9), loss of maternal allele (n = 9), hypermethylation of H19 (n = 6), hypomethylation of KCNQ1OT1 (n = 6), and deletion of CDKN1C (n = 1). We have shown no difference in the frequency of pUPD 11p15.5 in all groups. Thus, we have proven that changes in the 11p15.5 are not only specific to the embryonal RMS (ERMS), but are often also present in alveolar RMS (ARMS). We have found changes that have not yet been described in RMS. We also demonstrated new potential diagnostic markers for ERMS (paternal duplication and UPD of whole chromosome 11) and for ARMS PAX+ (hypomethylation KCNQ1OT1).

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Down‐regulation of the cyclin‐dependent kinase inhibitor p57 is mediated by Jab1/Csn5 in hepatocarcinogenesis

Guo

Cheng

et al. 2016

Hepatology

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Down-regulation of p57 (KIP2) cyclin-dependent kinase inhibitors accelerates the growth and invasion of hepatocellular carcinoma (HCC), suggesting that p57 may play an important role in liver carcinogenesis. However, the mechanism or oncogenic signal leading to p57 down-regulation in HCC remains to be determined. Herein, we demonstrated that Jab1/Csn5 expression is negatively correlated with p57 levels in HCC tissues. Kaplan-Meier analysis of tumor samples revealed that high Jab1/Csn5 expression with concurrent low p57 expression is associated with poor overall survival. The inverse pattern of Jab1 and p57 expression was also observed during carcinogenesis in a chemically induced rat HCC model. We also found that mechanistically, Jab1-mediated p57 proteolysis in HCC cells is dependent on 26S-proteasome inhibitors. We further demonstrated that direct physical interaction between Jab1 and p57 triggers p57 down-regulation, independently of Skp2 and Akt pathways, in HCC cells. These data suggest that Jab1 is an important upstream negative regulator of p57 and that aberrant expression of Jab1 in HCC could lead to a significant decrease in p57 levels and contribute to tumor cell growth. Furthermore, restoration of p57 levels induced by loss of Jab1 inhibited tumor cell growth and further increased cell apoptosis in HCC cells. Moreover, silencing Jab1 expression further enhanced the antitumor effects of cisplatin-induced apoptosis in HCC cells. Conclusion: Jab1-p57 pathway confers resistance to chemotherapy and may represent a potential target for investigational therapy in HCC. (HEPATOLOGY 2016;63:898-913) H epatocellular carcinoma (HCC) is the sixth most prevalent cancer in the world and is the third leading cause of cancer-related mortality. (1) Only 10% to 20% of HCC tumors can be removed completely by surgery in patients with HCC, and the reported cumulative 5-year recurrence rate after curative hepatectomy averages above 70% in both Eastern and Western medical centers. (2) At present, there is not only a lack of predictive and prognostic biomarkers in HCC patients but also a lack of effective therapeutic targets. Systemic treatment approaches are still the main option for patients with advanced HCC. Cisplatin-based regimens result in higher objective response rates than do non-cisplatin-based regimens in advanced HCC. However, the 15% response rate significantly limits the overall therapeutic benefit. (3) Abbreviations: CDK, cyclin-dependent kinase; HCC, hepatocellular carcinoma; siRNA, small interfering RNA; TCGA, the Cancer Genome Atlas; TGF-b, transforming growth factor b.

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Regulation of p57KIP2 during Muscle Differentiation: Role of Egr1, Sp1 and DNA Hypomethylation

Cited by 41 publications

References 55 publications

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

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

Changes on chromosome 11p15.5 as specific marker for embryonal rhabdomyosarcoma?

Down‐regulation of the cyclin‐dependent kinase inhibitor p57 is mediated by Jab1/Csn5 in hepatocarcinogenesis

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