Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

Sansom, Owen J.; Maddison, Kathryn; Clarke, Alan R.

doi:10.1038/ncponc0812

Cited by 100 publications

(74 citation statements)

References 82 publications

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“…S2). Activation and posttranslational modification of p53 by acetyltransferases (p300, PCAF, TIP60) are known to be key regulators of p53-mediated apoptosis (12,(22)(23)(24). Consequently, we investigated whether p53 or acetyltransferases interact with endogenous KAISO under normal and etoposide-treated conditions.…”

Section: Kaiso Induces Cell Cycle Arrest and Apoptosis And Forms A Prmentioning

confidence: 99%

KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes

Koh

Han

Ryu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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An unresolved issue in genotoxic stress response is identification of induced regulatory proteins and how these activate tumor suppressor p53 to determine appropriate cell responses. Transcription factor KAISO was previously described to repress transcription following binding to methylated DNA. In this study, we show that KAISO is induced by DNA damage in p53-expressing cells and then interacts with the p53-p300 complex to increase acetylation of p53 K320 and K382 residues, although decreasing K381 acetylation. Moreover, the p53 with this particular acetylation pattern shows increased DNA binding and potently induces cell cycle arrest and apoptosis by activating transcription of CDKN1A (cyclin-dependent kinase inhibitor 1) and various apoptotic genes. Analogously, in Kaiso KO mouse embryonic fibroblast cells, p53-to-promoter binding and up-regulation of p21 and apoptosis gene expression is significantly compromised. KAISO may therefore be a critical regulator of p53-mediated cell cycle arrest and apoptosis in response to various genotoxic stresses in mammalian cells.KAISO | p53 | cell cycle arrest | apoptosis | p300

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Section: Kaiso Induces Cell Cycle Arrest and Apoptosis And Forms A Prmentioning

confidence: 99%

KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes

Koh

Han

Ryu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…This family of proteins consists of five members all containing a homologous methyl-CpG-binding domain (Sansom et al, 2007). In addition, a non-homologous protein called Kaiso has also been shown to bind a methylated CGCG motif (Sansom et al, 2007).…”

Section: Regulation Of Transcription By Dna Methylationmentioning

confidence: 99%

DNA methylation: The nuts and bolts of repression

Miranda

Jones

2007

Journal Cellular Physiology

589

485

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DNA methylation is an epigenetic modification which plays an important role in chromatin organization and gene expression. DNA methylation can silence genes and repetitive elements through a process which leads to the alteration of chromatin structure. The mechanisms which target DNA methylation to specific sites in the genome are not fully understood. In this review, we will discuss the mechanisms which lead to the long-term silencing of genes and will survey the progression that has been made in determining the targeted mechanisms for de novo DNA methylation.

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“…Methyl binding domain (MBD) proteins have a crucial role in linking DNA methylation with transcriptional silencing and may be potential targets for epigenetic therapies which would reactivate gene expression by inhibiting the repressive effects of MBD-dependent epigenetic silencing (Sansom et al 2007 ). MBD2 knockdown in tumour cell lines causes upregulation of specifi c epigenetically silenced genes, e.g.…”

Section: Future Epigenetic Targets In Solid Tumoursmentioning

confidence: 99%

Epigenetic Therapies in Solid Tumours: From Preclinical Models to Clinical Trial Results

Brown

Steinmann

Graham

et al. 2013

Epigenetic Therapy of Cancer

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Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

Cited by 100 publications

References 82 publications

KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes

KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes

DNA methylation: The nuts and bolts of repression

Epigenetic Therapies in Solid Tumours: From Preclinical Models to Clinical Trial Results

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