p53-Targeted LSD1 Functions in Repression of Chromatin Structure and Transcription In Vivo

Dept. of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 1000, Houston, TX 77030, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/2008; 28(17):5139-46. DOI: 10.1128/MCB.00287-08
Source: PubMed


Despite years of study focused on the tumor suppressor p53, little is understood about its functions in normal, differentiated
cells. We found that p53 directly interacts with lysine-specific demethylase 1 (LSD1) to alter chromatin structure and confer developmental repression of the tumor marker alpha-fetoprotein
(AFP). Chromatin immunoprecipitation (ChIP) and sequential ChIP of developmentally staged liver showed that p53 and LSD1 cooccupy
a p53 response element, concomitant with dimethylated histone H3 lysine 4 (H3K4me2) demethylation and postnatal repression
of AFP transcription. In p53-null mice, LSD1 binding is depleted, H3K4me2 is increased, and H3K9me2 remains unchanged compared to
those of the wild type, underscoring the specificity of p53-LSD1 complexes in demethylation of H3K4me2. We performed partial
hepatectomy of wild-type mouse liver and induced a regenerative response, which led to a loss of p53, increased H3K4me2, and
decreased LSD1 interaction at AFP chromatin, in parallel with reactivation of AFP expression. In contrast, nuclear translocation of p53 in mouse embryonic fibroblasts led to p53 interaction with p21/CIP1
chromatin, without recruitment of LSD1, and to activation of p21/CIP1. These findings reveal that LSD1 is targeted to chromatin by p53, likely in a gene-specific manner, and define a molecular
mechanism by which p53 mediates transcription repression in vivo during differentiation.

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    • "Recent evidence shows that KDM1A plays an important role in a variety of biological processes, including cell proliferation [6], adipogenesis [7], chromosome segregation, and embryonic development [8] [9]. Furthermore, KDM1A can also promote tumor development by inhibiting the tumor suppressor activity of p53 [10] [11] and KDM1A inhibitors have shown anticancer effects in cells [12] [13], supporting their potential as cancer drugs [14] [15]. "
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    ABSTRACT: Covalent modifications, such as methylation and demethylation of lysine residues in histones, play important roles in chromatin dynamics and the regulation of gene expression. The lysine demethylases (KDMs) catalyze the demethylation of lysine residues on histone tails and are associated with diverse human diseases, including cancer, and are therefore proposed as targets for the therapeutic modulation of gene transcription. High-throughput assays have been developed to find inhibitors of KDMs, most of which are fluorescence-based assays. Here we report the development of a coupled scintillation proximity assay (SPA) for 3 KDMs: KDM1A (LSD1), KDM3A (JMJD1A) and KDM4A (JMJD2A). In this assay methylated peptides are first demethylated by a KDM, and a protein methyltransferase (PMT) is added to methylate the resulting peptide with tritiated SAM. The enzyme activities were optimized and kinetic parameters were determined. These robust coupled assays are suitable for screening KDMs in 384-well format (Z'-Factors of 0.70-0.80) facilitating discovery of inhibitors in the quest for cancer therapeutics.
    Analytical Biochemistry 07/2014; 463. DOI:10.1016/j.ab.2014.06.023 · 2.22 Impact Factor
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    • "It is worth noting that the interference of enhancer is only one of the mechanisms underlying the p53-mediated repression. p53 uses many different ways to repress gene transcription in different cell types, although most of these mechanisms involve the promoter binding of p53 [60-63]. In human cells, p53 has also been shown to bind to the enhancers of development- and environment-associated genes [64]. "
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    ABSTRACT: The viability and subtle developmental defects of p53 knockout mice suggest that p53 does not play major role in development. However, contradictory evidence also exists. This discrepancy mainly results from the lack of molecular and cellular mechanisms and the general fact that p53 activation requires stresses. Recent studies of p53 in mouse and human ES cells and induced pluripotent stem (iPS) cells shed new light on the mechanisms of the developmental roles of p53. This review summarizes these new studies that support the developmental roles of p53, highlights the possible underlying molecular mechanisms, and discusses the potential relationship between the developmental roles and the tumor suppressive function of p53. In summary, the molecular mechanisms underlying the developmental roles of p53 are emerging, and the developmental roles and tumor suppressive function of p53 may be closely related.
    Cell and Bioscience 10/2013; 3(1). DOI:10.1186/2045-3701-3-42 · 3.63 Impact Factor
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    • "This results in a loss of p53-53BP1 interaction, leading to a decrease in the promotion of apoptosis by p53, possibly contributing to cancer progression. p53 directly interacts with LSD1, and this interaction serves to promote LSD1 binding to and activity at specific promoters [20]. Demethylation of E2F1 by LSD1 promotes apoptosis by stabilizing the protein, allowing its accumulation through a mechanism involving the inhibition of the ubiquitination of the E2F1 protein [21]. "
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    ABSTRACT: Lysine-specific demethylase 1 (Lsd1/Aof2/Kdm1a), the first enzyme with specific lysine demethylase activity to be described, demethylates histone and non-histone proteins and is essential for mouse embryogenesis. Lsd1 interacts with numerous proteins through several different domains, most notably the tower domain, an extended helical structure that protrudes from the core of the protein. While there is evidence that Lsd1-interacting proteins regulate the activity and specificity of Lsd1, the significance and roles of such interactions in developmental processes remain largely unknown. Here we describe a hypomorphic Lsd1 allele that contains two point mutations in the tower domain, resulting in a protein with reduced interaction with known binding partners and decreased enzymatic activity. Mice homozygous for this allele die perinatally due to heart defects, with the majority of animals suffering from ventricular septal defects. Molecular analyses revealed hyperphosphorylation of E-cadherin in the hearts of mutant animals. These results identify a previously unknown role for Lsd1 in heart development, perhaps partly through the control of E-cadherin phosphorylation.
    PLoS ONE 04/2013; 8(4):e60913. DOI:10.1371/journal.pone.0060913 · 3.23 Impact Factor
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