The candidate tumor suppressor BTG3 is a transcriptional target of p53 that inhibits E2F1

Ou, Yi-Hung; Chung, Pei-Han; Hsu, Fu-Fei; Sun, Te-Ping; Chang, Wen-Ming; Shieh, Sheau‐Yann

doi:10.1038/sj.emboj.7601825

Cited by 97 publications

(111 citation statements)

References 39 publications

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“…Expression of LIMK2b, but not LIMK2a, is induced by DNA damage in a p53-dependent manner To identify genes whose expression was altered by DNA damage, we previously conducted microarray analyses of LNCaP cells with or without ionizing radiation (IR) treatment (Ou et al, 2007). After analysis of the gene expression profiles, LIMK2, a known regulator of actin dynamics, was identified as a DNA damage-induced gene.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously used a method of combining small interfering RNA (siRNA) knockdown of CHK1 with microarray analysis to identify genes whose expression was altered by DNA damage in a CHK1-dependent manner (Ou et al, 2007). Here, we report the identification of a differentially expressed gene, LIMK2, a member of the LIMK serine/threonine protein kinase family that includes LIMK1.…”

Section: Introductionmentioning

confidence: 99%

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p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control

Lin

Chen

et al. 2010

Oncogene

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The p53 tumor suppressor protein is widely known for its role as a sequence-specific transcription factor that regulates the expression of stress response genes. Here, we report the identification of LIMK2, which encodes a kinase that regulates actin dynamics through phosphorylation of cofilin, as a p53 target upregulated by DNA damage. Interestingly, the splice variant LIMK2b, but not LIMK2a, was induced in a p53-dependent manner through an intronic consensus p53-binding site. Depletion of LIMK2b leads to early exit of G2/M arrest after DNA damage, whereas its overexpression prolongs the arrest. These responses are recapitulated by ectopic expression of the active cofilin S3A mutant and the inactive cofilin S3D mutant, respectively, suggesting that LIMK2b may modulate G2/M arrest through cofilin phosphorylation. Furthermore, in support of its potential role as a tumor suppressor, LIMK2b was downregulated in esophageal and thyroid cancers, as well as in a number of established cancer cell lines, and its expression suppresses cancer cell migration. Taken together, our results unveil a novel pathway whereby LIMK2b, acting downstream of p53, ensures proper execution of checkpoint arrest by modulating the dynamics of actin polymerization.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control

Lin

Chen

et al. 2010

Oncogene

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“…The beads were then precipitated, washed three times in the same buffer, resuspended in SDS sample buffer, boiled and analyzed by SDS-PAGE followed by immunoblotting as described below. Interaction between His-FEM1B and GST-Rad9 in the presence or absence of ethidium bromide was examined as described (Ou et al, 2007).…”

Section: Fem1b As a Novel Chk1 Mediator T-p Sun And S-y Shiehmentioning

confidence: 99%

“…Cytosolic (C) and nuclear fractions (N) were prepared as described (Ou et al, 2007). To isolate chromatin fractions, cells were first resuspended in buffer A (10 mM HEPES, pH 7.9, 10 mM KCl, 1.5 mM MgCl 2 , 0.34 M sucrose, 10% glycerol, 1 mM DTT) containing protease and phosphatase inhibitors.…”

Section: Cell Fractionationmentioning

confidence: 99%

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Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

Shieh

2009

Oncogene

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Human checkpoint kinase 1 (CHK1) is an essential kinase required to preserve genome stability, and is activated by DNA replication blockage through the ataxia-telangiectasia-mutated-and-Rad3-related (ATR)/ATRIP-signaling pathway. In this report, we show that a novel CHK1-interacting protein, FEM1B (human homologue of the Caenorhabditis elegans sex determination fem1 protein), identified by a yeast two-hybrid screen, is involved in the activation of CHK1 by replication stress. Depletion of FEM1B by small interfering RNA in cancer cells impairs the activation of CHK1 kinase activity and attenuates the induction of CHK1 Ser345 phosphorylation upon replication interference. It is to be noted that, CHK2 Thr68 phosphorylation is not altered by FEM1B downregulation. By fractionation, we further demonstrated that FEM1B is able to associate with chromatin, and such association facilitates chromatin loading of the Rad9 protein. Consistently, ATR activity is poorly maintained in FEM1B knockdown cells; and FEM1B-ablated cells are as sensitive to replication block as CHK1-depleted cells. Our study has uncovered an adaptor protein FEM1B, which acts as a bridge linking CHK1 and Rad9, thus facilitating checkpoint signaling induced by replication stress.

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Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B‐Cell translocation gene 3 in prostate cancer

Majid

Dar

Shahryari

et al. 2009

Cancer

133

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Background BTG3/ANA/APRO4 is a candidate tumor suppressor gene in some malignancies. We report here that BTG3 is transcriptionally down-regulated in prostate cancer and the mechanism of inactivation is through promoter hypermethylation. Methods Prostate cancer and normal cell lines were treated with different doses of genistein and 5-aza-2’-deoxycytidine (5Aza-C). BTG3 mRNA expression was determined by quantitative real-time PCR in tissues and cell lines. BS-PCR, cloning and sequencing were used to examine promoter methylation in tumor samples and cell lines. Enzyme activity/inhibition assays were done to check the effect of genistein and 5Aza-C on DNA methyltransferases. ChIP assay was performed to analyze chromatin modifications caused by genistein treatment. Results BTG3 mRNA expression was down-regulated in cancer tissues and cells. Genistein and 5Aza-C induced BTG3 mRNA expression in all PC cell lines. Complete methylation of BTG3 promoter in tumor samples and cancer cell lines was observed. Genistein and 5Aza-C treatment significantly decreased promoter methylation, reactivating BTG3 expression. Genistein and 5Aza-C increased levels of acetylated histones 3, 4, 2H3K4, 3H3K4 and Pol II, decreased DNMTase, MBD2 activity and increased HAT activity. Conclusion This is the first report to show that BTG3 is silenced in prostate cancer and can be reactivated by genistein induced promoter demethylation and active histone modification. Genistein showed similar effects to that of 5Aza-C, which is currently undergoing phase II clinical trials as a treatment for prostate cancer. Since genistein is a natural, non-toxic, dietary isoflavone, these results indicate that genistein is a novel, advantageous therapeutic agent for treating prostate cancer.

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The candidate tumor suppressor BTG3 is a transcriptional target of p53 that inhibits E2F1

Cited by 97 publications

References 39 publications

p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control

p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control

Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B‐Cell translocation gene 3 in prostate cancer

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