Involvement of the MAP Kinase Pathways in Induction of GADD45 Following UV Radiation

Tong, Tong; Fan, Wenhong; Zhao, Hongcheng; Jin, Shunqian; Fan, Feiyue; Blanck, Patricia; Alomo, Isaac; Baskaran, Rathinasamy; Liu, Yusen; Holbrook, Nikki J.; Zhan, Qimin

doi:10.1006/excr.2001.5312

Cited by 59 publications

(46 citation statements)

References 31 publications

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“…Based on these data, it is likely that JNK functions as an upstream regulator of, rather than simply a downstream target for, GADD45. In accordance with this conclusion, induction of GADD45 by ultraviolet light or arsenite has been shown to be partially JNK-dependent (Chen et al, 2001;Tong et al, 2001). Recently, it has been found that in HepG2 hepatoma cells TRO activated JNK, which correlated with an induction of apoptosis.…”

Section: Discussionsupporting

confidence: 53%

“…ERK MAPK also functioned as a negative regulator among the various osmosignaling pathways regulating GADD45 expression. In marked contrast, induction of GADD45 by ultraviolet light has been shown to be ERK MAPK-dependent (Tong et al, 2001), while signaling through p38 MAPK delivered neither a positive nor negative input to the GADD45 gene. From these studies, it is apparent that each MAPK signaling branch can exert a positive, negative, or neutral effect to regulate GADD45 depending on the precise stress stimulus experienced by a specific cell type.…”

Section: Discussionmentioning

confidence: 90%

“…In addition, recent data indicated that MAPK family members play a role in the regulation of GADD45 gene (Tong et al, 2001;Sarkar et al, 2002). To determine whether MAP kinase activities are affected by TRO treatment, cells were grown in the presence or absence of TRO.…”

Section: Tro-regulated Apoptosis and Cell Cycle Genes In Mcf-7 Cellsmentioning

confidence: 99%

“…In general, activation of the MEK/ERK pathway is associated with cell survival and proliferation. In contrast, JNK and p38 MAPKs are primarily activated by stress stimuli (such as UV radiation and DNA-damaging agents) (Rouse et al, 1994;Raingeaud et al, 1995;Finkel and Holbrook, 2000;Tong et al, 2001) that can lead to cell growth inhibition and/or apoptosis. Since TRO induces both growth arrest and apoptosis in MCF-7 breast carcinoma cells, we examined whether upregulation of GADD45 occurred concomitant with these effects.…”

Section: Introductionmentioning

confidence: 99%

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Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells

et al. 2004

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We previously reported that the PPARc agonist troglitazone (TRO) inhibits proliferation and induces apoptosis in human MCF-7 breast carcinoma cells. To understand the mechanisms of antiproliferative and pro-apoptotic effects of TRO, we screened a limited DNA array containing 23 genes involved in regulating either the cell cycle and/or apoptosis. Four of the 23 genes screened exhibited regulation by TRO, with growth arrest and DNA damage-inducible gene 45 (GADD45) being the most strongly upregulated. TRO induced GADD45 mRNA expression in a time-and dose-dependent manner. Depletion of GADD45 by siRNA abrogated TROinduced apoptosis in MCF-7 cells demonstrating the physiological relevance of GADD45 upregulation. Signaling pathways mediating TRO-induced GADD45 were also investigated. Several mitogen-activated protein kinase (MAPK) pathways were involved in the induction of GADD45 by TRO. Inhibition of the c-jun N-terminal kinase MAPK pathway by SP600125 partially abolished TRO-induced GADD45 mRNA, and protein expression and apoptosis. In contrast, inhibition of the p38 MAPK pathway by SB203580, or through overexpression of a dominant-negative mutant of p38 MAPK, augmented GADD45 mRNA induction and GADD45 promoter activation as well as cell apoptosis by TRO. Blockade of the extracellular signal-regulated kinase MAPK pathway by PD98059 also enhanced TRO's effects on GADD45 and apoptosis. Two other PPARc agonists pioglitazone and rosiglitazone did not induce GADD45 expression. Our finding of GADD45 induction by TRO may provide a new insight concerning the mechanisms for TRO's antiproliferative and pro-apoptotic effects in breast cancer cells.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 90%

Section: Tro-regulated Apoptosis and Cell Cycle Genes In Mcf-7 Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells

et al. 2004

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“…Activation of transcription factors by DNA damage directly enhances/represses the transcription of their targeted genes, which can exert biological functions in cellular responses. Several transcription factors, such as p53, c-Myc, AP-1 (c-jun and c-fos) and Oct-1, have been characterized to play important roles in the control of cell cycle checkpoints, apoptosis and signaling transduction pathways (Amundson et al, 1998;Haas and Kaina, 1995;Hollander and Fornace, 1989;Jin et al, 2001;Kastan et al, 1992;Kumari and Alvarez-Gonzalez, 2000;Rupnow et al, 1998;Tong et al, 2001;Yu et al, 2002;Zhan et al, 1994a;Zhao et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth

et al. 2002

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Mammalian cells have a remarkable diverse repertoire of response to genotoxic stress that damage DNA. Cellular responses to DNA damaging agents will initially exhibit gene induction, which is regulated by complex mechanism(s) and probably involves multiple signaling pathways. In this paper, we demonstrate that induction of ATF3 protein, a member of the ATF/CREB family of transcription factors, by ionizing radiation (IR) requires normal cellular p53 function. In contrast, induction of ATF3 after UV radiation (UV) or Methyl methanesulphonate (MMS) is independent of p53 status. Induction of ATF3 by DNA damage is rapid, transient, and through a transcriptional mechanism. The ATF3 promoter is induced by UV and MMS, but not by IR. In addition, ATF3 promoter can be activated by MEKK1, an upstream activator of the ERK and JNK kinase pathway, but not induced following p53 expression. Those results indicate that regulation of ATF3 induction after DNA damage utilizes both the p53-dependent andindependent pathways, and may also involve MAP kinase signaling pathways. Using the tetracyclineinducible system (tet-off), we have found that overexpression of ATF3 protein moderately suppresses cell growth. Interestingly, over-expression of ATF3 protein is able to slow down progression of cells from G1 to S phase, indicating that ATF3 protein might play a negative role in the control of cell cycle progression.

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Epstein‐Barr virus‐encoded EBNA‐5 forms trimolecular protein complexes with MDM2 and p53 and inhibits the transactivating function of p53

Kashuba

Yurchenko

Yenamandra

et al. 2010

Intl Journal of Cancer

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We report that MDM2, a negative regulator of p53, can bind to EBNA-5. Using GST pull-down assay, immunoprecipitation, surface plasmon resonance and immunostaining of lymphoblastoid cells, we found that trimolecular complexes are formed between EBNA-5, MDM2 and p53, where MDM2 serves as a bridge. The EBNA-5 binding to MDM2 counteracted destabilizing effect of the latter on the p53. In ubiquitination and degradation assays in vitro, EBNA-5 inhibited p53 polyubiquitination (but not monoubiquitination) in a concentration-dependent manner. This resembles the effect of p14ARF on p53. Moreover, EBNA-5 was found to inhibit the degradation of p53 in vitro. High levels of p53 expression were maintained in LCLs. The binding of EBNA-5 to MDM2 also could impair the functional activity of p53. The p53-dependent genes P21 and VDR were not induced in EBV-infected, in contrast to mitogen-activated cells. This may explain the tolerance of established LCLs to high levels of p53 without undergoing apoptosis.

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Involvement of the MAP Kinase Pathways in Induction of GADD45 Following UV Radiation

Cited by 59 publications

References 31 publications

Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells

Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells

ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth

Epstein‐Barr virus‐encoded EBNA‐5 forms trimolecular protein complexes with MDM2 and p53 and inhibits the transactivating function of p53

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