Regulation of p53 expression by the RAS-MAP kinase pathway

Agarwal, Munna L.; Ramana, Chilakamarti V.; Hamilton, Mark; Taylor, William R.; DePrimo, Samuel E.; Bean, Lora Jh; Agarwal, Archana; Agarwal, Megha; Wolfman, Alan; Stark, George R.

doi:10.1038/sj.onc.1204353

Cited by 48 publications

(30 citation statements)

References 41 publications

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“…HT1080 cells express wild type p53 (24,25), which binds to its recognition motif in the MMP-2 promoter (14), and our EMSA data (Fig. 5A) were consistent with these previous reports.…”

Section: Fig 2 Atf3 Represses Mmp-2 Expressionsupporting

confidence: 82%

ATF3 Represses 72-kDa Type IV Collagenase (MMP-2) Expression by Antagonizing p53-dependent trans-Activation of the Collagenase Promoter

Yan

Wang

Boyd

2002

Journal of Biological Chemistry

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The murine homologue of the ATF3 transcription factor increases tumor metastases but, surprisingly, represses 72-kDa type IV metalloproteinase (MMP-2) expression. The current study describes a novel mechanism by which ATF3 regulates transcription. Progressive deletions of the MMP-2 promoter indicated a 38-base pair region (؊1659/؊1622) necessary for the ATF3-mediated repression. This region lacked CREB/ AP-1 motifs but contained a consensus p53 motif shown previously to regulate MMP-2 expression. The activity of a p53 response element-driven luciferase reporter was reduced in ATF3-expressing HT1080 clones. Although MMP-2 promoter activity was not repressed by ATF3 in p53-deficient Saos-2 cells, p53 re-expression increased MMP-2 promoter activity and restored the sensitivity to ATF3. The activity of a GAL4-driven reporter in HT1080 cells co-expressing the full-length p53 sequence fused to the GAL4 DNA binding domain was diminished by ATF3. p53-ATF3 protein-protein interactions were demonstrated both in vivo and in vitro. Cell cycle analysis, performed as an independent assay of p53 function, revealed that ␥-irradiation-induced slowed G 2 /M cell cycle progression (attributable to p53) was countered by ATF3. Thus, ATF3 represses MMP-2 expression by decreasing the trans-activation of this gene by p53.ATF3 (the human homologue of Ti241) is a member of the ATF/CREB subfamily of bZIP transcription factors (1) and encoded by a four-exon gene spanning 15 kb. Transcription of this gene yields a 2-kb mRNA (1), or an alternatively spliced isoform ATF3⌬Zip (2), the former transcript encoding the fulllength protein product (ϳ 22 kDa) (2). ATF3 homo-and heterodimers bind specifically to the ATF/CREB and AP-1 motifs (3, 4) and regulate the expression of several genes (2, 4 -6) as well as gluconeogenic enzymes in transgenic mice as shown recently (7).In a previous study comparing gene expression in metastatic and non-metastatic tumors, Ishiguro and co-workers (8) identified the murine homologue of ATF3 (Ti241) as overexpressed in metastatic melanoma and extended these studies to show a causal role for this gene in tumor dissemination. However, these authors did not determine the mechanism by which Ti241 induced this behavior. Considering the established role of type IV metalloproteinases in tumor metastases (9 -13), we were interested in identifying which, if any, type IV collagenase(s) are regulated by ATF3 (the human homologue of Ti241). We report herein the unexpected finding that the 72-kDa type IV collagenase gene (MMP-2) 1 is transcriptionally down-regulated by this transcription factor. More importantly, this transcriptional repression is achieved by ATF3 interfering with p53-dependent trans-activation of MMP-2 gene expression via a mechanism in which p53 transcriptional activity, but not DNA binding, is attenuated. Thus, our findings reveal a novel transcriptional mechanism in which ATF3 interferes with p53-dependent gene expression.

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“…HT1080 cells express wild type p53 (24,25), which binds to its recognition motif in the MMP-2 promoter (14), and our EMSA data (Fig. 5A) were consistent with these previous reports.…”

Section: Fig 2 Atf3 Represses Mmp-2 Expressionsupporting

confidence: 82%

ATF3 Represses 72-kDa Type IV Collagenase (MMP-2) Expression by Antagonizing p53-dependent trans-Activation of the Collagenase Promoter

Yan

Wang

Boyd

2002

Journal of Biological Chemistry

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“…ERK is required to activate p53 gene expression and maintain p53 pathway activation status (44). Further, DAPK-1 activates p53 in an oncogene signaling pathway by an undefined mechanism (7).…”

Section: Discussionmentioning

confidence: 99%

A Germ Line Mutation in the Death Domain of DAPK-1 Inactivates ERK-induced Apoptosis

Stevens

Lin

Sanchez

et al. 2007

Journal of Biological Chemistry

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p53 is activated genetically by a set of kinases that are components of the calcium calmodulin kinase superfamily, including CHK2, AMP kinase, and DAPK-1. In dissecting the mechanism of DAPK-1 control, a novel mutation (N1347S) was identified in the death domain of DAPK-1. The N1347S mutation prevented the death domain module binding stably to ERK in vitro and in vivo. Gel filtration demonstrated that the N1347S mutation disrupted the higher order oligomeric nature of the purified recombinant death domain miniprotein. Accordingly, the N1347S death domain module is defective in vivo in the formation of high molecular weight oligomeric intermediates after cross-linking with ethylene glycol bis(succinimidylsuccinate). Full-length DAPK-1 protein harboring a N1347S mutation in the death domain was also defective in binding to ERK in cells and was defective in formation of an ethylene glycol bis(succinimidylsuccinate)-cross-linked intermediate in vivo.Full-length DAPK-1 encoding the N1347S mutation was attenuated in tumor necrosis factor receptor-induced apoptosis. However, the N1347S mutation strikingly prevented ERK:DAPK-1-dependent apoptosis as defined by poly(ADP-ribose) polymerase cleavage, Annexin V staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling imaging. Significant penetrance of the N1347S allele was identified in normal genomic DNA indicating the mutation is germ line, not tumor derived. The frequency observed in genomic DNA was from 37 to 45% for homozygous wild-type, 41 to 47% for heterozygotes, and 12 to 15% for homozygous mutant. These data highlight a naturally occurring DAPK-1 mutation that alters the oligomeric structure of the death domain, de-stabilizes DAPK-1 binding to ERK, and prevents ERK:DAPK-1-dependent apoptosis.

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“…In drug resistance, cross-talk between alterations in signal transduction pathways and the p53 gene has been suggested (Agarwal et al, 2001). To identify whether either of these pathways might be relevant in the treatment of breast cancer, this study was performed to establish the effect of doxorubicin and vinorelbine on signal transduction and p53 expression.…”

mentioning

confidence: 99%

Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines

et al. 2003

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In the treatment of breast cancer, combination chemotherapy is used to overcome drug resistance. Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission. Alterations in protein kinase-mediated signal transduction and p53 mutations may play a role in drug resistance with cross-talk between signal transduction and p53 pathways. The aim of this study was to establish the effects of doxorubicin and vinorelbine, as single agents, in combination, and as sequential treatments, on signal transduction and p53 in the breast cancer cell lines MCF-7 and MDA-MB-468. In both cell lines, increased p38 activity was demonstrated following vinorelbine but not doxorubicin treatment, whether vinorelbine was given prior to or simultaneously with doxorubicin. Mitogen-activated protein kinase (MAPK) activity and p53 expression remained unchanged following vinorelbine treatment. Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity. These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms. This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer.

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Regulation of p53 expression by the RAS-MAP kinase pathway

Cited by 48 publications

References 41 publications

ATF3 Represses 72-kDa Type IV Collagenase (MMP-2) Expression by Antagonizing p53-dependent trans-Activation of the Collagenase Promoter

ATF3 Represses 72-kDa Type IV Collagenase (MMP-2) Expression by Antagonizing p53-dependent trans-Activation of the Collagenase Promoter

A Germ Line Mutation in the Death Domain of DAPK-1 Inactivates ERK-induced Apoptosis

Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines

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