p53 downregulates expression of the G1/S cell cycle phosphatase Cdc25A

Rother, Karen; Kirschner, R.; Sänger, Katja; Böhlig, Levin; Mössner, Joachim; Engeland, Kurt

doi:10.1038/sj.onc.1209989

Cited by 55 publications

(57 citation statements)

References 41 publications

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“…22,23 Taken together, these findings support the hypothesis that hypoxic inhibits CdC25A gene expression by selectively displacing Myc binding in the promoter region. In addition, no p53 binding was detected in the promoter 27 and the intron, even though Sp1 interacted only with the promoter. Sp1 has been shown to be a mediator of the HIF-1a-Myc pathway, 22 and accordingly knockdown of Sp1 expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although it appears to be dispensable in the hypoxic upregulation of Cdkn1A, 11,22 p53 has been shown recently to downregulate CdC25A expression. 27 To test the possible involvement of p53 in CdC25A repression by Three independent sets of total RNA were analyzed by oligonucleotide microarrays. The Fold Change describes the fold difference of the genomic means between hypoxic samples and normoxic samples.…”

Section: Resultsmentioning

confidence: 99%

“…26 The CdC25A reporter plasmids 0.7wtNP-GL3 and 0.7mutNP-GL3 14 were kindly provided by K. Galaktionov, and CdC25A-luc was a kind gift of K. Engeland. 27 The Myc effect on the reporter was examined by cotransfection with 0.4 µg pMyc 11 or as specified.…”

Section: Methodsmentioning

confidence: 99%

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Hypoxic Suppression of the Cell Cycle GeneCDC25Ain Tumor Cells

Hammer¹,

Yoo³

et al. 2007

Cell Cycle

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Hypoxia, a key microenvironmental factor for tumor development, not only stimulates angiogenesis and glycolysis for tumor expansion, but also induces cell cycle arrest and genetic instability for tumor progression. Several independent studies have shown hypoxic blockade of cell cycle progression at the G 1 /S transition, arising from the inactivation of S-phase-promoting cyclin E-CDK2 kinase complex. Despite these findings, the biochemical pathways leading to the cell cycle arrest remain poorly defined. We recently showed that hypoxic activates the expression of CDNK1A encoding the CDK2 inhibitor p21 Cip1 , through a novel HIF-1a-Myc pathway that involves Myc displacement from the CDNK1A promoter by the hypoxia-inducible transcription factor HIF-1a. In pursuit of further understanding of the hypoxic effects on cell cycle in tumor cells, here we report that hypoxia inhibits the expression of CDC25A, another cell cycle gene encoding a tyrosine phosphatase that maintains CDK2 activity. In accordance with the HIF-1a-Myc pathway, hypoxia requires HIF-1a for CDC25A repression, resulting in a selective displacement of an activating Myc from the CDC25A promoter without affecting a canonical Myc binding in the intron. Intriguingly, HIF-1a alone fails to recapitulate the hypoxic effect, indicating that HIF-1a is necessary but insufficient for the hypoxic repression. Taken together, our studies indicate that hypoxia inhibits cell cycle progression by controlling the expression of various cell cycle genes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Hypoxic Suppression of the Cell Cycle GeneCDC25Ain Tumor Cells

Hammer¹,

Yoo³

et al. 2007

Cell Cycle

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“…It responds to multiple cellular stresses, including DNA damage, hypoxia, heat shock, ionizing radiation as well as oncogenic stimulation by regulating genes linked to cell cycle, apoptosis, and other essential molecular pathways associated with the cell fate (11,12,15,16). Functions of normal p53 protein are frequently mislaid in various human cancers, including breast tumors primarily through the mutations or deletions of this gene (15,17,18).…”

Section: Introductionmentioning

confidence: 99%

Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2

et al. 2008

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CCN5/WISP-2 is overexpressed in noninvasive breast cancer cells and tissue samples, whereas its expression is minimal or undetected in invasive conditions. CCN5/WISP-2 has been considered as an antiinvasive gene because CCN5/WISP-2 silencing augments the invasive phenotypes in vitro. However, the mechanism of silencing of CCN5 during the progression of the disease has been elusive. Because p53 mutations are associated with breast cancer progression and have been shown to correlate inversely with CCN5/WISP-2 expression in other cancer cell types, the objective of this study was to explore whether p53 mutants suppress CCN5 expression in breast tumor cells resulting in the progression of this disease. We found CCN5 expression is inversely correlated with the mutational activation of p53 in human breast tumor cells. The ectopic expression of p53 mutants in ER-positive noninvasive breast tumor cells silenced the CCN5/WISP-2 expression and enhanced invasive phenotypes, including the induction of morphologic changes from the epithelial-to-mesenchymal type along with the alterations of hallmark proteins of these cell types and an augmentation of the migration of these cells. The suppression of CCN5 by the p53 mutants can be nullified by estrogen signaling in these cells through the transcriptional activation of the CCN5 gene. Moreover, the invasive changes can be imitated by blocking the CCN5/WISP-2 expression through RNA interference or can be reversed by the addition of CCN5/WISP-2 recombinant protein in the culture. Thus, these studies suggest that CCN5 inactivation could be an essential molecular event for p53 mutant-induced invasive phenotypes. [Cancer Res 2008;68(12):4580-7]

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“…16,17 More recently the STAT3 factor, p21 and p53 were also described as CDC25A transcriptional regulators. 18,19 Posttranslational modifications of CDC25A also modify its cellular level through phosphorylation events leading to its degradation by the proteasome (reviewed in ref. 20).…”

Section: Introductionmentioning

confidence: 99%