p53 Inhibits Hypoxia-inducible Factor-stimulated Transcription

Blagosklonny, Mikhail V.; An, Won Gun; Romanova, Larisa Y.; Trepel, Jane B.; Fojo, Tito; Neckers, Len

doi:10.1074/jbc.273.20.11995

Cited by 256 publications

(172 citation statements)

References 19 publications

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“…62 This interaction between HIF-1a and p53 leads to an inhibition of HIF-1 activity because HIF-1a is targeted for degradation by Mdm2. 63 By contrast, in less severe hypoxia, hypoxia silences the p53 transactivation pathway by promoting a significant decrease in S392 phosphorylation on p53, which is a CK2 phosphorylation site. 64 It would thus result in increased HIF-1 activity.…”

Section: Discussionmentioning

confidence: 99%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in vivo. The HIF-1a subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF-1a degradation, but also increase in the transactivation activity of HIF-1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/ threonine kinase, in the regulation of HIF-1 activity. Hypoxia was capable of increasing the expression of the b subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the a subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6-dichloro-1-b-D-ribofuranosyl-benzimidazole), TBB (4,5,6,7-tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2a, were shown to inhibit HIF-1 activity as measured by a reporter assay and through hypoxiainduced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF-1a protein level. DNA-binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF-1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF-1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive. ' 2005 Wiley-Liss, Inc.Key words: casein kinase 2; HIF-1; neoangiogenesis HIF-1 (hypoxia-inducible factor-1) is a key regulator of cell response to reduced oxygen level. In response to hypoxic conditions, HIF-1 increases the expression of downstream target genes such as erythropoietin (EPO), vascular endothelial growth factor (VEGF) and glycolytic enzymes (aldolase A, enolase-a) and mediates adaptation of cells to decreased oxygen level. 1 The role of HIF-1 in the regulation of tumor growth by hypoxia via the initiation of angiogenesis is certainly the best example of such an adaptive response. 2 Oncogene activation and tumor-suppressor inactivation result in deregulated cellular proliferation. However, most tumors grown larger than 1 mm 3 contain regions of low oxygen tension (hypoxia) due to an imbalance between oxygen supply and consumption. Formation of new blood vessels or ''neoangiogenesis'' is thus essential for further tumor growth. It is also important to allow tumor cell dissemination at distant sites, i.e., metastasis.Several studies using HIF-1 mutant cells have shown that HIF-1 has a profound effect on tumor biology. For example, tumors grown from HIF-1a-defective embryonic stem cells display abnormal vascularity and reduced growth rate. 3 Moreover, HIF-1 is upregulated in a broad r...

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Section: Discussionmentioning

confidence: 99%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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“…HCT116 cells were cotransfected with p53 WT-LUC (0.5 mg), p53 MT1-LUC (0.5 mg) or p53 MT2-LUC (0.5 mg) reporter plasmids together with RSV-bGAL (0.4 mg). Transfected cells were treated with 1 or 2 mM daunomycin for 6 h. LUC and bGAL activities were determined as described in Figure 2 (HIF1a) (Avantaggiati et al, 1997;Blagosklonny et al, 1998). The p53/Sp1 complex displays, in vitro, a high a nity for Sp1 or p53 consensus sites and positively regulates target gene expression (Borellini and Glazer, 1993;Gualberto and Baldwin, 1995), while the association between p53 and WT1 increases p53 stability, its transcriptional activity and gadd45 expression (Zhan et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

et al. 2000

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The tumor suppressor p53 plays a pivotal role in the cellular response to DNA damage as it controls DNA repair, cell cycle arrest and apoptosis. We studied the autoregulation of human p53 gene transcription in colon cancer cell lines. Wild-type p53 has been shown to autoregulate its own transcription either positively or negatively and probably in a cell-type-speci®c manner. Indeed, a p53 binding site has been described in the human and murine p53 promoters, but a direct binding of wild-type p53 protein to this site has never been reported.In this study, we demonstrated a transactivation of human p53 promoter by wild-type p53 in human colon cancer cells. We identi®ed in the human p53 promoter a novel potential p53-responsive element that binds wildtype p53. Moreover, wild-type p53 protein transactivated a reporter plasmid containing a luciferase gene driven by a minimal promoter harboring this p53 binding site. Finally, as the p53 promoter contains an NF-kB binding site, we demonstrated an additive e ect when NF-kB subunits and p53 protein combined to transactivate the human p53 promoter. Oncogene (2000) 19, 4787 ± 4794.

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“…Such a mechanism has been described for the inhibition of HIF-activated transcription by wild-type p53. p53 forms a trimeric complex with the transcriptional HIF/p300 complex and thereby inhibits transcriptional activity of HIF (Blagosklonny et al, 1998). In this respect, it is worth noting that an interaction with the CBP/p300 coactivators is crucial for the transcriptional activities of both ets-1 and p53 (Avantaggiati et al, 1997;Lill et al, 1997;Jayaraman et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

et al. 2003

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Cancer formation and progression is a complex process determined by several mechanisms that promote cell growth, invasiveness, neo-angiogenesis, and render neoplastic cells resistant to apoptosis. The tumor suppressor p53 and the proto-oncogenic factor ets-1 are important regulators of such mechanisms. While it is well established that p53 and ets-1 influence various aspects of cell behavior by regulating the transcription of specific genes, little is known about the functional relationship between these transcription factors. We found that the gene encoding thromboxane synthase (TXSA), which we recently identified as a factor promoting invasion and resistance to apoptosis in gliomas, is a novel target gene for both p53 and ets-1. We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and interrelated manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. Negative interference with ets-1 transcription requires functional p53 and is lost in mutant p53 proteins. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53. An important implication of our findings is that the loss of p53-mediated negative control over ets-1-dependent transcription may lead to the acquisition of an invasive phenotype in tumor cells.

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p53 Inhibits Hypoxia-inducible Factor-stimulated Transcription

Cited by 256 publications

References 19 publications

Role for casein kinase 2 in the regulation of HIF‐1 activity

Role for casein kinase 2 in the regulation of HIF‐1 activity

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

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