Stabilization of wild-type p53 by hypoxia-inducible factor 1α

An, Won Gun; Kanekal, M; Simon, M. Celeste; Maltepe, Emin; Blagosklonny, Mikhail V.; Neckers, Leonard Μ.

doi:10.1038/32925

Cited by 787 publications

(526 citation statements)

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“…CK2 is also known to phosphorylate p53, enhancing its stability and its activity. 60 In severe hypoxia or in anoxia, HIF-1a has been described to increase p53 stability 61 through an inhibition of its degradation by Mdm2. 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.…”

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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“…Similarly, Evans et al 107 demonstrated that knockdown of pVHL resulted in E-cadherin suppression via HIF-dependent induction of E2 box-dependent transcriptional repressors Snail and SIP1, and Krishnamachary et al 108 reported that HIF-1 activation in VHL-deficient cells downregulated Ecadherin, led to the loss of cell-cell adhesion and promoted epithelial to mesenchymal transition through the induction of transcriptional repressors TCF3, ZFHX1A and ZFHX1B/SIP1. Therefore, cellular changes, such as loss of intercellular junctions and epithelial de-differentiation involving HIFdependent as well as HIF-independent molecular pathways 48,[106][107][108] in addition to HIF-dependent and -independent alterations in p53 or NF-kB activity, 34,35,49,51 HGF signaling, 45,50,109 and modifications in ECM turnover and re-modeling [42][43][44][45][46][47] create the molecular environment for the development CC-RCC, which most likely requires additional genetic events. The importance of HIF activation in CC-RCC pathogenesis and growth is furthermore underscored by experimental and clinical studies, which demonstrated that inhibition of HIF-a translation by pharmacological targeting of mTOR correlated with reduced tumor growth, 110 and that increased expression of certain HIF target genes, such as CXCR4, as well as E-cadherin suppression was associated with disease progression.…”

Section: Pvhl and Renal Cell Cancermentioning

confidence: 99%

“…These include, among others, tumor suppressor protein p53 and the c-Myc proto-oncogene. [34][35][36] A more recent example is the ability of HIF-1a to associate with the intracellular domain of Notch (Notch ICD), thereby increasing the expression of Notch-target genes, such as Hey and Hes. 37 This and other HIF-a/non-PAS domain protein interactions have to be considered when interpreting experimental phenotypes that result from VHL gene deletion in the laboratory mouse.…”

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confidence: 99%

The VHL tumor suppressor and HIF: insights from genetic studies in mice

2008

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The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive a-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al. 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

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“…Expression of VEGF is required to stimulate angiogenesis and solid tumor vascularization, a critical step in tumor progression and also in hematologic malignancies (Semenza, 2000;Maxwell et al, 2001). Intrinsically, hypoxic conditions in solid tumors are supposed to allow selection for P53 mutations (Graeber et al, 1996;An et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

et al. 2006

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The transcription factor hypoxia inducible factor 1 (HIF1), an HIF1a-aryl hydrocarbon receptor nuclear translocator (ARNT) dimeric factor, is essential to the cellular response to hypoxia. We described a t(1;12)(q21;p13) chromosomal translocation in human acute myeloblastic leukemia that involves the translocated Ets leukemia (TEL/ETV6) and the ARNT genes and results in the expression of a TEL-ARNT fusion protein.Functional studies show that TEL-ARNT interacts with HIF1a and the complex binds to consensus hypoxia response element. In low oxygen tension conditions, the HIF1a/TEL-ARNT complex does not activate transcription but exerts a dominant-negative effect on normal HIF1 activity. Differentiation of normal human CD34 þ progenitors cells along all the erythrocytic, megakaryocytic and granulocytic pathways was accelerated in low versus high oxygen tension conditions. Murine 32Dcl3 myeloid cells also show accelerated granulocytic differentiation in low oxygen tension in response to granulocyte colony-stimulating factor. Interestingly, stable expression of the TEL-ARNT in 32Dcl3 subclones resulted in impaired HIF1-mediated transcriptional response and inhibition of differentiation enhancement in hypoxic conditions. Taken together, our results underscore the role of oxygen tension in the modulation of normal hematopoietic differentiation, whose targeting can participate in human malignancies.

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Stabilization of wild-type p53 by hypoxia-inducible factor 1α

Cited by 787 publications

References 20 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

The VHL tumor suppressor and HIF: insights from genetic studies in mice

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

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