HIF activation identifies early lesions in VHL kidneys

Mandriota, Stefano J.; Turner, Kevin; Davies, David R.; Murray, Paul G.; Morgan, Neil V.; Sowter, Heidi M.; Wykoff, Charles C.; Maher, Eamonn R.; Harris, Adrian L.; Ratcliffe, Peter J.; Maxwell, Patrick H.

doi:10.1016/s1535-6108(02)00071-5

Cited by 432 publications

(164 citation statements)

References 47 publications

Supporting

Mentioning

148

Contrasting

Order By: Relevance

“…Somatic inactivation of the von Hippel-Lindau (VHL) gene is common in sporadic ccRCC and is considered an important initiating event (Martinez et al, 2000;Mandriota et al, 2002). The VHL protein functions as the recognition element of a multiprotein E3 ubiquitin ligase complex, involved in rapid degradation of hypoxia-inducible factors (HIFs) under physiological oxygen conditions (normoxia) (Maxwell et al, 1999).…”

Section: G250mentioning

confidence: 99%

Strict regulation of CAIXG250/MN by HIF-1α in clear cell renal cell carcinoma

Grabmaier¹,

Weijert²,

Verhaegh³

et al. 2004

Oncogene

164

118

View full text Add to dashboard Cite

Renal cell carcinoma of the clear cell type (ccRCC) is associated with loss of functional von Hippel-Lindau (VHL) protein and high, homogeneous expression of the G250 MN protein, an isoenzyme of the carbonic anhydrase family. High expression of G250MN is found in all ccRCCs, but not in most normal tissues, including normal human kidney. We specifically studied the mechanism of transcriptional regulation of the CAIX G250 gene in RCC. Previous studies identified Sp1 and hypoxia-inducible factor (HIF) as main regulatory transcription factors of G250 MN in various non-RCC backgrounds. However, G250MN regulation in RCC has not been studied and may be differently regulated in view of the HIF accumulation under normoxic conditions due to VHL mutations. Transient transfection of different G250 MN promoter constructs revealed strong promoter activity in G250 MN -positive RCC cell lines, but no activity in G250 MN -negative cell lines. DNase-I footprint and bandshift analysis demonstrated that Sp1 and HIF-1a proteins in nuclear extracts of RCC cells bind to the CAIX promoter and mutations in the most proximal Sp1 binding element or HIF binding element completely abolished CAIX promoter activity, indicating their critical importance for the activation of G250 expression in RCC. A close correlation between HIF-1a expression and G250 MN expression was observed. In contrast, no relationship between HIF-2a expression and G250 MN was seen. The participation of cofactor CBP/p300 in the regulation of G250 transcription was shown. In conclusion, HIF-1a and Sp1, in combination with CBP/p300, are crucial elements for G250 MN expression in ccRCC, and CAIX G250 can be regarded as a unique HIF-1a target gene in ccRCC.

show abstract

Section: G250mentioning

confidence: 99%

Strict regulation of CAIXG250/MN by HIF-1α in clear cell renal cell carcinoma

Grabmaier¹,

Weijert²,

Verhaegh³

et al. 2004

Oncogene

164

118

View full text Add to dashboard Cite

show abstract

“…In contrast, overexpression of HIF-1a was found to retard the growth of similar RCC-derived experimental tumours. Interestingly, clinical RCC shows an unusual bias to greater HIF-2a rather than HIF-1a expression (Krieg et al, 2000;Turner et al, 2002), and in kidneys from patients with VHL disease, greater HIF-2a expression is associated with more advanced lesions (Mandriota et al, 2002). Taken together, these findings strongly suggest that HIF-2a has pro-tumorigenic actions in RCC that are isoform specific, and not shared by HIF-1a.…”

mentioning

confidence: 97%

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Lau¹,

Tian²,

Raval³

et al. 2007

Br J Cancer

View full text Add to dashboard Cite

Inactivation of the von Hippel -Lindau tumour suppressor in renal cell carcinoma (RCC) leads to failure of proteolytic regulation of the a subunits of hypoxia-inducible factor (HIF), constitutive upregulation of the HIF complex, and overexpression of HIF target genes. However, recent studies have indicated that in this setting, upregulation of the closely related HIF-a isoforms, HIF-1a and HIF-2a, have contrasting effects on tumour growth, and activate distinct sets of target genes. To pursue these findings, we sought to elucidate the mechanisms underlying target gene selectivity for HIF-1a and HIF-2a. Using chromatin immunoprecipitation to probe binding to hypoxia response elements in vivo, and expression of chimaeric molecules bearing reciprocal domain exchanges between HIF-1a and HIF-2a molecules, we show that selective activation of HIF-a target gene expression is not dependent on selective DNAbinding at the target locus, but depends on non-equivalent C-terminal portions of these molecules. Our data indicate that post-DNA binding mechanisms that are dissimilar for HIF-1a and HIF-2a determine target gene selectivity in RCC cells.

show abstract

“…VHL mutation is an important event in the development of RCC, and activation of components of the HIF pathway can be detected early in pre-malignant cysts that precede the development of cancer in patients harboring a germline mutation in VHL (29). However, within the spectrum of the VHL mutation, tumors can demonstrate either stabilization of one or both of these HIF factors, and may promote the transcriptional activation of certain subsets of the repertoire of hypoxia responseinduced genes (27).…”

mentioning

confidence: 99%

Identification of Ror2 as a Hypoxia-inducible Factor Target in von Hippel-Lindau-associated Renal Cell Carcinoma

Wright

Rathmell

2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Ror2 is an orphan receptor tyrosine kinase with expression normally restricted to early stages of development. However, emerging evidence has placed aberrantly expressed Ror2, leading to an invasive phenotype, in several cancers including renal cell carcinoma (RCC). Although Ror2 is currently identified as up-regulated in an assortment of cancers, neither the regulatory role or mechanism of action have been delineated. We sought to place Ror2 in the most commonly mutated pathway of RCC, the loss of the tumor suppressor von Hippel-Lindau (VHL), which causes hypoxia-inducible factor (HIF)-1␣ and -2␣ stabilization and the transcriptional activation of a broad repertoire of response genes. We found that Ror2 was indeed associated with the pVHL loss in RCC as well as with VHL somatic mutations tightly coordinated with the induction of RCC. Additionally, knockdown and rescue analysis of HIF expression suggests that Ror2 is dependent on pathologic stabilization of either HIF-1␣ or HIF-2␣. Subsequent evaluation of the ROR2 promoter suggests that HIF-2␣ and its dimerization partner, aryl hydrocarbon nuclear transferase localize to the ROR2 promoter via a cryptic transcriptional element. This data substantiates a unique regulation pattern for Ror2 in the VHL-HIF axis that has the potential to be applied to other cancer etiologies.The tyrosine kinase Ror2 was initially identified as a homologue of the Trk neurotrophin receptors (1) and later as a member of the receptor tyrosine kinase superfamily (2). Ror2 is an orphan receptor with expression in the developing embryo identified in the embryonic limb buds, heart, primitive genitalia, developing somites, and mesenchymal cells in the developing lung, kidney, and cephalic regions (3-5). In the adult organism, Ror2 expression is present as a part of osteoblast differentiation, highly induced in the preosteoblast stage (6), and is suppressed as these cells terminally differentiate as osteocytes. This pattern of expression is inversely related to that of secreted frizzled related protein 1 (sFRP1), and can be transcriptionally suppressed by ectopic expression of sFRP1 in this cell type, but further insights into the major elements of Ror2 regulation are not known.Aside from developmental programs regulating bone morphogenesis and primitive organ development, Ror2 has only recently been recognized to play a role in the adult organism. We have identified Ror2 expression as a characteristic of many renal cell carcinoma (RCC) 2 cell lines and human tumors (7), where its expression is associated with increased cell migration and anchorage-independent growth. Ror2 also plays a prominent role in osteosarcoma (8) and has recently been identified in squamous cell carcinoma of the head and neck, where expression parallels the development of invasive features of these tumors (9). Furthermore, in a tumor genomic analysis of invasive gastric cancers, Ror2 was identified as a frequent target of mutagenesis (10). These findings place Ror2 as a frequently up-regulated feature of human cancers, ...

show abstract

HIF activation identifies early lesions in VHL kidneys

Cited by 432 publications

References 47 publications

Strict regulation of CAIXG250/MN by HIF-1α in clear cell renal cell carcinoma

Strict regulation of CAIXG250/MN by HIF-1α in clear cell renal cell carcinoma

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Identification of Ror2 as a Hypoxia-inducible Factor Target in von Hippel-Lindau-associated Renal Cell Carcinoma

Contact Info

Product

Resources

About