The von Hippel-Lindau Gene, Kidney Cancer, and Oxygen Sensing

Kaelin, William G.

doi:10.1097/01.asn.0000092803.69761.41

Cited by 119 publications

(62 citation statements)

References 107 publications

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“…Von Hippel-Lindau protein (pVHL), which is a component of the E3 ubiquitin ligase complex, recognizes prolylhydroxylated HIF-1a and drives its polyubiquitination and proteasomal degradation. Under hypoxia, HIF-1a subunit is stabilized and dimerizes with HIF-1b, translocates to the nucleus, and activates transcription of target genes via binding to hypoxia-responsive elements (HREs) [22,28]. HIF-1 induces the expression of more than 100 genes [29], including the vascular endothelial growth factor (VEGF), glycolytic enzymes [30], and various genes involved in proliferation and cell cycle progression, to insure the cancer cell survival [20,31,32].…”

Section: Introductionmentioning

confidence: 99%

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Fanale

Bazan

Corsini

et al. 2013

Breast Cancer Res Treat

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Numerous microarray-based gene expression studies performed on several types of solid tumors revealed significant changes in key genes involved in progression and regulation of the cell cycle, including AURKA that is known to be overexpressed in many types of human malignancies. Tumor hypoxia is associated with poor prognosis in several cancer types, including breast cancer (BC). Since hypoxia is a condition that influences the expression of many genes involved in tumorigenesis, proliferation, and cell cycle regulation, we performed a microarray-based gene expression analysis in order to identify differentially expressed genes in BC cell lines exposed to hypoxia. This analysis showed that hypoxia induces a down-regulation of AURKA expression. Although hypoxia is a tumor feature, the molecular mechanisms that regulate AURKA expression in response to hypoxia in BC are still unknown. For the first time, we demonstrated that HIF-1 activation downstream of hypoxia could drive AURKA down-regulation in BC cells. In fact, we found that siRNA-mediated knockdown of HIF-1a significantly reduces the AURKA down-regulation in BC cells under hypoxia. The aim of our study was to obtain new insights into AURKA transcriptional regulation in hypoxic conditions. Luciferase reporter assays showed a reduction of AURKA promoter activity in hypoxia. Unlike the previous findings, we hypothesize a new possible mechanism where HIF-1, rather than inducing transcriptional activation, could promote the AURKA down-regulation via its binding to hypoxia-responsive elements into the proximal region of the AURKA promoter. The present study shows that hypoxia directly links HIF-1 with AURKA expression, suggesting a possible pathophysiological role of this new pathway in BC and confirming HIF-1 as an important player linking an environmental signal to the AURKA promoter. Since AURKA down-regulation overrides the estrogen-mediated growth and chemoresistance in BC cells, these findings could be important for the development of new possible therapies against BC.

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Section: Introductionmentioning

confidence: 99%

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Fanale

Bazan

Corsini

et al. 2013

Breast Cancer Res Treat

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“…Through transcriptional regulation, hypoxia-inducible factor promotes glucose uptake and expression of angiogenic, growth and mitogenic factors, including vascular endothelial growth factor, platelet derived growth factor, erythropoietin and transforming growth factor a, known to be involved in tumorigenesis. [7][8][9][10] Clinical criteria for the diagnosis of VHL disease include one of the following items: (1) more than one hemangioblastoma in CNS or retina; (2) a single hemangioblastoma in CNS or retina plus a visceral complication (such as multiple renal, pancreatic or hepatic cysts, pheochromocytoma or renal cancer) with the exception of epididymal and renal cysts; (3) any one of above manifestations with a family history. 11 There is also a classification of VHL disease based on its clinical manifestations.…”

Section: Introductionmentioning

confidence: 99%

Family history of von Hippel–Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients

Zhang²,

Wang

et al. 2012

J Hum Genet

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“…The main causes of death are complications linked to highly angiogenic renal carcinomas and hemangioblastomas within the central nervous system (45,59). The VHL gene is ubiquitously expressed (60) and the role of the VHL gene product (pVHL) in renal cell carcinoma (RCC) has been extensively studied (31,49). There are currently no established, successful therapies, e.g., radiation or chemotherapy, for RCC other than nephrectomy in situations with no evidence of metastases.…”

mentioning

confidence: 99%

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

Miao²,

Khan³

2007

American Journal of Physiology-Renal Physiology

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Wu KL, Miao H, Khan S. JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism. Am J Physiol Renal Physiol 293: F1836-F1846, 2007. First published September 26, 2007; doi:10.1152/ajprenal.00096.2007 disease is a cancer syndrome, which includes renal cell carcinoma (RCC), and is caused by VHL mutations. Most, but not all VHL phenotypes are due to failure of mutant VHL to regulate constitutive proteolysis of hypoxia-inducible factors (HIFs). Janus kinases (JAK1, 2, 3, and TYK2) promote cell survival and proliferation, processes tightly controlled by SOCS proteins, which have sequence and structural homology to VHL. We hypothesized that in VHL disease, RCC pathogenesis results from enhanced SOCS1 degradation, leading to upregulated JAK activity. We find that baseline JAK2, JAK3, and TYK2 activities are increased in RCC cell lines, even after serum deprivation or coincubation with cytokine inhibitors. Furthermore, JAK activity is sustained in RCC stably expressing HIF2␣ shRNA. Invasion through Matrigel and migration in woundhealing assays, in vitro correlates of metastasis, are significantly greater in VHL mutant RCC compared with wild-type cells, and blocked by dominant-negative JAK expression or JAK inhibitors. Finally, we observe enhanced SOCS2/SOCS1 coprecipitation and reduced SOCS1 expression due to proteasomal degradation in VHLnull RCC compared with wild-type cells. The data support a new HIF-independent mechanism of RCC metastasis, whereby SOCS2 recruits SOCS1 for ubiquitination and proteasome degradation, which lead to unrestricted JAK-dependent RCC invasion. In addition to commonly proposed RCC treatment strategies that target HIFs, our data suggest that JAK inhibition represents an alternative therapeutic approach. Janus kinase; suppressor of cytokine signaling; von Hippel-Lindau syndrome VON HIPPEL-LINDAU (VHL) disease is a heritable multisystem cancer syndrome caused by germline mutations in VHL, which is located on chromosome 3p25 (30). The main causes of death are complications linked to highly angiogenic renal carcinomas and hemangioblastomas within the central nervous system (45, 59). The VHL gene is ubiquitously expressed (60) and the role of the VHL gene product (pVHL) in renal cell carcinoma (RCC) has been extensively studied (31, 49). There are currently no established, successful therapies, e.g., radiation or chemotherapy, for RCC other than nephrectomy in situations with no evidence of metastases.pVHL contains an ϳ100-residue NH 2 terminus (␤-domain) and a smaller COOH-terminal ␣-helix (␣-domain). Under normoxic conditions, the pVHL ␤-domain interacts with ␣-subunits of hypoxia-inducible factors (HIF)-1 and -2 transcription factors (48, 60), while the VHL ␣-domain and a small portion of the ␤-domain interact with Elongin C, a component of an E3 ubiquitin ligase complex that targets HIF-1␣ subunits for proteasomal degradation (31, 43, 64) and thereby prevents HIF transcription factor binding to target gene...

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The von Hippel-Lindau Gene, Kidney Cancer, and Oxygen Sensing

Cited by 119 publications

References 107 publications

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Family history of von Hippel–Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

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