scholarly journals von Hippel-Lindau Tumor Suppressor Protein Regulates the Assembly of Intercellular Junctions in Renal Cancer Cells through Hypoxia-Inducible Factor–Independent Mechanisms

2006 ◽  
Vol 66 (3) ◽  
pp. 1553-1560 ◽  
Author(s):  
Maria J. Calzada ◽  
Miguel A. Esteban ◽  
Monica Feijoo-Cuaresma ◽  
Maria C. Castellanos ◽  
Salvador Naranjo-Suárez ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Renal Cancer ◽  
Hypoxia Inducible Factor ◽  
Intercellular Junctions ◽  
Tumor Suppressor Protein ◽  
Von Hippel Lindau

scholarly journals Downregulation ofCap43 gene by von Hippel-Lindau tumor suppressor protein in human renal cancer cells

2003 ◽  
Vol 105 (6) ◽  
pp. 803-810 ◽  
Author(s):  
Katsuaki Masuda ◽  
Mayumi Ono ◽  
Masahiro Okamoto ◽  
Wataru Morikawa ◽  
Michihiro Otsubo ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Renal Cancer ◽  
Tumor Suppressor Protein ◽  
Von Hippel Lindau

scholarly journals Downregulation of integrins by von Hippel-Lindau (VHL) tumor suppressor protein is independent of VHL-directed hypoxia-inducible factor alpha degradation

2008 ◽  
Vol 86 (3) ◽  
pp. 227-234 ◽  
Author(s):  
Qingzhou Ji ◽  
Robert D. Burk
Keyword(s):  
Tumor Suppressor ◽  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Intercellular Junctions ◽  
Suppressor Gene ◽  
Wild Type ◽  
Von Hippel Lindau ◽  
Degradation Activity ◽  
Factor Alpha ◽  
Vhl Tumor Suppressor Protein

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene occurs in the majority of clear-cell renal cell carcinomas (RCCs). It was previously shown that VHL decreased the abundance of integrins α2, α5, and β1, which is consistent with VHL-associated changes in cell–cell and cell – extracellular matrix adhesions. We investigated the mechanism by which VHL downregulates integrins. Although VHL can target hypoxia-inducible factor alpha (HIFα) subunits for degradation, VHL-dependent reduction of integrins was independent of O2 concentration and HIFα levels. VHL reduced the half-lives of integrins, and this activity was blocked by proteasomal inhibition. Although ectopically expressed FLAG-VHL retained HIFα degradation activity, it neither downregulated integrins nor promoted adherens and tight intercellular junctions, in contrast to expressed wild-type VHL. Moreover, integrins co-immunoprecipitated with wild-type VHL, but not FLAG-VHL. These data indicate that the downregulation of integrins by VHL is distinct from the regulation of HIFα subunits by VHL, and suggests that the loss of this activity contributes to VHL-associated RCC development through disruption of adherens and tight junctions.

scholarly journals Clusterin Is a Secreted Marker for a Hypoxia-Inducible Factor-Independent Function of the von Hippel-Lindau Tumor Suppressor Protein

2006 ◽  
Vol 168 (2) ◽  
pp. 574-584 ◽  
Author(s):  
Eijiro Nakamura ◽  
Paula Abreu-e-Lima ◽  
Yasuo Awakura ◽  
Takahiro Inoue ◽  
Toshiyuki Kamoto ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hypoxia Inducible Factor ◽  
Tumor Suppressor Protein ◽  
Independent Function ◽  
Von Hippel Lindau

scholarly journals Hypoxia Inducible Factor-α Binding and Ubiquitylation by the von Hippel-Lindau Tumor Suppressor Protein

2000 ◽  
Vol 275 (33) ◽  
pp. 25733-25741 ◽  
Author(s):  
Matthew E. Cockman ◽  
Norma Masson ◽  
David R. Mole ◽  
Panu Jaakkola ◽  
Gin-Wen Chang ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hypoxia Inducible Factor ◽  
Tumor Suppressor Protein ◽  
Von Hippel Lindau ◽  
Factor Α

scholarly journals Oxygen-Dependent Ubiquitination and Degradation of Hypoxia-Inducible Factor Requires Nuclear-Cytoplasmic Trafficking of the von Hippel-Lindau Tumor Suppressor Protein

2002 ◽  
Vol 22 (15) ◽  
pp. 5319-5336 ◽  
Author(s):  
Isabelle Groulx ◽  
Stephen Lee
Keyword(s):  
Tumor Suppressor ◽  
Rna Polymerase Ii ◽  
Nuclear Export ◽  
Hypoxia Inducible Factor ◽  
Tumor Suppressor Protein ◽  
Nuclear Compartment ◽  
Von Hippel Lindau ◽  
Substrate Protein ◽  
Subsequent Degradation ◽  
Substrate Proteins

ABSTRACT It is becoming increasingly evident that the degradation of nuclear proteins requires nuclear-cytoplasmic trafficking of both the substrate proteins, as well as the E3 ubiquitin-ligases. Here, we show that nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein (VHL) is required for oxygen-dependent ubiquitination and degradation of the alpha subunits of hypoxia-inducible factor (HIF-α). VHL engages in a constitutive transcription-sensitive nuclear-cytoplasmic shuttle unaffected by oxygen tension or levels of nuclear substrate HIF-α. Ubiquitinated forms of HIF-α, as well as VHL/ubiquitinated HIF-α complexes, are found solely in the nuclear compartment of normoxic or reoxygenated VHL-competent cells. HIF-α localizes exclusively in the nucleus of hypoxic cells but is exported to the cytoplasm upon reoxygenation. Oxygen-dependent nuclear ubiquitination and nuclear export of HIF-α can be prevented by treatment with an HIF-specific prolyl hydroxylase inhibitor. Treatment with inhibitors of RNA polymerase II activity, which interfere with the ability of VHL to engage in nuclear export, also prevents cytoplasmic accumulation of HIF-α in reoxygenated cells. This caused a marked increase in the HIF-α half-life without affecting its nuclear ubiquitination. We present a model by which VHL-mediated ubiquitination of HIF-α and its subsequent degradation are dependent upon dynamic nuclear-cytoplasmic trafficking of both the E3 ubiquitin-ligase and the nuclear substrate protein.

Proline hydroxylation at different sites in hypoxia-inducible factor 1α modulates its interactions with the von Hippel–Lindau tumor suppressor protein

2018 ◽  
Vol 20 (27) ◽  
pp. 18756-18765
Author(s):  
Hongsheng Qian ◽  
Yu Zou ◽  
Yiming Tang ◽  
Yehong Gong ◽  
Zhenyu Qian ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Conformational Change ◽  
Hypoxia Inducible Factor ◽  
Tumor Suppressor Protein ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1Α ◽  
Proline Hydroxylation

Proline hydroxylation of HIF-1α affects the interaction affinity between pVHL and HIF-1α and allosterically induces the conformational change of pVHL.

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