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rdf:type |
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lifeskim:mentions |
umls-concept:C0007097,
umls-concept:C0007634,
umls-concept:C0017262,
umls-concept:C0023688,
umls-concept:C0185117,
umls-concept:C0205263,
umls-concept:C0206734,
umls-concept:C0522503,
umls-concept:C0597357,
umls-concept:C1332823,
umls-concept:C1955901,
umls-concept:C2911684
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pubmed:issue |
14
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pubmed:dateCreated |
2005-7-18
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pubmed:abstractText |
The genetic hallmark of hemangioblastomas and clear cell-renal cell carcinomas (CC-RCCs) is loss-of-function of the von Hippel-Lindau (VHL) tumor suppressor protein. VHL is required for oxygen-dependent degradation of hypoxia-inducible factor-1alpha (HIF-1alpha). In hemangioblastomas and CC-RCCs, HIF-1alpha is constitutively overexpressed leading to increased transcription of HIF-1-regulated genes, including vascular endothelial growth factor (VEGF). Because loss of VHL function is associated with increased expression of the chemokine receptor CXCR4 in CC-RCCs, we investigated the expression of HIF-1alpha, CXCR4, and its ligand stromal cell-derived factor-1alpha (SDF-1alpha) in hemangioblastomas and CC-RCCs. Immunohistochemistry revealed overexpression of both CXCR4 and SDF-1alpha within tumor cells and endothelial cells of hemangioblastomas and CC-RCCs. HIF-1alpha was detected in tumor cell nuclei of both hemangioblastomas and CC-RCCs. A specific ELISA showed that hemangioblastomas and CC-RCCs expressed SDF-1alpha protein at levels that were significantly higher than those found in normal tissue. Analysis of the VHL-null RCC line 786-0 revealed that SDF-1alpha mRNA levels were 100-fold higher than in a subclone transfected with the wild-type VHL gene. Expression of CXCR4 and SDF-1alpha mRNA was significantly decreased in HIF-1alpha-null compared with wild-type mouse embryo fibroblasts (MEFs). ELISA and Western blot studies for SDF-1alpha and CXCR4 protein expression confirmed the RNA findings in RCC lines and MEFs. These results suggest that loss-of-function of a single tumor suppressor gene can up-regulate the expression of both a ligand and its receptor, which may establish an autocrine signaling pathway with important roles in the pathogenesis of hemangioblastoma and CC-RCC.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CXCL12 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Chemokine CXCL12,
http://linkedlifedata.com/resource/pubmed/chemical/Chemokines, CXC,
http://linkedlifedata.com/resource/pubmed/chemical/Cxcl12 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, CXCR4,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin-Protein Ligases,
http://linkedlifedata.com/resource/pubmed/chemical/VHL protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Endothelial Growth Factor A,
http://linkedlifedata.com/resource/pubmed/chemical/Von Hippel-Lindau Tumor Suppressor...
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
0008-5472
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
65
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6178-88
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:16024619-Adenocarcinoma, Clear Cell,
pubmed-meshheading:16024619-Adolescent,
pubmed-meshheading:16024619-Adult,
pubmed-meshheading:16024619-Aged,
pubmed-meshheading:16024619-Animals,
pubmed-meshheading:16024619-Cell Line, Tumor,
pubmed-meshheading:16024619-Cell Nucleus,
pubmed-meshheading:16024619-Cerebellar Neoplasms,
pubmed-meshheading:16024619-Chemokine CXCL12,
pubmed-meshheading:16024619-Chemokines, CXC,
pubmed-meshheading:16024619-Cytosol,
pubmed-meshheading:16024619-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:16024619-Female,
pubmed-meshheading:16024619-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:16024619-Hemangioblastoma,
pubmed-meshheading:16024619-Humans,
pubmed-meshheading:16024619-Immunohistochemistry,
pubmed-meshheading:16024619-Kidney Neoplasms,
pubmed-meshheading:16024619-Male,
pubmed-meshheading:16024619-Mice,
pubmed-meshheading:16024619-Middle Aged,
pubmed-meshheading:16024619-RNA, Messenger,
pubmed-meshheading:16024619-Receptors, CXCR4,
pubmed-meshheading:16024619-Signal Transduction,
pubmed-meshheading:16024619-Transfection,
pubmed-meshheading:16024619-Tumor Suppressor Proteins,
pubmed-meshheading:16024619-Ubiquitin-Protein Ligases,
pubmed-meshheading:16024619-Up-Regulation,
pubmed-meshheading:16024619-Vascular Endothelial Growth Factor A,
pubmed-meshheading:16024619-Von Hippel-Lindau Tumor Suppressor Protein
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pubmed:year |
2005
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pubmed:articleTitle |
Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor.
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pubmed:affiliation |
Microvascular and Molecular Neuro-oncology Laboratory, New York, New York, USA. dz4@nyu.edu
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, N.I.H., Extramural
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