Two novel VHL targets, TGFBI (BIGH3) and its transactivator KLF10, are up-regulated in renal clear cell carcinoma and other tumors.
Mutations in the VHL gene are associated with highly vascular tumors of kidney, brain, retina, and adrenal gland. The inability of the mutant VHL protein to destabilize HIF-1 plays a crucial role in malignant angiogenesis. VHL is also associated with ECM assembly but the molecular mechanisms of this activity remain unclear. We used expression arrays and cell lines with different VHL status to identify ECM-associated genes controlled by VHL. One of them, adhesion-associated TGFBI, was repressed by VHL and overexpressed in renal, gastrointestinal, brain, and other tumors. Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia. These data provide the molecular basis for the observed VHL effect on TGFBI and stimulate further research into the KLF10 and TGFBI roles in cancer.
Ivanov
Sergey V
SV
Basic Research Program, SAIC-Frederick, Inc., 462 First Avenue, Bellevue Hospital, Room 15N20, NY 10016, USA. Sergey.Ivanov@med.nyu.edu
Ivanova
Alla V
AV
Salnikow
Konstantin
K
Timofeeva
Olga
O
Subramaniam
Malayannan
M
Lerman
Michael I
MI
D000970:Antineoplastic Agents / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D051765:Early Growth Response Transcription Factors / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*; D000099222:betaIG-H3 Protein
D000970:Antineoplastic Agents; D051765:Early Growth Response Transcription Factors; D016326:Extracellular Matrix Proteins; D051741:Kruppel-Like Transcription Factors; D016212:Transforming Growth Factor beta; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099222:betaIG-H3 Protein; C098111:KLF10 protein, human; C497446:VHL protein, human