Clusterin is a secreted marker for a hypoxia-inducible factor-independent function of the von Hippel-Lindau tumor suppressor protein.
Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene predispose people to renal cancer, hemangioblastomas, and pheochromocytomas in an allele-specific manner. The best documented function of the VHL gene product (pVHL) relates to its ability to polyubiquitinate, and hence target for destruction, the alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF). pVHL mutants linked to familial pheochromocyctoma (type 2C VHL disease), in contrast to classical VHL disease, appear to be normal with respect to HIF regulation. Using a simple method for identifying proteins that are differentially secreted by isogenic cell line pairs, we confirmed that the HIF targets IGBP3 and PAI-1 are overproduced by pVHL-defective renal carcinoma cells. In addition, cells lacking wild-type pVHL, including cells producing type 2C pVHL mutants, were defective with respect to expression and secretion of clusterin, which does not behave like a HIF target. Decreased clusterin secretion by pVHL-defective tumors was confirmed in vivo by immunohistochemistry. Therefore, clusterin is a secreted marker for a HIF-independent pVHL function that might be especially important in pheochromocytoma development.
Nakamura
Eijiro
E
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA.
Abreu-e-Lima
Paula
P
Awakura
Yasuo
Y
Inoue
Takahiro
T
Kamoto
Toshiyuki
T
Ogawa
Osamu
O
Kotani
Hirokazu
H
Manabe
Toshiaki
T
Zhang
Guo-Jun
GJ
Kondo
Keiichi
K
Nosé
Vānia
V
Kaelin
William G
WG
D000310:Adrenal Gland Neoplasms / Q000378:metabolism / Q000473:pathology; D000311:Adrenal Glands / Q000378:metabolism; D014408:Biomarkers, Tumor; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000556:secondary; D049109:Cell Proliferation; D051152:Clusterin / Q000378:metabolism*; D019175:DNA Methylation; D015180:Electrophoresis, Gel, Two-Dimensional; D010450:Endopeptidases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015151:Immunoblotting; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D010673:Pheochromocytoma / Q000378:metabolism / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*; D006623:von Hippel-Lindau Disease / Q000378:metabolism
D014408:Biomarkers, Tumor; D051152:Clusterin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017395:Plasminogen Activator Inhibitor 1; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010450:Endopeptidases; C080473:insulin-like growth factor binding protein-3 protease