Details

Autor(en) / Beteiligte

• Razorenova, Olga V
• Finger, Elizabeth C
• Colavitti, Renata
• Chernikova, Sophia B
• Boiko, Alexander D
• Chan, Charles K.F
• Krieg, Adam
• Bedogni, Barbara
• LaGory, Edward
• Weissman, Irving L
• Broome-Powell, Marianne
• Giaccia, Amato J

Titel

VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2011-02, Vol.108 (5), p.1931-1936

Ort / Verlag

National Academy of Sciences

Erscheinungsjahr

2011

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCδ, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.