Oncotarget

Research Papers:

VHL missense mutations in the p53 binding domain show different effects on p53 signaling and HIFα degradation in clear cell renal cell carcinoma

Caroline Fanja Razafinjatovo, Daniel Stiehl, Eva Deininger, Markus Rechsteiner, Holger Moch and Peter Schraml _

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Oncotarget. 2017; 8:10199-10212. https://doi.org/10.18632/oncotarget.14372

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Abstract

Caroline Fanja Razafinjatovo1, Daniel Stiehl2, Eva Deininger1, Markus Rechsteiner1, Holger Moch1, Peter Schraml1

1Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland

2Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

Correspondence to:

Peter Schraml, email: peter.schraml@usz.ch

Keywords: clear cell renal cell carcinoma, VHL missense mutations, pVHL binding sites, p53, HIFα

Received: July 22, 2016    Accepted: December 15, 2016    Published: December 30, 2016

ABSTRACT

Clear cell Renal Cell Carcinoma (ccRCC) formation is connected to functional loss of the von Hippel-Lindau (VHL) gene. Recent data identified its gene product, pVHL, as a multifunctional adaptor protein which interacts with HIFα subunits but also with the tumor suppressor p53. p53 is hardly expressed and rarely mutated in most ccRCC. We showed that low and absent p53 expression correlated with the severity of VHL mutations in 262 analyzed ccRCC tissues. In contrast to nonsense and frameshift mutations which abrogate virtually all pVHL functions, missense mutations may rather influence one or few functions. Therefore, we focused on four VHL missense mutations, which affect the overlapping pVHL binding sites of p53 and Elongin C, by investigating their impact on HIFα degradation, p53 expression and signaling, as well as on cellular behavior using ccRCC cell lines and tissues. TP53 mRNA and its effector targets p21, Bax and Noxa, were altered both in engineered cell lines and in tumor tissues which carried the same missense mutations. Two of these mutations were not able to degrade HIFα whereas the remaining two mutations led to HIFα downregulation, suggesting the latter are p53 binding site-specific. The selected VHL missense mutations further enhanced tumor cell survival, but had no effects on cell proliferation. Whereas Sunitinib was able to efficiently reduce cell proliferation, Camptothecin was additionally able to increase apoptotic activity of the tumor cells. It is concluded that systematic characterization of the VHL mutation status may help optimizing targeted therapy for patients with metastatic ccRCC.


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