Clinical and functional properties of novel VHL mutation (X214L) consistent with Type 2A phenotype and low risk of renal cell carcinoma.
Bottom Line: In contrast, the variant was defective with respect to downregulation of JunB. pVHL X214L, like other pVHL variants associated with a low risk of clear cell renal carcinoma, largely preserves the ability to downregulate HIF.In contrast, this variant, like other pVHL variants linked to Type 2A disease, fails to suppress JunB.This underscores that JunB may play a role in the pathogenesis of Type 2A VHL disease.
Affiliation: City of Hope National Medical Center, Duarte, California 91010-3000, USA. firstname.lastname@example.orgShow MeSH
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Mentions: Prior studies suggest that pVHL mutants linked to familial pheochromocytoma fail to downregulate the c-Jun antagonist JunB, attenuating apoptosis, and setting the stage for neoplastic transformation (10). Using two independent, pVHL , RCC lines (786-O and RCC-4), we found that the X214L pVHL mutant is associated with abnormal JunB expression, when compared to wild-type pVHL (Fig. 3). The electrophoretic mobility of the exogenous HA-tagged pVHL (X214L) was slower than that of HA-tagged wild-type pVHL, consistent with the presence of 14 additional amino acids. HIF2α induction patterns were assessed after treatment with dimethyloxaloylglycine (DMOG), a prolyl hydroxylase inhibitor, in cell lines expressing wild-type or X214L pVHL. The X214L mutant pVHL appeared to downregulate HIFα protein expression, in a canonical, hydroxylation-dependent, manner. In contrast, X214L was defective relative to wild-type pVHL with respect to downregulation of JunB. In sum, X214L mutant protein was associated with low HIF2α expression and high JunB expression, a pattern consistent with a low risk of kidney cancer and high risk of pheochromocytoma.
Affiliation: City of Hope National Medical Center, Duarte, California 91010-3000, USA. email@example.com