Abstract
Clear cell renal cell carcinomas (RCC), the major histologic subtype of RCC accounting for more than 80% of cases, are typified by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. Although accumulation of hypoxia-inducible factor alpha (HIF-α) is the most well-studied effect of VHL inactivation, direct inhibition of HIFα or restoration of wild-type pVHL protein expression has not proved readily feasible, given the limitations associated with pharmacologic targeting of transcription factors (i.e., HIF-α) and gene replacement therapy of tumor suppressor genes (i.e., VHL). Here, we have established that phosphorylated c-Jun, a substrate of the c-Jun-NH(2)-kinase (JNK), is selectively activated in clear cell RCC patient specimens. Using multiple isogenic cell lines, we show that HIF-α-independent JNK hyperactivation is unique to the pVHL-deficient state. Importantly, pVHL-deficient RCCs are dependent upon JNK activity for in vitro and in vivo growth. A multistep signaling pathway that links pVHL loss to JNK activation involves the formation of a CARD9/BCL10/TRAF6 complex as a proximal signal to sequentially stimulate TAK1 (MAPKKK), MKK4 (MAPKK), and JNK (MAPK). JNK stimulates c-Jun phosphorylation, activation, and dimerization with c-Fos to form a transcriptionally competent AP1 complex that drives transcription of the Twist gene and induces epithelial-mesenchymal transition. Thus, JNK represents a novel molecular target that is selectively activated in and drives the growth of pVHL-deficient clear cell RCCs. These findings can serve as the preclinical foundation for directed efforts to characterize potent pharmacologic inhibitors of the JNK pathway for clinical translation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Anthracenes / pharmacology
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B-Cell CLL-Lymphoma 10 Protein
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Blotting, Western
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / metabolism
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Carcinoma, Renal Cell / drug therapy
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Carcinoma, Renal Cell / metabolism*
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Carcinoma, Renal Cell / pathology
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Cell Line, Tumor
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Enzyme Activation
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Female
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Kidney Neoplasms / drug therapy
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Kidney Neoplasms / metabolism*
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Kidney Neoplasms / pathology
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Mice, Nude
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-fos / metabolism
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Proto-Oncogene Proteins c-jun / metabolism
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RNA Interference
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism
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Von Hippel-Lindau Tumor Suppressor Protein / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
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Xenograft Model Antitumor Assays
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Zearalenone / analogs & derivatives
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Zearalenone / pharmacology
Substances
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7-oxozeanol
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Adaptor Proteins, Signal Transducing
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Anthracenes
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B-Cell CLL-Lymphoma 10 Protein
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BCL10 protein, human
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CARD Signaling Adaptor Proteins
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CARD9 protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-jun
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TNF Receptor-Associated Factor 6
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pyrazolanthrone
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Zearalenone
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Von Hippel-Lindau Tumor Suppressor Protein
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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MAP Kinase Kinase 4
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MAP2K4 protein, human
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VHL protein, human