Mechanism of von Hippel-Lindau protein-mediated suppression of nuclear factor kappa B activity.
Biallelic inactivating mutations of the von Hippel-Lindau tumor suppressor gene (VHL) are a hallmark of clear cell renal cell carcinoma (CCRCC), the most common histologic subtype of RCC. Biallelic VHL loss results in accumulation of hypoxia-inducible factor alpha (HIFalpha). Restoring expression of the wild-type protein encoded by VHL (pVHL) in tumors with biallelic VHL inactivation (VHL(-)(/)(-)) suppresses tumorigenesis, and pVHL-mediated degradation of HIFalpha is necessary and sufficient for VHL-mediated tumor suppression. The downstream targets of HIFalpha that promote renal carcinogenesis have not been completely elucidated. Recently, VHL loss was shown to activate nuclear factor kappa B (NF-kappaB), a family of transcription factors that promotes tumor growth. Here we show that VHL loss drives NF-kappaB activation by resulting in HIFalpha accumulation, which induces expression of transforming growth factor alpha, with consequent activation of an epidermal growth factor receptor/phosphatidylinositol-3-OH kinase/protein kinase B (AKT)/IkappaB-kinase alpha/NF-kappaB signaling cascade. We also show that components of this signaling pathway promote the growth of VHL(-)(/)(-) tumor cells. Members of this pathway represent viable drug targets in VHL(-)(/)(-) tumors, such as those associated with CCRCC.
An
Jiabin
J
Division of Hematology/Oncology, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System-West Los Angeles, CA 90073, USA.
Rettig
Matthew B
MB
D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D066246:ErbB Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497442:HIF1A protein, human; C494918:AKT1 protein, human; C497446:VHL protein, human