er normoxic conditions. Hif pathway is the master regulator of oxygen homeostasis. Under normoxic conditions, the Hif proteins are subject to hydroxylation by prolyl and asparagyl hydroxylases whose own enzymatic activities are oxygen dependent and require iron and 2-oxoglutarate as cofactors. The modified prolines are recognized by Vhl which then targets Hif for proteasomal degradation; the modified asparagine blocks the interaction of Hif with transcriptional activators. When the levels of oxygen are low, Hif is not modified, translocates to the nucleus where it forms heterodimers with the beta partner to regulate the expression of target genes. Targets include genes involved in glucose and energy homeostasis, erythropoiesis and angiogenesis, among others. There are numerous germline and somatic mutations in Vhl; somatic mutations are found in almost 90% of tumors although RCC with wild-type Vhl have also been reported. In either case, most mutations are associated with loss of function in both alleles. It is believed that specific mutations underlie distinct morbidity and mortality phenotypes. The inability to target Hif for degradation renders the pathway constitutively active regardless oxygen levels. Of the three Hif Additional stabilization of Hif appears to be due to mutations in fumarate hydratase (Fh) and succinate dehydrogenase (Sdhb and Sdhd of Sdh complex) enzymes of the citric acid cycle and in the case of Sdh of the electron transport chain as well where it functions as complex II. Mutations in Fh which catalyzes the conversion of fumarate to malate result in increased levels of fumarate which acts as a competitive inhibitor of 2-oxoglutarate. In the reaction, 2-oxoglutarate undergoes oxidative decarboxylation to succinate and accumulating succinate due to mutations in Sdh can act as product inhibitor of prolyl hydrolase mediated reaction (In the citric acid cycle, succinate is converted to malate by Sdh). Thus, either Fh or Sdh mutations affect the necessary modification of Hif under normoxic condition, creating a pseudohypoxic environment that promotes Hif activity even when Vhl might be wild type. In addition, large-scale sequencing experiments have identified novel mutated genes such as the lysine specific histone methylase Setd2 or the KDM5C and Kdm6a demethylases which appear to be present in less than 15% of the investigated cases while mutations in Pbrm1 component of the SWI/SNF ATP-dependent chromatin remodeling complex, have been found in 41% of cases. Regardless the degree of incidence, it is interesting to note that the genes are part of the chromatin modification/remodeling machinery that modulate chromatin compaction, in turn affecting replication, transcription and DNA repair. Although the exact role these mutations have in the context of RCC remains to be established, it is possible that they affect in some fashion the transcriptional activity of Hif and its outcomes. It is worth mentioning that, at least in the case of alpha 1 isoform, studies show binding and regulation of expression of several Jumonji domain containing histone lysine demethylases Several miRNAs (micro-RNA) have been found deregulated, both up- and down-regulated in tumors as compared to normal tissues. miRNAs are important regulators of gene expression that post-transcriptionally repress their target genes. Predicted targets include Hif alpha and a number of its targets; several miRNAs have been documented to be downstream targets of Hif pathway. A number of drugs are being used in the targeted therapy of RCC; they include those that target direct and indirect targets of Hif pathway such as vascular endothelial growth factor and receptors or platelet derived growth factor receptors and those that target mTOR pathway which controls the translation of Hif. Among the adverse events (AEs) associated with the drugs, gastrointestinal and dermatologic, hypertension and hemorrhage, headache and fatigue or treatment-related infections have been reported and the kind and severity varies with the drug. To see the ontology report for annotations, Gviewer and download, click here . To see the Disease Ontology report for genes that in some fashion have been associated with RCC or suspected to confer susceptibility, click here Click to see associated KEGG map map05211]...(less)