William Kaelin

..This is changing as a result of the increased availability of chemical and genetic tools for perturbing gene function in somatic cells...

..Here, we review literature pertinent to hypothetical connections between metabolic and epigenetic states in eukaryotic cells...

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..2-Oxoglutarate-dependent dioxygenases therefore provide a link between altered metabolism and cancer...

..HIF affects signaling pathways that influence development, metabolism, inflammation, and integrative physiology. Accordingly, HIF-modulatory drugs are now being developed for diverse diseases...

..It is hypothesized that tumor-associated alleles of these genes allow primitive sympathoadrenal precursors to escape developmental culling, and that such cells are at increased risk of forming tumors...

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..Pharmacological manipulation of HIF activity might be beneficial in diseases characterized by abnormal tissue oxygenation including myocardial infarction, cerebrovascular disease, and cancer...

..Thus, E2F appears to be a physiologically relevant target of pRB action, and deregulation of E2F-responsive genes is a common, and possibly universal, step in human carcinogenesis...

..This chapter will review the role of E2F in cancer and outline opportunities for the development of anticancer agents based on E2F biology...

..This review summarizes the current knowledge of the molecular pathogenesis of von Hippel-Lindau disease and the role of the VHL gene product (pVHL) in kidney cancer and the mammalian oxygen sensing pathway...

..The existence of three human EGLN family members, as well as other putative hydroxylases, raises the possibility that this signal is used in other contexts by other proteins...

..Genotype-phenotype correlations in VHL disease suggest, however, that pVHL has targets in addition to HIF. Elucidating these targets should provide a more complete picture of how pVHL suppresses tumor growth...

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..These studies, in turn, are laying the foundation for the treatment of a diverse set of disorders, including cancer, myocardial infarction and stroke...

..In this regard, it is perhaps noteworthy that elongin C and Cul2 are homologous to yeast proteins Skp1 and Cdc53. These latter proteins participate in the formation of complexes that target certain proteins for ubiquitination...

..Additional studies are required to determine the role, if any, that p73 and p51 play in cell growth control and carcinogenesis...

..The untimely activation of E2F responsive genes can induce apoptosis. This comes about at least partly through the induction of ARF, which leads to the stabilization and activation of p53. BioEssays 1999;21:950-958...

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..A number of JmjC-containing proteins, including RBP2 and PLU-1, are 2-oxoglutarate-dependent dioxygenases that demethylate histones. Preclinical data suggest that inhibition of RBP2 or PLU-1 would suppress tumor growth...

..These approaches will hopefully facilitate the discovery of safer, more efficacious anticancer drugs that exploit vulnerabilities that are unique to cancer cells by virtue of the mutations they have accrued during tumor progression...

..Moreover, they detected SDH5 mutations in a large kindred with familial paraganglioma...

..Loss of the primary cilium probably facilitates the development of preneoplastic renal cysts, whereas increased NFkappaB might contribute to the resistance of kidney cancers to conventional cytotoxic agents...

..In this issue, Simon and coworkers show that the molecular signature of VHL(-/-) kidney cancers is profoundly influenced by whether they produce both HIF2alpha and HIF1alpha or HIF2alpha alone...

..On the other hand, clear genotype-phenotype correlations are emerging in VHL disease and can be rationalized if pVHL has functions separate from its control of HIF...

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..Moreover, EglN3 proapoptotic activity requires SDH activity because EglN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis...

..A model compound of this series stabilized HIF in a variety of cells, leading to the increased production of its downstream target, vascular endothelial growth factor...

..These studies prove that HIF is a critical downstream target of pVHL and establish that activation of HIF target genes can promote tumorigenesis in vivo...

..This pathway may involve chromatin remodeling since the HDAC inhibitor Trichostatin A downregulates VEGF in TSC2(-/-) cells...

..These results establish that tumor suppression by pVHL is linked to regulation of HIF target genes...

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..2005) used genetic tools to establish that ROS produced by mitochondria are required for the normal induction of HIF (hypoxia-inducible factor), which is a master regulator of oxygen-sensitive gene expression, by low oxygen...

..The conference format combined brief presentations with extended periods of discussion. The conclusions and recommendations are summarized in this paper and presented in more detail in the individual papers that follow...

..Mutant p53 can inactivate p73 and downregulation of mutant p53 enhanced chemosensitivity. These findings indicate that p73 is a determinant of chemotherapeutic efficacy in humans...

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..Therefore, clusterin is a secreted marker for a HIF-independent pVHL function that might be especially important in pheochromocytoma development...

..Therefore, quantitative differences with respect to HIF deregulation are sufficient to account for the differential risks of kidney cancer linked to VHL mutations...

..Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia...

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..Our results suggest that senescence induced by VHL inactivation is a tumour-suppressive mechanism that must be overcome to develop VHL-associated neoplasias...

..How mTOR dysregulation after inactivation of LKB1 or TSC1/2 contributes to hamartoma development is not known. However, hypoxia-inducible factor (HIF) and VEGF are regulated by mTOR and are likely to play a contributory role...

..The latter is likely the result of hyperviscosity syndrome and volume overload, although a direct effect of chronic, high-level HIF stimulation on cardiac myocytes cannot be excluded...

..EglN2 depletion also impairs the fitness of lung, brain, and hematopoietic cancer lines. These findings support the exploration of EglN2 inhibitors as therapeutics for estrogen-dependent breast cancer and other malignancies...

..Therefore pVHL can serve as an adaptor for both a ubiquitin conjugating enzyme and a kinase. The latter activity, which promotes Card9 phosphorylation, links pVHL to control of NF-kappaB activity and tumorigenesis...

..Thus, neddylation regulates the activity of two specific subclasses of mammalian ubiquitin ligases...

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..These studies provide mechanistic insights into transcriptional regulation by RBP2 and provide the first example of a mammalian enzyme capable of erasing trimethylated H3K4...

..These findings explain the enhanced stability and oncogenicity of v-Jun relative to its cellular counterpart and reveal that GSK3 and Fbw7 coordinately regulate c-Jun and c-Myc...

..Therefore, the pathological changes caused by pVHL inactivation in skin and liver are due largely to dysregulation of HIF target genes...

..In theory, the approach described here could be used to develop bioluminescent reporters for any drug target that directly or indirectly affects the turnover of a ubiquitin ligase substrate...

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..These findings suggest that continued evaluation of VEGF inhibitors for ocular neovascular disorders is warranted...

..A session was devoted to the identification of markers of drug effectiveness. Two sessions were focused on opportunities for developing new specific molecular target-oriented therapies...

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..The results reveal an unexpected physical convergence between the pRB tumour-suppressor protein and E3 ligase complexes, and raise the possibility that pRB may direct APC/C to additional targets during pRB-mediated cell-cycle exit...

..Two of the three functional E2F sites (at -155 and -132) reside within this region. Our results suggest that regulation of p73 expression is primarily mediated through binding of E2F1 to target sites at -155 and -132...

..Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling...

..These results suggest that NEDD8 modification of pVHL plays an important role in fibronectin matrix assembly and that in the absence of such regulation, an intact HIF pathway is insufficient to prevent VHL-associated tumorigenesis...

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..How these agents should be combined with one another and with conventional agents is the subject of current trials...

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..Pathway-based regulation of hypoxia-inducible gene expression with DNA-binding small molecules may represent a new approach for targeting angiogenesis...

..In addition, recent work suggests that pVHL regulates neuronal apoptosis in an HIF-independent manner, and this activity is linked to the risk of developing pheochromocytoma...

..Our results suggest that promotion of differentiation by pRB involves neutralization of free RBP2 and transcriptional activation of RBP2 targets linked to euchromatin maintenance...

..This review focuses on the genetics of these tumors and suggests a possible link between familial pheochromocytomas/paraganglioma genes and control of neuronal apoptosis during embryological development...

..Encouraging in this regard are cell culture experiments and animal models that suggest that cancer cells often remain dependent on, and may become addicted to, the signals resulting from such early genetic changes...

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..These approaches should be generalizable to other ubiquitin-ligase substrate pairs...

..Such mice could be used to study diseases characterized by the presence of hypoxic cells, such as cancer, and could also be used to monitor pharmacodynamic effects of agents that alter tissue oxygenation and/or modulate HIF. ..

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..Reisolation of HIF in aims 2 and 3 would constitute proof of concept with respect to the potential utility of this approach. ..

..The functional significance of pRB/RBP2 interactions will be addressed in Specific aim 3 and specific aim 4 will ask whether EID1 and/or RBP2 contribute to the developmental abnormalities observed in RB-/- mice. ..

..This, in turn, is leading to new drugs that might be useful in diseases such as heart attack and stroke that are characterized by impaired oxygen delivery to tissues. ..

..This, in turn, is leading to new drugs that might be useful in diseases such as heart attack and stroke that are characterized by impaired oxygen delivery to tissues. ..

..This, in turn, is leading to new drugs that might be useful in diseases such as heart attack and stroke that are characterized by impaired oxygen delivery to tissues. ..

..Identification of additional proteins that bind to, and are regulated by, pVHL is the goal of specific aim 4. ..

..Moreover, they may establish a new paradigm for the selection of anticancer drug targets based on inactivating mutations of TSG. ..

..Furthermore, these cDNAs will likely be invaluable reagents for further exploring the functional significance of pVHL binding to these two proteins. ..

..Testing this hypothesis in a mouse model, as well as determining the biochemical basis for this activity, will form the basis of specific aim 2. ..

..This, in turn, is leading to new drugs that might be useful in diseases such as heart attack and stroke that are characterized by impaired oxygen delivery to tissues. ..