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HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing
It is found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated, which may play a key role in mammalian oxygen sensing. Expand
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
HIF plays a central role in the transcriptional response to changes in oxygen availability and is modulated by FIH1-mediated asparagine hydroxylation, and HIF-modulatory drugs are now being developed for diverse diseases. Expand
Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.
It is shown that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the Hypoxia-inducible gene REDD1/RTP801 to be inhibited, and that down-regulation of mTOR activity by hyp oxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxIA-Inducible REDD 1 gene. Expand
Role of VHL gene mutation in human cancer.
- William Y. Kim, W. Kaelin
- Biology, Medicine
- Journal of clinical oncology : official journal…
- 15 December 2004
Preliminary data indicate that HIF plays a critical role in pVHL-defective tumor formation, raising the possibility that drugs directed against HIF or its downstream targets (such as vascular endothelial growth factor) might one day play a role in the treatment of hemangioblastoma and renal cell carcinoma. Expand
The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins
It is shown that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). Expand
Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation
Findings define an enantiomer-specific mechanism by which the (R)-2HG that accumulates in IDH mutant brain tumours promotes transformation and provide a justification for exploring EGLN inhibition as a potential treatment strategy. Expand
Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex
It is shown that the F-box protein Skp2 is polyubiquitinated, and hence earmarked for destruction, by APCCDH1, and accumulation of SCFSKP2 requires prior inactivation of APCC DH1. Expand
Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex.
A novel role for the Cullin-based machinery in regulation of p53 is identified, which is remarkably similar to the von Hippel-Lindau tumor suppressor and SCF E3 ubiquitin ligase complexes. Expand
The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage
The results indicate that c-Abl and p73 are components of a mismatch-repair-dependent apoptosis pathway which contributes to cisplatin-induced cytotoxicity. Expand
Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein
It is shown that pVHL, through its β-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an α-domain-dependent manner, the first function to be ascribed to the pV HL β- domain. Expand