The protein encoded by VHL (pVHL) loses its function in 75% of kidney cancer patients, either through genetic mutations or loss of expression. pVHL is a targeting unit of a protein complex with E3 Ubiquitin ligase activity. In the presence of oxygen, the alpha subunits of Hypoxia-inducible Factors (HIFα) binds to the pVHL complex. In turn, pVHL promotes the ubiquitylation and subsequent proteasomal degradation of HIFα. In the absence of oxygen (hypoxia), HIFα is produced, but not recognized by pVHL; therefore, it is stabilized and can activate hundreds of hypoxia-responsive genes. In the absence of pVHL, the hypoxic response is constitutively active and has been shown to be extremely important for tumorigenesis in kidney cancer. Consistent with this, anti-angiogenic drugs have shown clear clinical benefits in patients with metastatic kidney cancer. However, much evidence indicates that HIF upregulation alone is not sufficient to increase the risk of kidney cancer. A major focus of Dr. Yang’s research is to identify novel targets other than HIFα that pVHL regulates, which could be useful therapeutically. Another focus is to understand how pVHL’s function could be disrupted by other oncogenic events that result in sustained angiogenesis (growth of blood vessels that “feed” tumor cells). Finally, he seeks to understand the mechanisms of drug resistance to anti-angiogenesis agents in kidney cancer patients.
Haifeng Yang, Yoji Andrew Minamishima, Qin Yan, et al. 2007. pVHL acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-kB Agonist Card9 by CK2. Molecular Cell. Vol. 28, 15-27.
Jung-Hyun Min, Haifeng Yang, Mircea Ivan, et al. 2002. Structure of a pVHL-HIF-1a Complex: Hydroxyproline Recognition in Intracellular Signaling. Science. Vol. 296(5574):1886-1889.
Mircea Ivan, Keiichi Kondo, Haifeng Yang, et al. 2001. HIFalpha Targeted for VHL-mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing. Science Vol. 292(5516):464-468.
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