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Haifeng Yang, Ph.D.Assistant StaffDepartment of Cancer Biology |
von-Hippel Lindau (VHL) tumor suppressor, Hypoxia-Inducible Factor (HIF), JARID1C, histone modification, drug resistance, EGFR degradation, anti-angiogenesis therapy, PBRM1, kidney cancer
The major interest of this lab is to study the mechanisms of how a major tumor suppressor gene, VHL, blocks the growth and development of tumors in HIF-dependent and HIF-independent manners.
The protein encoded by VHL (pVHL) loses its function in 75% of kidney cancer patients of clear cell subtype, either through genetic mutations or loss of expression. Also, germline (hereditary) mutations in VHL (which can be passed through generations) strongly predispose patients to kidney cancer, hemangioblastoma (benign tumors of the central nervous system) and pheochromocytoma (tumors of the adrenal glands). It is now well known that pVHL forms a protein complex with Elongin B, Elongin C, Cul2, and Rbx1 that has Ubiquitin E3 ligase activity. In the presence of oxygen, the alpha subunits of Hypoxia-inducible Factors (HIFα) are prolyl hydroxylated, serving as a binding signal to recruit 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 pro-ubiquitylation function, 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, such as sunitinib and sorafenib, 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 binds and destroys, which could be useful therapeutically. Another focus is to understand how pVHL regulates histone modification and gene expression through demethylase JARID1C, a recently identified caner gene that is mutated in kidney cancer. Finally, he seeks to understand the mechanism of drug resistance to anti-EGFR inhibitors in kidney cancer patients.
Liang Zhou, Haifeng Yang*. The von Hippel-Lindau Tumor Suppressor Protein Promotes c-Cbl-independent poly-ubiquitylation and degradation of the activated EGFR. PLoS ONE 6:e23936, 2011. *Corresponding author.
Xiaohua Niu, Ting Zhang, Lili Liao, Liang Zhou, Ming Zhou, Daniel J. Lindner, Brian Rini, Qin Yan, Haifeng Yang*. The von Hippel-Lindau Tumor Suppressor Protein Regulates Gene Expression and Tumorigenesis through Histone Demethylase JARID1C. Oncogene advance online publication 4 July 2011; doi: 10.1038/onc.2011.266 *Corresponding author.
Haifeng Yang, Yoji Andrew Minamishima, Qin Yan, Susanne Schlisio, Benjamin L. Ebert, Xiaoping Zhang, Liang Zhang, William Y. Kim, Aria F. Olumi, and William G. Kaelin, Jr. 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.
SungwooLee, EijiroNakamura, HaifengYang, WenyiWei, Michelle S.Linggi, Mini P.Sajan, Robert V.Farese, Robert S.Freeman, Bruce D.Carter, William G.Kaelin Jr., and SusanneSchlisio. 2005. Neuronal Apoptosis Linked to EglN3 Prolyl Hydroxylase and Familial Pheochromocytoma Genes: Developmental Culling and Cancer. Cancer Cell. Vol. 8(2):155-167.
Haifeng Yang, Mircea Ivan, Hung-Hyun Min, William Kim, and William Kaelin, Jr. 2004. Analysis of von Hippel-Lindau Hereditary Cancer Syndrome: Implication of Oxygen Sensing. Methods in Enzymology. Vol. 381, 320-335.
Jung-Hyun Min, Haifeng Yang, Mircea Ivan, Frank Gertler, Willaim G. Kaelin, Jr., Nikola P. Pavletich. 2002. Structure of a pVHL-HIF-1a Complex: Hydroxyproline Recognition in Intracellular Signaling. Science. Vol. 296(5574):1886-1889.
Mircea Ivan, Thomas Haberberger, David Gervasi, Kristen Michelson, Volkmar Gunzler, Keiichi Kondo, Haifeng Yang, Irina Sorokina, Ron Conaway, Joan Conaway, and William G. Kaelin, Jr. 2002. Biochemical Purification and Pharmacological Inhibition of a Mammalian HIF Prolyl Hydroxylase. Proc. Natl. Acad. Sci. U S A. Vol. 99(21):13459-13464.
Michael A. Hoffman, Michael Ohh, Haifeng Yang, Jeffery M. Klco, Mircea Ivan, William G. Kaelin Jr. 2001. von Hippel-Lindau Protein Mutants Linked to Type 2C VHL Disease Preserve the Ability to Downregulate HIF. Hum. Mol. Genet. Vol. 10(10):1019-1027.
Haifeng Yang, William G. Kaelin Jr. 2001. Molecular Pathogenesis of the von Hippel-Lindau Hereditary Cancer Syndrome: Implications for Oxygen Sensing. Cell Growth. Differ. Vol. 12(9): 447-455.
Mircea Ivan, Keiichi Kondo, Haifeng Yang, William Kim, Jennifer Valiando, Michael Ohh, Adrian Salic, John M. Asara, William S. Lane, William G. Kaelin Jr. 2001. HIFalpha Targeted for VHL-mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing. Science Vol. 292(5516):464-468. (Comment in: Science. 2001. Vol. 292(5516):449-451.)