Last Updated: 1/13/2009

Research Interests
Research in our laboratory focuses on delineating the biological functions and molecular mechanisms of the ARF-Mdm2-p53 tumor suppression pathway. The tumor suppressors encoded by the p53 and ARF gene loci are the most frequently mutated in human cancers. The function of p53 is controlled by the proto-oncoprotein Mdm2, which is in turn controlled by ARF. Together, ARF, Mdm2 and p53 constitute a network that safeguards normal cells from developing into cancers. The broad goal of our lab is to uncover the complex regulatory network surrounding ARF-Mdm2-p53 tumor suppression pathway, thereby providing a possible means to manipulate p53 function. Postdoctoral fellows and graduate students will receive supervision in a multi-disciplinary program based on (but not limited to) the research outlined below that seeks to maximize trainees' abilities to successfully perform novel and speculative experiments. We are currently focusing on three related areas.

Role of ribosomal protein-Mdm2-p53 pathway in growth control
The first area of research interest in our laboratory is to understand how cell growth and cell division are coordinated. We recently discovered physical and functional interaction between Mdm2 and ribosomal proteins. We found that three ribosomal proteins-L5, L11 and L23, from the 60S large ribosomal subunit interact with and inhibit the function of Mdm2 and induce p53-dependent growth arrest. On the basis of this discovery, we have proposed a model suggesting that the ribosomal protein-Mdm2 interaction represents a signaling pathway coupling cell proliferation with ribosomal biogenesis-a means ensuring coordinated regulation of cell growth and cell division. Our study has raised some critical questions. First, whether and how the ribosomal protein-Mdm2 interaction functions in tumor suppression? Second, besides coordinating cell growth and proliferation, what else might be controlled by the ribosomal protein-Mdm2 interaction? Third, what specific roles are associated with each of the three Mdm2-interacting ribosomal proteins? Fourth, can this pathway offer an effective and tumor-specific general therapeutic strategy for treating cancer? Recent work in our laboratory uses both biochemical tools and mouse models to address these questions.

In vivo function of Mdm2 E3 ubiquitin ligase
The second area of research interest is to understand the function and mechanism of Mdm2 E3 ubiquitin ligase. For more than a decade, Mdm2 has been believed to regulate p53 primarily through two mechanisms: by masking p53's access to transcriptional machinery, and by ubiquitinating p53, targeting it for proteasomal degradation. This dogma was recently challenged by our data generated from knockin mice in which Mdm2's RING E3 ubiquitin ligase activity was abrogated by a single point mutation. We found that the RING mutant Mdm2 is fully capable of binding with p53, yet cannot suppress p53 activity, suggesting that Mdm2 cannot block p53 by binding alone without ubiquitination. Data from the RING knockin mice also revealed that endogenous Mdm2 does not, as previously thought, regulate its own stability by self-ubiquitination. Using this animal model, we are currently exploring the control mechanism of p53-induced cell cycle arrest vs. apoptosis. In addition, we are interested in investigating the role of Mdm2 RING E3 in regulation of Mdm4-a homologue of Mdm2 also critical in p53 regulation.

Function and mechanism of tumor suppressor ARF
The third area of our research interest is focused on delineating the broad tumor suppression role of ARF. Alterations in the gene locus of the tumor suppressor p53 are the most frequently observed lesions in human cancer, with more than 50% of all types of tumors bearing mutations in the p53 gene. Recent work from our lab and others has revealed that the tumor suppressor ARF that can interact with and inhibit the p53 negative-regulator Mdm2 and consequently activates p53. Coincidentally, the gene locus for ARF is the second-most frequently mutated gene after the p53 gene, occurring in about 40% of human cancers overall. Previously, we have identified the ARF-Mdm2 interaction and established the ARF-Mdm2-p53 pathway in control cell division. We then demonstrated the ARF-B23/NPM interaction and uncovered a function for ARF in regulating cell growth. We have recently discovered that ARF physically and functionally interactions with a mitochondrial protein known as p32, and through this interaction ARF helps to coordinate inhibitions of cell division with apoptosis-the same functions that are essential to restrain and to eliminate unwanted cancerous cells and are often perturbed in cancer development. Based on our findings, we propose an integrated role for ARF in cell growth, division and apoptosis: ARF concurrently controls cell growth, division and apoptosis through physical and functional interactions with B23, Mdm2 and p32, respectively. Several projects are currently ongoing aimed at understanding this integrated role of ARF in tumor suppression.

Recent Accomplishments and Honors
Honors and Awards:
2000 Howard Temin Award.
2000 Burroughs Wellcome Career Award in Biomedical Sciences.
2001 M. D. Anderson Research Trust Award.
2005 Junior Research Fellow, UNC Chapel Hill.
2007 Leukemia & Lymphoma Society Scholar Award

Training
Graduate students:
We welcome students from biochemistry, biology, pharmacology, genetics, neuroscience and bioengineering departments to visit and join our lab. For additional information about ongoing research projects, please contact Yanping Zhang via email: ypzhang@med.unc.edu


Postdoctoral Research Positions:
We welcome highly motivated individuals with training in biochemistry, genetics, cell biology, molecular biology, and molecular neurobiology to join us. We especially welcome candidates that are interested in cancer biology and have working experience with animal models. Please send CV and names of three references to: ypzhang@med.unc.edu

Publications
Kevin O'Keefe, Huiping Li, Yanping Zhang. Nucleocytoplasmic shuttling of p53 is essential for MDM2-mediated cytoplasmic degradation but not ubiquitination. Mol Cell Biol. 2003 Sept;23(18): 6396-6405.

Yanping Zhang, Gabrielle Whitewolf, Krishna Bhat, Aiwen Jin, Theresa Allio, William A. Burkhart, and Yue Xiong. Ribosomal protein L11 binds to and negatively regulates oncoprotein HDM2. Mol Cell Biol. 2003 Dec; 23(23): 8902-12.

Koji Itahana, Krishna Bhat, Aiwen Jin, Yoko Itahana, David Hawke, Ryuji Kobayashi, and Yanping Zhang. Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Molecular Cell, 2003 Nov; 12: 1151-64.

Yanping Zhang. The ARF-B23 connection: implications for growth control and cancer treatment. Cell Cycle, 2004; 3(3): 259-262.

Krishna Bhat, Koji Itahana, Aiwen Jin, and Yanping Zhang. Ribosomal protein L11 mediates an MDM2- and p53-dependent ribosomal-stress checkpoint. EMBO J. 2004 Jun 16;23(12): 2402-12.

Aiwen Jin, Koji Itahana, Kevin O'Keefe, and Yanping Zhang. Inhibition of HDM2 and activation of p53 by ribosomal protein L23. Mol Cell Biol. 2004 Sept; 24(17): 7669-80.

Judith A. Erkmann, Eric J. Wagner, Jian Dong, Yanping Zhang, Ulrike Kutay, and William F. Marzluff. Nuclear Import of the Stem-Loop Binding Protein and Localization during the Cell Cycle. Mol Biol Cell. 2005 Jun;16(6):2960-71

Yoko Itahana, Edward T. H. Yeh, and Yanping Zhang. Nucleocytoplasmic shuttling modulates activity and ubiquitination-dependent turnover of SUMO-specific protease 2. Mol Cell Biol. 2006 June; 26(12): 4675-89.

Takeharu Enomoto, Mikael S. Lindstrom, Aiwen Jin, Hengming Ke and Yanping Zhang. Essential role of the B23/NPM core domain in regulating ARF binding and B23 stability. J Biol Chem. 2006 Jul 7; 281(27):18463-72.

Mu-Shui Dai, Yetao Jin, Xiao-Xin Sun, Yanping Zhang, and Hua Lu. Differential regulation of ubiquitinated p53 and MDM2 levels by ribosomal protein L11 in cells. J Biol Chem. 2006 Aug 25; 281(34):24304-13.

Mikael S. Lindstrom and Yanping Zhang. NPM and ARF: Friends or Foes? Cell Biochemistry and Biophysics 2006;46(1):79-90.

Mikael S. Lindstrm, Aiwen Jin, Chad Deisenroth, and Yanping Zhang. Critical role for Mdm2 central zinc finger in mediating ribosomal protein interaction that is affected by cancer-associated Mdm2 mutations. Mol Cell Biol. 2007 Feb; 27(3):1056-68.

Mikael S. Lindstrm, Chad Deisenroth, and Yanping Zhang. Putting a finger on growth surveillance: Insight into MDM2 zinc finger-ribosomal protein interactions. Cell Cycle, 2007 Feb 18;6(4):434-437.

Min Huang, Koji Itahana, Yanping Zhang, and Beverly Mitchell. Guanine nucleotide depletion inhibits pre-ribosomal RNA synthesis and causes dislocalization of nucleolar proteins. Leukemia Res, 2008 Jan;32(1):131-41.

Koji Itahana, Hua Mao, Aiwen Jin, Hilary Clegg, Yoko Itahana, Mikael S. Lindstrm, Krishna P. Bhat, Virginia L. Godfrey, and Yanping Zhang. Targeted inactivation of Mdm2 E3 ubiquitin ligase activity in the mouse reveals novel mechanistic insights into p53 regulation. Cancer Cell, 2007 Oct 12:355-366 (Cover article).

Hilary Clegg, Koji Itahana, and Yanping Zhang. Unlocking the Mdm2-p53 loop: Ubiquitination is the key. Cell Cycle, 2008 Feb 1;7(3):1-6.

Koji Itahana and Yanping Zhang. Mitochondrial p32 is a critical mediator of ARF-induced apoptosis. Cancer Cell, 2008, Vol 13:542-553 (Featured article).

Mikael S. Lindstrm and Yanping Zhang. Physical and functional interactions between nucleolar B23/NPM and ribosomal protein S9 in cell growth and proliferation. J Biol Chem. 2008 Jun 6;283(23):15568-76.

Koji Itahana, Hilary Clegg, and Yanping Zhang. ARF in the mitochondria: the last frontier? Cell Cycle, 2008 Dec 16;7(23), 3641-3646.

Yoko Itahana, Hengming Ke, and Yanping Zhang. p53 oligomerization is essential for C-terminal lysine acetylation. (in press, J Biol Chem).

E-mail: ypzhang@med.unc.edu
Telephone: 919-966-7713 x262
FAX: 919-966-7681
Address: 1048 Gravely Building Chapel Hill, NC
URL: cancer.med.unc.edu/zhanglab/

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