Last Updated: 5/7/2009

Research Interests
Cell Cycle Control and Tumor Suppression

Inevitably, the molecular pathways controlling cell growth must interact with those regulating cell division. An alteration in this critical interaction may be the cause of human cancer, which is characterized by deregulated cell growth and division. The major goal of this laboratory is to combine genetic, cellular, biochemical and proteomic approaches to determine the mechanisms controlling the cell cycle in normal human cells, and how this control is altered during tumorigenesis. Three major areas of our current research are described below with representative publications.

1. CDK inhibitors in tumor suppression and stem cell cycle control
Eukaryotic cell cycle progression is primarily controlled by a family of protein serine/threonine kinases, known as cyclin-dependent kinases (CDKs), that consist of an activating cyclin subunit and a catalytic subunit CDK. The principle negative regulation of CDKs is provided by two families of CDK inhibitors which link cell cycle control to such diverse processes as DNA repair, terminal differentiation, tumor suppression, cell senescence and stem cell expansion. We are taking a genetic approach toward these issues by targeting specific CDK inhibitor genes (knock-out) in mice to determine their in vivo function. Our current research is focused on determining the mechanism underlying the function of INK4 family CDK inhibitor genes in stem and progenitor cell cycle control and tumor suppression in both lung and mammary tissues (Cell 71:505; Nature 366:701; Genes & Dev. 8:2939; Genes & Dev. 12:2899; Mol. Cell Bio. 20:6147; Cancer Res. 67:4732).

2. Regulation of INK4a and ARF gene expression
Through utilizing different promoters and alternative reading frames, the mammalian ARF-INK4a locus uniquely encodes two unrelated proteins, ARF and p16INK4a, which both function in cell cycle control and tumor suppression. The ARF-INK4a locus is frequently altered in human cancer, with an estimated frequency second only to p53 mutations. INK4a maintains the retinoblastoma (Rb) family proteins in their growth suppressive state through inhibition of cyclin D-dependent kinases 4 and 6 (CDK4 and CDK6) activity, while ARF binds to MDM2 and prevents MDM2-mediated p53 degradation, thereby activating p53. The physiologic signals and biochemical mechanisms regulating the INK4a and ARF gene expression, however, remain poorly understood. Our current research in this area is focused on elucidating the mechanisms leading to the activation and silencing of INK4a and ARF gene expression through histone acetylation, methylation and ubiquitination (Cell 92:725; Mol. Cell 3:579; Science 292:1910; Genes & Dev. 21:49).

3. Cullin-RING family E3 ubiquitin ligases
Most cellular processes, including notably cell cycle control and tumor suppression, are regulated in large part by the ubiquitin-mediated modification and degradation of key regulatory proteins. The mechanisms targeting specific proteins for ubiquitination, in most cases, are poorly understood. We previously discovered two novel RING finger proteins in mammalian cells, ROC1 and ROC2 (for RING of cullins), which constitute active ubiquitin ligases with members of the cullin family. We have also discovered that Cullins 3 and 4 could assemble in vivo as many as 200 and 100 distinct E3 ubiquitin ligases through interacting with a conserved protein motif, the BTB domain and WD40 repeats, respectively. Taking combined genetic, biochemical and proteomic approaches, our current research in this area is focused on the systematic identification and functional characterization of the substrates of the cullin-Roc family E3 ligases (Mol. Cell 3:535; Mol. Cell 10:1511; Nat. Cell Biol. 5:1001; Nat. Cell Biol. 6:1003; Genes & Dev. 20:2949).

Recent Accomplishments and Honors
1. Function of CDK inhibitors in tumor suppression and development.
Following our initial discovery, we targeted both the p18Ink4c and p19Ink4d CDK inhibitor genes in mice and carried out extensive analysis for their function in tumor suppression and development over the past five years. We found that mice lacking p18 develop gigantism, wide spread organomegaly and hyperplasia. We provided the first evidence for a functional collaboration between CDK inhibitor genes that mice mutant for both the p18 and p27 CDK inhibitors spontaneously developed seven different types of tumors at an early age. This phenotype is reminiscent of human multiple endocrine neoplasia (MEN) syndromes.

2. Tumor suppressor ARF inhibits Mdm2 oncoproteins and activates p53
The ARF-INK4a locus is commonly altered in human cancer, with a frequency second only to p53 mutations. ARF has been implicated as a major checkpoint control factor whose role is to monitor oncogene-activated hyperproliferation. In 1998, we discovered that ARF binds to MDM2 and stabilizes p53, providing biochemical evidence that ARF functions as a tumor suppressor by activating p53.

3. ARF inhibits nuclear export of Mdm2 and p53
In 1999, we determined the mechanism underlying ARF-mediated Mdm2 inhibition. We demonstrated that frequently occurring tumor-associated mutations in human ARF impair its normal nucleolar localization and its ability to block p53 nuclear export, identifying a molecular pathway of ARF-mediated p53 activation that is frequently targeted by oncogenic mutations in human cancer.

4. DNA damage-induced phosphorylation regulates p53 nuclear export
In 2001, we identified a novel nuclear export signal in the N-terminus of p53 that contains residues phosphorylated following DNA damage and is required for p53 export. We demonstrated that DNA damage-induced phosphorylation may achieve optimal p53 activation through inhibiting both MDM2 binding to and the nuclear export of p53.

5. Discovery of Roc1 and Roc2
Many cellular processes, including cell cycle control, are regulated via ubiquitin-mediated proteolysis. In 1999, we discovered two evolutionarily conserved RING finger proteins, ROC1 and ROC2 (for RING of cullins), that associate with all cullins to constitute a large number of ubiquitin ligases. We showed that the ROC1-cullin 1 ligase controls degradation of various substrates, including G1 cyclin, CDK inhibitor and IkBa. This finding contributes to the discovery of the RING family of E3 ubiquitin ligases.

Honors and Awards:
1999 UNC Hettleman Award for Scholarly Achievement
1999 AACR Gertrude B. Elion Cancer Research Award
1999 United States Department of Defense Breast Cancer Research Career Development Award

Training
Graduate students:
We welcome students from most BBSP discipline areas such as biochemistry, biology, pharmacology, genetics, neuroscience and bioengineering departments to visit and join our lab. For additional information about ongoing research projects, please contact Yue Xiong via email: yxiong@email.unc.edu

Publications
For a full list of publications, please visit:
http://cancer.med.unc.edu/xionglab/public_html/Publications/

Representative Publications:

Pei, X-H., Bai, F., Smith, MD, Usary, J, Fan, C, Pai, S-Y, Ho, I-C, Perou, CM, and Xiong Y. (2009) CDK inhibitor p18INK4c is a downstream target of GATA3 and restrains mammary luminal progenitor cell proliferation and tumorigenesis. Cancer Cell, 15:389-401.

Zhao, S-M, Li, Y, Xu, W, Jiang, W-Q, Zha, Z-Y, Yu, W, Li, Z-Q, Gong, L-L, Peng, Y-J, Ding, J-P, Lei, Q-Y, Guan, K-L, Xiong, Y. (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1a. Science, 324:261-265.

Hu, J, Zacharek, S, He, Y-J, Lee, H, Shumway, S, Duronio, RJ, and Xiong, Y. (2008) WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase. Genes & Development 22:866-871.

Kotake, Y, Cao, R, Viatour, P, Sage, J, Zhang, Y, Xiong, Y. (2007) pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4a tumor suppressor gene. Genes & Development 21:49-54.

He, YJ, McCall, CM, Zeng, Y, Xiong, Y. (2006) DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4–ROC1 ubiquitin ligases. Genes & Development 20:2949-2954.

Hu, J, McCall, CM, Ohta, T, Xiong, Y. (2004) Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nature Cell Biology 6:1003-1009.

Furukawa, M, He, YJ, Borchers, C, Xiong, Y. (2003) Targeting protein ubiquitination by BTB-cullin 3-Roc1 ubiquitin ligases. Nature Cell Biology 5:1001-1007.

Liu, J, Furukawa, M, Matsumoto,T, Xiong, Y. (2002) NEDD8 modification of CUL1 dissociates p120CAND1, an inhibitor of CUL1-SKP1 binding and SCF ligases. Molecular Cell 10:1511-1518.

Zhang, Y, and Xiong, Y. (2001) A role of p53 N-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation. Science 292:1910-1915.

E-mail: yxiong@email.unc.edu
Telephone: (919) 962-2142
FAX: (919) 962-4296
Address: 22-012 Lineberger Comprehensive Cancer Center Chapel Hill, NC 27599-7295
URL: cancer.med.unc.edu/xionglab/

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