Research in this laboratory focuses on the control of cell division cycles in development and diseases, especially cancer. We are particularly interested in how the cell cycle checkpoints are activated in response to internal and external stimuli and what are the consequences should these checkpoints fail.
Cellular proliferation is controlled by cyclin-dependent kinases whose activities are absolutely required for cell cycle progression. Cdks are regulated positively by cyclins and negatively by Cdk inhibitors (CKIs). Loss of cell cycle control is the underlying mechanisms of tumor development and causes congenital birth defects due to problems incurred during embryonic development. There are two very important control points during cell cycle. One is the G1 to S transition where cells decide whether to commit themselves to another round of division or to take a different developmental fate. The other is mitosis when the duplicated genome is equally partitioned to two daughter cells. Errors in this process leads to gain/loss of chromosomes, or chromosomal instability, a potential driving force in tumorigenesis.
The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase essential for sister chromatid separation and segregation in mitosis. Misregulation of its activity can lead to chromosome missegregation, producing aneuploid daughter cells. Through analyses of mice that are compromised in the regulation of APC/C, we demonstrated that aneuploidy was tumroigenic and uncovered a mechanism eliminates aneuploid cells: the aneuploidy checkpoint (Fig. 1). Our more recent work point to the involvement of APC/C in DNA damage repair by helping recruitment of BRCA1 to damage sites. Thus, APC/C plays important roles in the maintenance of genome stability, from ensuring faithful chromosome segregation to helping DNA damage repair.
By taking advantage of the massive proteomics power available in PHOENIX Center and the newest CRISPR gene editing technology, we are systemically profiling druggable targets in human proteome with the aim to identify cancer-specific drug targets. Our pilot experiment has demonstrated feasibility of this approach and has yield exciting results.
1. Lin, H., Ha, K., Lu, G., Fang, X., Cheng, R., Zuo, Q., and Zhang, P. (2015) Cdc14A and Cdc14B redundantly regulate DNA double strand break repair. Mol. Cell Biol. MCB.00233-15. [Epub ahead of print]. PMID: 26283732
2. Cheng, R., Peng, J., Yan, Y., Cao, P., Wang, J., Qiu, C., Tang, L., Liu, D., Tang, L., Jin, J., Huang, X., He, F., and Zhang, P. (2014) Efficient gene editing in adult mouse livers via adenoviral delivery of CRISPR/Cas9. FEBS Lett. 588: 3954-3958. PMID: 25241167
3. Hatcher, R. J., Dong, J., Liu, S., Bian, G., Zou, Q., Contreras, A., Wang, T., Hilsenbeck, S., Li, Y., and Zhang, P. (2014) Pttg1/Securin is required for the branching morphogenesis of the mammary gland and suppresses mammary tumorigenesis. Proc Natl Acad Sci USA 111: 1008–1013. PMID: 24395789
4. Shen, B., Zhang, J., Wu, H., Wang, J., Ma K, Li, Z., Zhang, X., Zhang, P, Huang X. (2013) Generation of gene-modified mice via Cas9/RNA-mediated gene targeting. Cell Res. 23:720-3.
5. Mork, L., Maaktouk, D.M., McMahon, J. A., Guo, J. J., Zhang, P., McMahon, A. P., Capel, B. (2012) Temporal differences in granulosa cell specification in the ovary reflect distinct follicle fates in mice. Biol Reprod. 86: 37. PMID: 21976597
6. Fang, X. and Zhang, P. (2011). Aneuploidy and tumorigenesis. Semin. Cell Dev. Biol. 22(6): 595-601. PMID: 21392584.
7. Wei, Z., Peddibhotla, S., Lin, H., Fang, X., Li, M., Rosen, J. M., and Zhang, P. (2011). Early onset aging and defective DNA damage response in Cdc14b-deficient mice. Mol. Cell Biol. 31: 1470-7.
8. Li, M. Fang, X., Baker, D.J., Guo, L., Gao, X., Wei, Z., Han, S., van Derusen, J., and Zhang, P. (2010). The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis in mice. Proc Natl Acad Sci USA 107: 14188-93.
9. Li, M., Fang, X., Wei, Z., York, J. P. and Zhang, P. (2009). Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice. J. Cell Biol. 185, 983-994.
10. Huang X, Andreu-Vieyra CV, York JP, Hatcher R, Lu T, Matzuk MM, and Zhang, P. (2008). Inhibitory phosphorylation of separase is essential for genome stability and viability of murine embryonic germ cells. PLoS Biol. 6, e15.
11. Li, M., Shin, Y. H., Lin, F., Klann, E. and Zhang, P. (2008). The adaptor protein of the anaphase promoting complex Cdh1 plays an essential role in maintaining replicative life span and in learning and memory. Nat Cell Biol. 10, 1083-3089.
12. Li, M., York, J. P., and Zhang, P. (2007). Loss of Cdc20 causes a securin-dependent metaphase arrest in two-cell mouse embryos. Mol. Cell Biol. 27, 3481-8.
13. Peng, X., York, J.P., and Zhang, P. (2006). A transgenic approach for RNA interference-based genetic screening in mice. Proc Natl Acad Sci USA 103, 2252-2256.
14. Huang, X., Tran, T., Zhang, L., Hatcher, R., Zhang, P. (2005). DNA damage induced mitotic catastrophe is mediated by the Chk1-dependent mitotic exit DNA damage checkpoint. Proc Natl Acad Sci USA. 102:1065-70.
15. Huang, X., Hatcher, R., York, J.P., and Zhang, P. (2005). Securin and separase phosphorylation act redundantly to maintain sister chromatid cohesion in mammalian cells. Mol Biol Cell 16: 4725-32
16. Zhang, P., Liu, M., and Elledge, S. (2002). Towards genetic genome projects: genomic library screening and gene targeting vector construction in a single step. Nature Genet. 30, 31-39.