beth israel deaconess medical center a harvard medical school teaching hospital

Find a Doctor

Request an Appointment

Smaller Larger

Wenyi Wei Lab

Aberrant cell cycle regulation leads to cancer development. Proper cell cycle transitions are driven by waves of ubiquitin-dependent degradation of key cell cycle regulators by APC or SCF, the two major E3 ligase complexes. SCF is active from late G1 phase until G2 phase and mediates the ubiquitination of G1 cyclins and Cdk inhibitors, while APC is active from late G2 phase to mid-G1 phase, and is responsible for degradation of mitotic cyclins, securin, and geminin.

My previous research demonstrated that APC/cdh1 complex ubiquitinates and thus targets Skp2 for degradation in early G1 phase. This finding provides important insights into why SCF and APC activity is mutually exclusive and how the orchestration of SCF and APC activity affects cell cycle progression. More importantly, it also impinges on the function of Cdh1 as a tumor suppressor. I am also interested in understanding how SCF complexes regulate the G1-S transition by degradation of their specific substrates. More recently, I discovered that Fbw7 regulates the degradation of c-Jun in a GSK-3 phosphorylation dependent manner. My results assign a biological significance to the v-Jun S243F point mutation and also underscore the important function of Fbw7 in both cell proliferation and tumor suppression.

The major focus of research in my new laboratory will be aimed at understanding how APC and SCF activities contribute towards cell cycle regulation and subsequent tumor formation. More specifically, I am interested in elucidating the underlying mechanisms that define the oscillation of APC and SCF activity in different cell cycle phases. Currently I am pursuing the underlying mechanisms that timely regulate APC/Cdh1 activity in different cell cycle phases. Additionally, I am also interested in understanding whether other layers of crosstalk between the APC and SCF complex exist. Furthermore, I would like to identify novel downstream targets for both APC and SCF complexes, which will help pinpoint their functions in both cell cycle control and tumor formation. To this end, I have developed biochemical purification approaches that would allow me to identify novel downstream targets for APC/Cdh1 and SCF/Fbw7 complexes. In addition, I am also interested in defining the tumor suppressor function of Cdh1 utilizing conditional Cdh1 knockout mice. To achieve these goals, my lab will use multidisciplinary approaches including biochemical and genetic analysis. In the long term, I hope that a better understanding of the multilayer regulation of the delicate proteolysis pathways will lead us to the design of more efficient intervention strategies to combat cancer and other diseases.

Selected Recent Publications

Wei, W., Jin, J., Schlisio, S., Harper, J. W., and Kaelin, W. G., Jr., (2005) v-Jun escapes Fbw7 mediated protein degradation by disruption of GSK3-dependent phosphorylation. Cancer Cell 8(1): 25-33

Lee, S., Nakamura, E., Yang, H., Wei, W., Linggii, M. S., Sajan, M. P., Farese, R. V., Freeman, R. S., Carter, B., D., Kaelin, W. G. Jr. and Schlisio, S. (2005) Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 8(2): 155-67.

Wei, W.*, Ayad, N. G.*, Wan, Y., Zhang, G.-J., Kirschner, M. W. and Kaelin, W. G., Jr. (2004) Degradation of the SCF component Skp2 in cell cycle G1 by the anaphase promoting complex. Nature 428: 194-8.

Zhang, G.-J., Safran, M., Wei, W., Sorensen, E., Lassota, P., Zhelev, N., Shapiro, G. and Kaelin, W. G., Jr. (2004) Bioluminescent imaging of Cdk2 inhibition in vivo. Nature Medicine 10(6):643-8.

Wei, W., Jobling, W. A., Chen, W., Hahn, W. C. and Sedivy, J. M. (2002) Abolition of cyclin-dependent kinase inhibitor p16Ink4a and p21Cip1/Waf1 functions permits Ras-induced anchorage-independent growth in telomerase-immortalized human fibroblasts. Molecular and Cellular Biology 23(8):2859-70.

Contact Information

Wenyi Wei Ph.D.
Beth Israel Deaconess Medical Center
E/CLS 534
330 Brookline Avenue
Boston, MA 02215