BBS Faculty Member - Wenyi Wei

Wenyi Wei

Department of Pathology

Beth Israel Deaconess Medical Center
CLS Building Room 637
330 Brookline Avenue
Boston, MA 02115
Tel: 617-735-2495
Fax: 617-735-2480
Email: wwei2@bidmc.harvard.edu
Lab Members: 6 postdoctoral fellows



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. 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. 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 laboratory is 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.


















Last Update: 6/18/2014



Publications

Gao, D., Inuzuka, H., Tseng, A., Chin, R., Toker, A. and Wei, W. (2009) Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APC/Cdh1-medaited Skp2 destruction. Nature Cell Biology 11(4): 397-408

Inuzuka, H., Tseng, A., Gao, D., Zhai, B., Zhang, Q., Shaik, S., Wan, L., Ang, X.L., Mock, C., Yin, H., Stommel, J.M., Gygi, S., Lahav, L., Asara, J., Xiao, Z., Kaelin, W. G., Jr., Harper, J. W. and
Wei, W. (2010) Phosphorylation by Caesin Kinase I promotes the turnover of the Mdm2 oncoprotein via the SCFb-TRCP ubiquitin ligase. Cancer Cell 18(2): 147-159

Inuzuka, H., Shaik, S., Onoyama, I., Tseng, A., Gao, D., Maser, R., Zhai, B., Wan, L., Gurierrez, A., Lau, A., Xiao, Y., Christie, A., Aster, J., Settleman, J., Gygi, S, Kung, A. L., Look, T., Nakayama, K. I., DePinho, R. A. and
Wei, W. (2011) SCFFbw7 regulates cellular apoptosis by targeting the Mcl-1 oncoprotein for ubiquitination and destruction. Nature 471:104-9.

Inuzuka, H.*, Gao, D.*, Finley, L., Yang, W., Wan, L., Fukushima, H., Chin, Y. C., Zhai, B., Shaik, S., Lau, A. W., Wang, Z., Gygi, S. P., Nakayama, K., Teruya-Feldstein, J., Toker, A., Haigis, M., Pandolfi, P.P. and
Wei, W. (2012) Acetylation-Dependent Regulation of Skp2 Function. Cell 150(1): 179-193

Liu, P., Gao, D., Wan, L., Inuzuka, H., Fukushima, H., Lazorchak, A. S., Wang, Z., Yu, Y., Arojo, O., Liu, D., Zhai, B., Yuan, M., Shai, S., Gygi, S. P., Asara, J. M., Blenis, J., Su, B. and
Wei, W. (2013) mTORC1/S6K negatively regulates mTORC2 integrity and activity by phosphorylation of Sin1. Nature Cell Biology 15(11): 1340-1350

Liu, P., Bagley, M., Inuzuka, H., Ginzberg, M., Gao, D., Tsou, P., Kim, B. M., Wan, L., Singh, A., Zhai, B., Yuan, M., Wang, Z., Gygi, S. P., Asara, J. M., Lee, T. H., Lu, K. P., Toker, A., Kirschner, M. W., Cantley, L. and
Wei, W. (2014) Cell cycle-regulated activation of Akt kinase by phosphorylation of its carboxyl-terminal terminus. Nature 508(7497):541-5

Wan, L., Tan, M., Yang, J., Inuzuka, H., Wu, T., Liu, J., Dai, X., Malumbres, M., Kirschner, M. W., Sun, Y. and
Wei, W. (2014) APCCdc20 suppresses apoptosis through targeting Bim for ubiquitination and destruction. Developmental Cell 29(4):377-91



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