Research Faculty

Address
1130 St. Nicholas Avenue
ICRC# 609A
New York, NY 10032


Phone: 212-851-5282
Fax: 212-851-5284

wg8@columbia.edu
Education and Training
1986 B.S., Biological Science, Peking University, Beijing
1995 Ph.D., Cancer Biology, Columbia University, NY
1998 Postdoc., Biochemistry, Rockefeller University, NY
Wei Gu, Ph.D.
Professor of Pathology and Cell Biology
Research Summary

The primary goal of this laboratory is to investigate the roles of protein modifications in cancer pathways. In addition to phosphorylation, ubiquitination and acetylation are now recognized as major protein modifications in cancer pathways. Indeed, small molecule inhibitors of deacetylases and proteasome such as SAHA and Bortezomib have recently been approved by the FDA for cancer therapy, which further validates the importance of these modifications in human cancer. For the past several years, our laboratory has played a leading role in the field to discover reversible protein modifications (acetylation and ubiquitination) of the p53 tumor suppressor as critical events in stress responses and tumorigenesis. However, the precise roles and mechanisms of these modifications are still not well understood. We plan to further dissect molecular basis of these dynamic interplays and identify novel factors in controlling the key events in cancer pathways.

Project I: Ubiquitination in tumor suppression pathways

Tumor development is a multi-step process that depends upon the successive activation of oncogenes and inactivation of tumor suppressor genes. p53 is mutated in about 50% of human tumors and the p53 protein is known as a "guardian of the genome" because of its crucial role in coordinating cellular responses to varies types of stress. The tumor suppression effects of p53 are mediated by a number of mechanisms including cell cycle arrest, apoptosis, DNA repair, cell metabolism and autophagy. p53 is tightly regulated, such that its protein product usually exists in a latent form, and at low levels, in unstressed cells. However, the steady-state levels and transcriptional activity of p53 increase dramatically in cells that sustain various types of stress. While the precise mechanisms of p53 activation are not fully understood, they are generally thought to involve post-translational modifications of the p53 polypeptide. Ubiquitination regulates a diverse spectrum of cellular processes by providing a specific signal for intracellular protein degradation as well as some degradation-independent functions. It is well accepted that the ubiquitin-proteasome pathway plays a major part in the scope of p53 regulation; however, it is becoming more apparent that the role of ubiquitination in the balance of p53 is not as simple as once thought. We are currently working on several important issues in this area: (1) the precise mechanism of p53 stabilization in vivo; (2) identification of additional key factors in regulating p53 ubiquitination; (3) mechanistic studies of mono-ubiquitination mediated nuclear export of p53; (4) key deubiquitinases in human cancer.

Project II: Acetylation of non-histone proteins in cancer and aging

p53 promotes tumor suppression primarily by serving as a transcription factor. Indeed, a number of genes involved in cell growth arrest, apoptosis, metabolism, autophagy or DNA repair have already been identified as direct p53 targets. The importance of its transcriptional activity is underscored by the fact that most tumor-associated p53 mutations occur within the domain responsible for sequence-specific DNA binding. However, it still remains unclear how the p53-mediated transcription program is controlled. In our early studies, we showed that CBP/p300, a protein possessing histone acetyl-transferase (HAT) activity, serves as a coactivator of p53 that potentiates its transcriptional activity and biological functions. At the time, it was widely accepted that histone acetylation stimulates the initiation of RNA transcription and that transcription factors can modulate gene expression by recruiting HAT activity. However, we discovered that p53 is the first example as a non-histone substrate for histone acetyl-transfereases. This study led to the notion that acetylation is a general protein modification for the regulation of non-histone proteins. Moreover, we have identified several additional important factors in cancer pathways regulated by acetylation such as FOXO family proteins, E2F1, and BCL-6. Acetylation of p53 is also reversible in the presence of deacetylases such as HDAC1 and SIRT1 and the dynamic regulation of non-histone proteins by acetylation and deacetylation is now verified in the studies of many cellular factors. Nevertheless, the precise roles of acetylation in modulating the functions of non-histone proteins need to be defined and the molecular mechanisms of acetylated-mediated effects remain to be further elucidated. We are now focusing on several important issues in this area: (1) dissecting the molecular basis of the p53-mediated transcriptional program; (2) identification of key regulators in modulating p53-dependent transcriptional activation; (3) mechanisms of p53 acetylation-mediated functional consequences; (4) regulation of the Sirt1 deacetylase in cancer and aging.

Selected Publications

1. Luo, J, Su, F., Chen, D., Shiloh, A., and Gu, W. (2000) Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408, 377-381.

2. Luo, J., Nikolaev, A. Y., Imai, S., Chen, D., Su, F., Shiloh, A., Guarente, L., and Gu, W. (2001) Negative control of p53 by Sir2a promotes cell survival under stress. Cell. 107, 137-148.

3. Li, M., Chen, D., Shiloh, A., Luo, J., Nikolaev, A. Y., Qin, J., and Gu. W. (2002). Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416, 648-653.

4. Nikolaev, A. Y., Li, M., Puskas, N., Qin, J., and Gu, W. (2003). Parc: a cytoplasmic anchor for p53. Cell 112, 29-40.

5. Li, M., Brooks, C, Wu-Baer, F., Chen, D., Baer, R., and Gu, W. (2003). Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302, 1972-5.

6. Li M, Brooks CL, Kon N, and Gu, W. (2004). A Dynamic Role of HAUSP in the p53-Mdm2 Pathway. Mol. Cell, 13, 879-86.

7. Chen, D., Kon, N., Li, M., Zhang, W., Qin, J., and Gu, W. (2005) ARF-BP1 is a critical mediator of the ARF tumor suppressor. Cell. 121,1071-83.

8. Tang, Y., Luo, J., Zhang, W., and Gu, W. (2006) Tip60-dependent acetylation of p53 modulates the decision between cell cycle arrest and apoptosis. Mol. Cell 24, 827-839.

9. Zhao, W., Kruse, JP, Tang, Y., Jung, S., Qin, J., and Gu, W. (2008) Negative Regulation of the Sirt1 deacetylase by DBC1. Nature 451, 587-590.
10. Kruse, J.P. and Gu, W. (2008) Snapshot: p53 post-translational modifications. Cell 133, 930.

11. Tang, Y., Zhao, W., Chen, Y., Zhao, Y., and Gu, W. (2008) Acetylation is indispensible for p53 activation. Cell 133, 612-626.

12. Kruse JP, Gu W. (2009) Modes of p53 regulation Cell. 137, 609-622.

13. Chen, D., Shan, J., Zhu, W., Qin, J. and Gu, W. (2010) Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses. Nature. 464, 624-627.

14. Li M, Gu W. (2011) A Critical Role for Noncoding 5S rRNA in Regulating Mdmx Stability. Mol Cell, 43, 1023-32. PMID: 21925390.

15. Li T., Kon N., Jiang L., Tan M., Ludwig T., Zhao Y., Baer R., and Gu W. (2012) Tumor suppression in the absence of p53-mediated cell cycle arrest, apoptosis, and senescence. Cell, 149, 1269-1283. PMID: 22682249.

16. Chen, D., Kon, K., Zhong J., Zhang, P., Yu, L., and Gu, W. (2013) Differential effects on ARF stability by normal vs. oncogenic levels of c-Myc expression. Mol Cell, 51-46-56. PMID: 23747016

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