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Ying E. Zhang, Ph.D.

Portait Photo of Ying Zhang
Laboratory of Cellular and Molecular Biology
Senior Investigator
Center for Cancer Research
National Cancer Institute
Building 37, Room 2056B
Bethesda, MD 20892-4256
Phone:  
301-496-6454
Fax:  
301-496-8479
E-Mail:  
zhangyin@mail.nih.gov

Biography

Dr. Ying Zhang received her B.S. degree in Chemistry and M.S. degree in Biochemistry from Peking University, China. She obtained her Ph.D. degree from University of Wisconsin-Madison in 1995 and completed her postdoctoral training with Dr. Rik Derynck in University of California, San Francisco. She joined the Laboratory of Cellular and Molecular Biology in 2000 as a tenure-track investigator and became a senior investigator in 2007.

Research

Molecular mechanisms of TGF-beta signaling pathway

TGF-β and its related factors regulate a broad range of cellular functions, including proliferation, differentiation, apoptosis, migration and adhesion, and play very important roles in cancer and many other diseases. Our research has focused on three aspects of TGF-β signaling in an attempt to gain further appreciation of its regulation, mechanisms of action and function in development and tumorigenesis.

The first area of our research focused on the regulation of TGF-β signaling modulators by post-translational modification that translate quantitative difference in ligand concentration into proportional transcriptional output, particularly the ubiquitin modification catalyzed by Smurf1 and Smurf2, which are HECT-domain E3 ligases. Resorting to mouse genetic approaches, we generated knockout alleles of both Smurf1 and Smurf2 genes to address their roles under physiological conditions. We found that Smurf1 and Smurf2 have both common and unique functions during embryogenesis and in maintaining adult physiological homeostasis. Our earlier work on characterizing Smurf1 knockout mice revealed a novel function of Smurf1 in the regulation of osteoblast function and bone homeostasis (Cell 2005), suggesting that targeting Smurf1 may prove to be an effective strategy for treating age-related bone losses in osteoporosis. Our recent work on characterizing Smurf2 knockout mice clarified contradictory reports in the literature about Smurf regulation of TGF-β signaling by showing that Smurf2 indeed has an inhibitory role, but it does so by attenuating Smad3 activity through mono-ubiquitination rather than promoting its degradation as previously reported (EMBO J 2011). Our study also led to an unexpected discovery of a previously unrecognized function of Smurf2 as a tumor suppressor that normally maintains genomic stability by controlling epigenetic landscape of histone modifications via RNF20 (Nature Medicine 2012).

Although Smads are involved in most actions of the TGF-β superfamily, activated TGF-β receptors also transduce signals through other intracellular signaling pathways, especially those mediated by MAP kinases. The second area of research of our research focuses on the specific mechanism by which TGF-β receptors activate non-Smad pathways, and the biological significance of these Smad-independent pathways in TGF-β signaling. Previously, we found that TGF-β receptor can signal through multiple intracellular pathways, obtained definite biochemical proof for the long-suspected Smad-independent receptor signaling mechanism (EMBO J 2002), and further identified TRAF6 as the mediator of this Smad-independent signaling conduit that exerts its control of downstream gene expression via activation of the JNK/p38 kinase (Molecular Cell 2008). These findings shed light on a decade-old puzzle of why tumor cells, which often develop a resistance to TGF-β-induced growth inhibition as they progress, can retain an otherwise functional TGF-β signaling pathway. Currently we are working to identify other downstream mediators that are responsible for Smad-independent TGF-β receptor signaling. These studies could uncover novel molecular mechanisms that account for a number of Smad-independent TGF-β signaling responses.

In the third line of investigation, we created mouse liver cancer models by forced expression of Smad3 tissue-specifically in the liver using the Tet-off inducible system. we found that up-regulating Smad3 protects the liver against carcinogenic insult, and demonstrated that this tumor-protective role is afforded by the ability of Smad3 to down-regulate Bcl-2 expression via p38 kinase (Cancer Cell 2006). This finding offers a new insight into designing novel approaches for treating the liver cancer.

This page was last updated on 3/26/2014.