Faculty and Research
Faculty by Name
Qing Zhong
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Qing Zhong
Assistant Professor of Biochemistry and Molecular Biology
Lab Homepage: http://mcb.berkeley.edu/labs/zhong/
Research Interests
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Apoptosis and autophagy are critical in tissue homeostasis, genome maintenance and quality control of cellular organelles. We are interested in DNA damage induced apoptosis and stress induced autophagy, two pathways involved in pathogenesis of human cancers, neurodegenerative disease, heart disease, infectious disease, and diabetes. The research projects in my laboratory are focused on (1) Upstream signaling pathway controlled by Mule in mitochondria-mediated apoptosis (this project is funded by NIH/NCI). (2) Biochemical dissection of Autophagy pathway (this project is partly funded by Ellison Medical Foundation) (3) Autophagic responses to oncogenic stress, environmental toxicants exposure, and energy crisis.
Current Projects
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Upstream signaling pathway controlled by Mule in mitochondria-mediated apoptosis
Cancer remains a major killer that impacts a large number of new patients every year. One major cause of cancer is an inappropriate response to DNA damage. Efficient elimination of DNA lesions is essential for maintaining DNA integrity and to limit their mutational and oncogenic potential. DNA damage triggers an intrinsic apoptotic pathway that is initiated from mitochondria. However, the molecular mechanisms that elicit DNA damage signals and how they are transmitted to mitochondria to initiate apoptosis is of great clinical significance, but still largely unknown. Degradation of the anti-apoptotic protein Mcl-1 is required for DNA damage-induced apoptosis, and occurs proximal to several hallmarks events in apoptosis including cytochrome c release and caspase activation. Through biochemical purification, we have cloned a novel ubiquitin ligase responsible for Mcl-1 degradation, Mule (Mcl-1 ubiquitin ligase e3). Mule was also found to regulate p53, a pivotal player in the DNA damage response and tumor suppression, thus adding another intriguing link to the apoptosis pathway. We aim to address the functions of Mule in DNA damage response through biochemical and genetic approaches. A mechanistic understanding of this pathway will help us to decipher how apoptosis becomes disregulated in cancers and to identify potential new targets for therapeutic intervention.
Biochemical dissection of Autophagy pathway
Autophagy is a cellular process that has a newly recognized role in combating cancer and many other human diseases, probably through eliminating damaged proteins and organelles. In autophagy, damaged components, including mitochondria, are sequestered into double membrane-bound structures known as autophagosomes. The autophagosome then fuses with the lysosome to initiate the degradation of the delivered cargo, and thereby recycles worn-out constituents back into reusable building blocks. Dysfunction of autophagy may lead to the retention of older, defective mitochondria that serve as a source of reactive oxygen species that can cause further damage. Genes involved in the control of autophagy have been newly identified as tumor suppressor genes. In autophagy, class III PI3 kinase (PI3K C3), a lipid kinase that catalyzes the conversion of PtdIns to PtdIns3P, is the rate-limiting factor required for the formation of autophagosomes. The gene encoding Beclin-1, a major regulatory component of this complex, meets the criteria of a classical tumor suppressor gene because it is frequently monoallellically deleted in ovarian, breast and prostate cancers. Autophagy modulation thus provides a novel direction to fighting cancers. However, a critical question about how Beclin 1 and its associated PI3K C3 complex are controlled in autophagy remains elusive.
We have recently demonstrated that Beclin 1 is specifically regulated by a novel adaptor protein, Barkor. Barkor is essential for stress-induced autophagy. Mechanistically, Barkor competes with another Beclin 1 binding protein - UVRAG for interaction with Beclin 1, and the complex formation of Barkor and Beclin1 is required for their localizations to autophagosomes. This newly defined regulatory signaling pathway might represent a potential target for drug development in the treatment of human diseases implicated in autophagic dysfunction.
Barkor is cloned in our affinity purified Beclin 1 complex in human cells. In the same complex, we have also identified two additional novel components. The functional characterization of these new players is underway. In the long run, we aim to reconstitute the PI3 kinase class III activity in autophagosome formation. We are also interested in the downstream events after autophagosome nucleation by PI3KC3, such as regulation of Atg5/Atg12/Atg16 and LC3 ubiquitin-like conjugation systems in autophagy.
Autophagic responses to oncogenic stress, environmental toxicants exposure, and energy crisis.
We are also interested in autophagic responses to oncogenic stresses, heavy metal toxicants exposure, amino acids deprivation and fatty acids stimulation. Hopefully knowledge we gain in these studies will provide insights into mechanism of pathogenesis of cancers, autoimmune disease, heart disease and type II diabetes.
Selected Publications
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Sun Q, Fan W, Chen K, Ding X, Chen S, Zhong Q. (2008) Identification of Barkor as a Mammalian Autophagy-Specific Factor for Beclin 1 and Class III Phosphatidylinositol 3-Kinase. Proc Natl Acad Sci U S A. 105(49):19211-6.
Qing Zhong: scoring a slam dunk on the autophagy court. Zhong Q. J Cell Biol. (2008) Oct 20;183(2):174-5.
JR, Kow E, Nevis KR, Lu CK, Luce KS, Zhong Q, Cook JG. (2007) Cdc6 Stability Is Regulated by the Huwe1 Ubiquitin Ligase after DNA Damage. Mol Biol Cell. 13; 3340-50.
Q, He X, Hsu JM, Xia W, Chen CT, Li LY, Lee DF, Liu JC, Zhong Q, Wang X, Hung MC. (2007) Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol. 27(11):4006-17.
Zhong Q, Gao W, Du F, Wang X. (2005) Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell, 121: 1085-1095.
Nijhawan D, Fang M, Traer E, Zhong Q, Gao W, Du F, Wang X. (2003) Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes and Dev., 17:1475-1486.
Zhong Q, Chen C-F, Chen P-L, and Lee W-H. (2002) BRCA1 facilitates microhomology-mediated end joining of DNA double strand breaks. J Biol Chem., 277: 28641-28647.
Zhong Q, Boyer TG, Chen P-L, and Lee W-H. (2002) Deficient nonhomologous end-joining activity in cell-free extracts from Brca1-null fibroblasts. Cancer Res., 62: 3966-3970.
Zhong Q, Chen C-F, Li S, Chen Y, Wang C-C, Xiao J, Chen P-L, Sharp ZD, and Lee WH. (1999) Association of BRCA1 with the hRad50-hMre11-p95 Complex and the DNA Damage Response. Science, 285: 747-750.
Last Updated 2009-05-12