Full Directory Information
Director of Cancer Research Laboratory and Professor of Immunology and Pathogenesis
Lab Homepage: http://mcb.berkeley.edu/labs/winoto/Our lab is interested in the molecular mechanisms of apoptosis and cell cycle in relationship to cancer, T cell development and innate immunity. We are using a combination of biochemical, molecular biological and mouse transgenic/gene targeting approaches in our studies.
Fas and a subset of related tumor necrosis factor (TNF) receptor family members contain a death domain in their cytoplasmic tails. Stimulation by the corresponding TNF ligand family members leads to recruitment of an adapter protein called FADD. FADD in turn recruits caspase 8, activation of which can lead to cell death. FADD is a universal adapter for all receptor-mediated death but surprisingly, FADD also has a role in proliferation and in innate immunity. Current projects include biochemical characterization of FADD-associated proteins involved in regulating the balance between proliferation and apoptosis and in the host interferon response against viral infection .
PTEN is a lipid phosphatase that negatively regulates the PI3 kinase-AKT pathway. Mutation in this PTEN tumor suppressor gene is frequently detected in human cancer. T-cell specific PTEN-deficient mice succumb to mature T cell lymphomas in spleen and lymph nodes by 16 weeks of age. However, development of lymphoma is dependent on neoplasia first detected in immature thymoyctes at 8-9 weeks of age. Transient elimination of immature thymocytes in adult mice (without affecting the mature T cell compartment) led to a significant rescue of these mice from lymphoma and lethality. We are using this model to understand why the immature thymocyte "cancer stem cells" don't become tumor and how cellular responses like senescence seen in these cells might limit tumor development.
The orphan steroid nuclear receptor Nur77 and its family member Nor-1 are two of the genes that are rapidly induced during TCR-induced apoptosis. We showed that a dominant negative Nur77 mutant can inhibit TCR-mediated apoptosis and constitutive expression of Nur77 or Nor1 leads to massive apoptosis in immature T cells. Nur77 induces transcription of several apoptotic molecules but recent data indicate that Nur77 can also initiate apoptosis by translocating to mitochondria and converting the anti-apoptotic Bcl-2 protein into a pro-apoptotic molecule. Current projects include generation of tissue specific Nor-1 deficient mice, understanding the mechanisms of Nur77-mediated apoptosis and characterizing Nur77 upstream regulatory network that involves the ERK5 MAP kinase pathway.
Coupling of the cell cycle and apoptosis machineries in developing T cells [Xue, L., Sun, Y., Chiang, L., He, B., Kang, C. Nolla, H. and Winoto, A. (2009) Submitted].
Normal Development is an Integral Part of Tumorigenesis in T-cell specific PTEN-deficient Mice [Xue, L., Nolla, H., Suzuki, A., Mak, T.W. and Winoto, A (2008) Proc. Natl. Acad. Sci. USA 105, 2022-2027]
Bcl-2 associates with the Nur77 family members and exposes its BH3 pro-apoptotic domain during Negative Selection [Thompson, J. and Winoto, A. (2008) J. Exp. Med. 205, 1029-1036]
The role of the PI3K-AKT kinase pathway in T-cell development beyond the beta checkpoint [Xue, L., Chiang, L., Kang, C., and Winoto, A. (2008) Eur. J. Immunol. 38, 3200-3207]
Non-redundant Function of the MEK5-ERK5 Pathway in Thymocyte Apoptosis [Sohn, S. J., Lewis, G. and Winoto, A. (2008) EMBO J. 27, 1896–1906]
Constitutive phosphorylation mutation in fadd results in early cell cycle defects [Osborn, S., Sohn, S.J. and Winoto A. (2007) J. Biol. Chem. 282, 22786-22792]
Apoptosis during negative selection of autoreactive lymphocytes [Sohn, S.J., Thompson, J and Winoto, A. (2007) Curr. Opion. Immunol. 19, 510-515]
Transcriptional Regulation of Tissue-specific genes by the ERK5 MAP Kinase [Sohn, S.J., Li, D., Lee, L. K. and Winoto, A. (2005) Mol. Cell Biol. 25, 8553-8566]
Phosphorylation of FADD at serine 194 by CKI-alpha regulates its non-apoptotic activities [Alappat E.C. et al (2005) Mol. Cell 19, 321-332]
Last Updated 2009-06-24