Astar Winoto

Director of Cancer Research Laboratory and Professor of Immunology and Pathogenesis

Lab Homepage: http://mcb.berkeley.edu/labs/winoto/

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Research Interests

Our lab is interested in the molecular mechanisms of cell death (apoptosis and programmed necrosis), T cell development and innate immunity. We are using a combination of biochemical, molecular biological and mouse transgenic/gene targeting approaches in our studies.

Current Projects

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 and caspase-8 are also negative regulators of an alternative form of cell death called necroptosis (programmed necrosis). Loss of FADD leads to resistance to apoptosis but FADD-deficient cells undergo necroptosis instead. Current projects are aimed to understand the physiological role of necroptosis in the immune system.

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 and Nor-1 can also initiate apoptosis by translocating to mitochondria and converting the anti-apoptotic Bcl-2 protein into a pro-apoptotic molecule. Current projects are aimed to understand this novel mechanism of cell death.

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 changes first detected in immature thymoyctes  at 8-9 weeks of age. Changes include activation of the AKT pathway and c-myc translocation.  Transient elimination of immature thymocytes in adult mice led to a significant rescue of these mice from lymphoma and lethality.  We are using this model to understand the molecular steps of lymphomagenesis.

Selected Publications

Fas-associated death domain (FADD) and the E3 ubiquitin-protein ligase TRIM21 interact to negatively regulate virus-induced interferon production [Young*, J. A., Sermwittayawong*, D., Kim, H., Nandu, S., An, N.S., Erdjument-Bromage, H., Tempst, P., Coscoy, L. and Winoto, A. (2011) J. Biol. Chem. 286, 6521-6531. *co-authorship]

FADD is a negative regulator of T cell receptor-mediated necroptosis [Osborn, S. L., Diehl, G., Hans, S-J., Xue, L., Kurd, N., Hsieh, K, Cado, D., Robey, E.A. and Winoto, A. (2010) Proc. Natl. Acad. Sci. USA. e107, 13034-13039]

Protein Kinase C regulates mitochondrial targeting of Nur77 and its family member Nor-1 in thymocytes undergoing apoptosis [Thompson, J., Burger, M., Whang, H. and Winoto, A. (2010) Eur. J. Immunol. 40, 2041-2049]

FoxM1, a Forkhead transcription factor is a master cell cycle regulator for mature but not immature mouse T cells [Xue, L, Chiang, L., He, B., Zhao, Y-Y, and Winoto, A. (2010) PLOS One, 5 (2):e9229]

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. (2010) J. Biol.Chem. 285, 7556-7565]

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] 

Last Updated 2011-08-05