Home Faculty and Research Faculty by Name Astar Winoto

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 apoptosis and proliferation, two fundamental events that take place during development of most cell types and play important roles in tumorigenesis.  We are interested in how these two seemingly opposite processes can influence each other and how tumors arise when cells undergoing uncontrolled proliferation have also overcome the tendency to undergo apoptosis. We are using a combination of biochemical and mouse transgenic/gene targeting approaches and are developing an in vitro model of T lymphocyte differentiation using human embryonic stem cells.  More recently, our lab is also using pathogens to understand how the mouse immune system handles infection and why proteins involved in apoptosis also play an important role in innate immunity. 

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 also has a role in proliferation. FADD^-/- T cells are defective in T cell receptor (TCR)-stimulated proliferation and exhibit abnormal regulation of cell cycle proteins. We showed that regulation of FADD phosphorylation is crucial for its function in cell cycle progression. Current projects include biochemical characterization of FADD-associated proteins involved in regulating the balance between proliferation and apoptosis and in innate immunity.

TRAIL (TNF- related apoptosis inducing ligand) is a cytokine that can kill a variety of tumor cells but leave normal cells largely intact. However, the physiological function of TRAIL and its receptor (TRAIL-R) remains unclear. By generating TRAIL-R deficient mice and challenging them with a variety of pathogens, we found that TRAIL-TRAIL-R pathway plays a negative role in innate immunity.  Understanding how dendritic cells/macrophages respond to pathogens when TRAIL-R is absent and how TRAIL-R signals in these cells is the focus of the current studies.

PTEN is a lipid phosphatase that negatively regulates PI₃ kinase.  Deletion of this PTEN tumor suppressor locus is frequently detected in human cancer.  T-cell specific PTEN-deficient mice succumb to lymphomas by 16 weeks of age. We are using this lymphoma mouse model to elucidate how anti-apoptotic and senescent pathways contribute to tumorigenesis.  

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.

Human embryonic stem cell lines offer unprecedented opportunity to develop potential tools for disease treatment and basic research.   We are developing an in vitro system of T cell differentiation from human embryonic stem cells.  The eventual goal is to generate sufficient suppressor T regulatory cells that can potentially be used to treat a wide variety of autoimmune diseases.   The molecular requirements for lineage decision toward CD4, CD8 T cells or T regulatory cells will also be studied.

Selected Publications

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. In Press]

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]

TRAIL-R as a negative regulator of innate immune cell responses [Diehl, G.E., Yue, H. H., Hsieh, K., Kuang, A.A., Ho, M., Morici, L., Lenz, L.L., Cado,D., Riley, L.W. and Winoto, A. (2004) Immunity, 21, 877-889]

Essential Role of Survivin, an Inhibitor of Apoptosis Protein, in T Cell Development, Maturation, and Homeostasis [Xing, Z., Conway, E. M., Kang, C., and Winoto, A. (2004). J. Exp. Med. 199, 69-80]

A Function of Fas-Associated Death Domain Protein in Cell Cycle Progression Localized to a Single Amino Acid at Its C-Terminal Region [Hua, Z.C., Sohn, S.J., Kang, C., Cado, D. and Winoto, A. (2003) Immunity 18, 513-521]

Nuclear Hormone Receptors in T lymphocytes [Winoto, A. and Littman, D.R. (2002) Cell 109, S57-S66]

Last Updated 2007-08-03