): Apoptosis is a process fundamental to the development of multicellular organisms and plays a critical role in immune response. Appreciation for the importance of TNFR-related cytokine receptors (TNFR, Fas, DR4 and DR5) in regulating apoptosis has increased during the past several years. Fas is a prototype for apoptosis-inducing TNFR-like receptors and functions primarily in lymphocytes. Essential downstream mediators of Fas function (FADD and Daxx) have been identified by their ability to bind to the Fas cytoplasmic domain. It is now clear that FADD initiates a cascade of proteases, known as caspases, which may mediate apoptosis by causing nuclear lamin breakdown leading to nuclear fragmentation. The applicant have recently identified Daxx, a necessary component for Fas-induced apoptosis, which mediates the Fas signal through an alternative pathway involving the activation of Jun N-terminal Kinase (JNK). Interestingly, by structure and function analysis of Daxx, the applicants demonstrated that Daxx mediates both a pro-apoptotic (mediated by JNK) and an antiapoptotic (mediated by Akt) effect. Thus, Daxx appears to be involved in the balance between life and death signals. However, the molecular mechanisms by which Daxx mediates these functions need to be elucidated. Additionally, the signaling events that mediate Fas-induced cytoskeletal alterations and membrane blebbing are not known. Rho family proteins are critical regulators of cytoskeletal organization in Eukaryotic cells, and their role in Fas-induced signaling will be studied in this proposal. The overall goal of this proposal is to determine the molecular basis of signaling by Fas and related death receptors, with an emphasis on the pathways induced by Daxx.
The specific aims of this proposal are (1) to determine the role of Daxx and Daxx-induced signals in death receptor functions, (2) to identify novel downstream effectors of Daxx, and (3) to determine the physiological role of Daxx. The results of such studies may shed light on how cells decide to live or die, and may provide targets for the mechanism-driven design of therapeutic agents for cancer and autoimmune diseases.
| Ghaffari, Saghi; Jagani, Zainab; Kitidis, Claire et al. (2003) Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc Natl Acad Sci U S A 100:6523-8 |
| Pal, S; Datta, K; Khosravi-Far, R et al. (2001) Role of protein kinase Czeta in Ras-mediated transcriptional activation of vascular permeability factor/vascular endothelial growth factor expression. J Biol Chem 276:2395-403 |
