Analysis and biological relevance of c-Jun activation

Cells are constantly exposed to variety of extracellular signals that are integrated and co-ordinated, thus resulting in the appropriate cellular response. Most signals are transduced to the cellular interior via signalling cascades culminating in the activation of transcription factors, which are master switches turning "on" and "off" genetic responses. Very often, activation of the same transcription factor results in varied and seemingly opposite cellular responses, which appear to depend on the cell-type and signal context. How the various physiological outcomes are determined by the activation of a transcription factor is not very well understood at the molecular level. Understanding the mechanisms by which cell-fate is determined in response to various stimuli by the use of a small set of transcription factors is of utmost importance in gaining insights into the functioning of a cell, and has far- reaching implications in the treatment of pathological conditions such as cancer. The transcription factor c-Jun (a subfamily of AP-1 [activator protein 1]) co-operates with different cellular co- factors to bring about the various distinct biological processes. Thus a systematic analysis of how c-Jun is involved in regulating cellular processes such as proliferation and apoptosis is of paramount importance in understanding the biology of c-Jun and would provide nodal points for therapeutic interventions in pathological states. As such the specific aims of this proposal are: 1) To generate a cellular system to assess the role of c-Jun in regulating various cellular processes; 2) To identify cellular co-factors which co-operate with c-Jun in regulating proliferation and apoptosis; 3) To identify targets of unphosphorylated and phosphorylated c-Jun; 4) To identify other c-Jun activating kinases.