Rapid advances in the characterization of eukaryotic genomes have led to an awareness of the increasing complexity in cellular growth controls and the mechanisms by which their deregulation contributes to cancer. Signaling pathways are interconnected through multiple effectors that determine cell fate. The tumor suppressor gene p53 is one such critical effector.
Loss of p53 function is found in most human cancers and can be an early or late event in the malignant process. Accumulating evidence indicates that p53 is induced by and plays a major role in determining cellular responses to a variety of pathophysiologic stresses. p53 functions importantly in determining cell fate decisions, including growth arrest, replicative senescence, or apoptotic cell death.
The program goals are:
- To elucidate mechanisms involved in p53 regulation and functions from novel perspectives of discoveries made within the program.
- To elucidate signaling pathways critical to cellular stress responses.
The long-term objectives of this research are:
- To understand mechanisms by which p53 integrates responses to cellular stresses at the transcriptional level and plays important roles in innate immunity and inflammation.
- To understand the role of p53 in coordinating responses to genotoxic agents, including many cancer therapeutics, in determining cell fate decisions.
Major hypotheses to be tested include the following:
- p53 mediates pro-survival signaling involved in antiviral and inflammatory responses. These pathways also affect the tumor microenvironment to influence tumor progression.
- Post-translational modifications of p53, including acetylation, methylation, ubiquitination, and phosphorylation, have differential regulatory effects on p53 transcriptional functions through interplay with other transcriptional factors.
- Protein modification of p53, such as acetylation, plays a major part in the scope of controlling p53 function by directly affecting the interactions of p53 with Mdm2/Mdmx or other undefined cellular regulators in vivo, which enables p53 to activate transcription in a promoter-specific manner.