Rapid advances in the characterization of eukaryotic genomes have led to an awareness of the complexity of cellular growth controls and the mechanisms by which the deregulation of such genomes 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. Cell fate decisions, including growth arrest, replicative senescence, or apoptotic cell death, are determined by p53.
Goals and Objectives
The Program Project p53 Regulators and Effectors aims to elucidate:
- Mechanisms involved in p53 regulation and functions
- P53 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 such responses
- The role of p53 in coordinating responses to genotoxic agents, including many cancer therapeutics, in determining cell fate decisions
Hypotheses
We are testing major hypotheses, including:
- How p53 mediates pro-survival signaling involved in novel homeostatic stress responses. These pathways also affect the tumor microenvironment to influence tumor progression.
- The role of post-translational modifications of p53, including acetylation, methylation, ubiquitination, and phosphorylation in differential regulatory effects on p53 transcriptional functions through interplay with other transcriptional factors.
- How protein modifications of p53, such as acetylation, influence the scope of p53 functions by directly affecting the interactions of p53 with Mdm2/Mdmx or other cellular regulators in vivo to influence p53 transcriptional responses.