Joaquin Espinosa

Mechanisms of transcriptional regulation in the p53 network.

The p53 transcription factor protects cells from malignant transformation, and the development of most tumors is associated with loss of p53 function. The p53 transcriptional network is activated in response to potentially oncogenic signals, such as DNA damage, activation of oncogenes, and hypoxia. Upon activation, p53 manifests its tumor suppressor activity by inducing cell cycle arrest, apoptosis, senescence and block of angiogenesis. These properties are exploited in some anti-cancer therapies by triggering a p53 response through genotoxic stress. Many current research efforts are aimed at restoring or activating p53 in cancer cells for their selective elimination by more elegant means, such as non-genotoxic inhibition of the p53 repressor MDM2. However, little is known about the mechanisms that define whether a cancer cell dies or not in response to p53 activation.

The p53 transcriptional response is intriguingly complex. How cells react to p53 activation varies greatly depending on the nature of the activation signal and cellular context. It is now evident that p53 employs multiple stimulus-, cell type- and promoter-specific mechanisms of transcriptional regulation, and that such mechanistic diversity may provide the specificity required to tailor a specific response to a given stimulus. The goal of our research program is to decipher how this mechanistic diversity is achieved at the molecular level in cells. In the long term, this knowledge will enable us to devise ways to manipulate this regulatory network for therapeutic purposes.

We employ both cell-based and cell-free biochemical studies to investigate the regulation of multiple p53 target genes involved in distinct pathways. We have discovered the existence of gene- and stimulus-specific transcriptional coregulators that collaborate with p53 to regulate its target genes. Such differential cofactors act at distinct steps of the transacitivation process, and include histone modifying enzymes, transcriptional cyclin-dependent protein kinases, subunits of the Mediator complex, elongation factors and RNA processing factors.
 We aim to define how this combinatorial use of transcriptional coregulators helps to orchestrate alternative cellular responses to oncogenic stimuli.