Ted Hupp - Overview

I. Activation of p53-dependent transcription and tumour suppression.
P53 is a tumour suppressor gene that is mutated in the majority of human cancers. The tumour suppressor activity of p53 is linked to its function as a transcription factor, where it changes the expression of gene products implicated in growth control and apoptosis (1). Transcription driven by p53 protein is controlled post-translationally by protein kinase pathways that can regulate its DNA binding function (2, 3) and by modulating p53 protein-protein interactions with components of the transcriptional machinery (4, 5). Our research team aims to identify these p53-activating kinases to determine how they are regulated and how they bring about tumour suppression by p53. The identification of such novel regulatory enzymes that can control p53 function has led to the formation of assays that can be adapted for high-throughout screening for the isolation of small molecules that can be used to modify the p53 response.

II. Developing Cancer Progression Models.
Injury to epithelial cells in the gastrointestinal tract by environmental damaging agents is a contributing factor in the development of cancer. We are interested in determining the enzymatic processes whereby normal epithelial cells either repair damage or protect themselves from injury and how dysregulation of these signalling cascades contributes to cancer development. Mutations in the p53 gene can be an early genetic alteration in the development of oesophageal cancer and stresses such as acid reflux are thought to play a role in the selection of cells containing mutations in p53. We have examined the basic stress-protein responses in squamous epithelial cells, leading to the discovery of a novel stress-protein pathway operating in human epithelial cells, including proteins such as SEP53 and Anterior gradient-2 (6). Future work will center around studying regulation of these novel stress-responses and how they integrate with p53 thus modulating the rate of cellular injury.