Dolziel, H.H.; Pohler, E.; Craig, A.L.; Kernohan, N.; Hopwood, D.; Dillon, J.F.; Hupp, T.R.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA7
Academic Journal
The epithelial cells of the oesophagus are routinely exposed to unique environmental pressures, including thermal stress, acid and bile reflux, and dietary carcinogens, which appear to play a role in development of metaplasia, increased selection pressure for early mutation of p53, and therefore a heavy burden on stress-responsive and cell-cycle checkpoint control systems. The human oesophageal epithelium is easily accessible by endoscopy and provides a unique opportunity to integrate biochemical and clinical studies of stress protein responses relevant to understanding mechanisms of initiation of the cancer progression sequence to the intermediate Barrett's metaplasia. To begin to address these issues, we have performed a comprehensive analysis on the nature of the stress responsive systems in normal squomous epithelium and Barrett's metaplasia. We have unexpectedly found that the major stress-responsive genes (SEP53, SEP70, and Transglutaminase) of normal epithelium represent a novel stress control system generally confined to normal squamous epithelium. Strikingly, these stress responsive proteins are shown to be differentially expressed in Barrett's epithelium from different patients, thus identifying a likely epigenetic pathway involved in modulating disease progression. Transfection of the SEP53 gene into cells enhances prolifi eration as judged by colony formation assays. This ability of SEP53 to enhance proliferation is similar to oncogenic mutant p53, indicating that SEP53 functions as a proto-oncogenic survival factor. Together, these data suggest two functions for SEP53 depending upon cell type: (a) in normal epithelium, the ubiquitous expression of SEP53 suggests o role in maintaining normal tissue integrity; and (b) in patients with Barrett's metaplasia, high levels of expression of SEP53 are likely to result in enhanced cellular proliferation, whereas patients with no SEP53 are likely to have higher rates of cell death. These biochemical studies...


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