Transactivation of growth factor receptor genes by p53

Epidermal growth factor receptor (EGFr) expression has long been regarded as an indicator of malignancy in certain forms of human cancer. Therefore, it is of considerable interest that high EGFr expression has often been found to accompany p53 abnormalities. EGFr over-expression has shown significant correlation with p53 mutation status in oesophageal carcinomas (Esteve et al, 1993). p53 over-expression is strongly correlated with EGFr expression in breast cancer (Horak et al., 1991). Wright et al. (1991) found that p53 and/or EGFr over-expression was strongly associated with invasive transitional cell carcinoma of the bladder, but there was no statistically significant association between p53 and EFGr expression. Amplification of c-erbB2 was found together with mdm2 amplification in breast cancer (Fontana et al., 1994). Overexpression of p53 and erbB2 has been reported in breast cancer (Horak et al., 1991; Tsuda et al, 1993), in bladder cancer (Moch et al., 1993), and in adenocarcinoma of the stomach (Sasano et al, 1993). Although there appears to be a general association between growth factor receptors and p53 broadly in the same tumour, it is unclear whether the amplification of these markers occur concomitantly in the same cells within a tumour. Co-localisation of the proteins can occur in a proportion of cells within a tumour (Sasano et al., 1993). Unfortunately, there are too few studies of this rather important feature of co-expression. Nevertheless, it should be pointed out that wild-type p53 can transactivate the human EGFr promoter (Deb et al, 1994). It is therefore conceivable that wild-type p53 will induce EGFr expression in some cell types and possibly under specific conditions, e.g. post-G, delay for DNA repair. Since the EGFr induction effect is apparently dose-dependent (Deb et al., 1994), it is feasible that this could provide a pathway for mutant p53 proteins, which accumulate in large amounts on account of their significantly long half-life, to participate in cell proliferation. Alternatively, EGFr and p53 signal transduction may follow independent paths, because EGFr expression can also occur where no concomitant increase in p53 expression occurs (Gilhus et al, 1995).

0 0

Post a comment