Abstract
Direct interactions between the genes that regulate development and those which regulate the cell cycle would provide a mechanism by which numerous biological events could be better understood. We have identified a direct role for PAX5 in the control of p53 transcription. In primary human diffuse astrocytomas, PAX5 expression inversely correlated with p53 expression. The human p53 gene harbours a PAX binding site within its untranslated first exon that is conserved throughout evolution. PAX5 and its paralogues PAX2 and PAX8 are capable of inhibiting both the p53 promoter and transactivation of a p53-responsive reporter in cell culture. Mutation of the identified binding site eliminates PAX protein binding in vitro and renders the promoter inactive in cells. These data suggest that PAX proteins might regulate p53 expression during development and propose a novel alternative mechanism for tumour initiation or progression, by which loss of p53 function occurs at the transcriptional level.
Highlights
One aim of genes that are involved in controlling developmental processes is to influence the cell cycle in time and space
PAX5 expression in human astrocytomas We have previously demonstrated a positive correlation between PAX5 expression and the level of malignancy in
PAX2, 5 and 8 modulate p53-dependent reporter activity In an attempt to investigate a possible relationship between PAX5 and p53, we studied the effect of PAX proteins on the activity of endogenous p53 in cell culture
Summary
One aim of genes that are involved in controlling developmental processes is to influence the cell cycle in time and space. By manipulating the cell cycle, developmental regulatory genes direct cellular growth and differentiation, and permit embryogenesis to proceed in an exquisitely controlled manner Such genes are likely candidates for involvement in oncogenesis, owing to their effects on cell growth. The p53 tumour suppressor gene encodes a nuclear transcription factor and is the most commonly mutated gene in human cancer far identified (Oren, 1992; Donehower and Bradley, 1993). These mutations commonly occur in its DNA binding domain, rendering it unable to transactivate its target genes (Prives, 1994). We discuss potential implications of these results for oncogenesis and we present a model for PAX-mediated regulation of the cell cycle and of specific differentiation events during embryonic development
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