Dissection of the functional interaction between p53 and the embryonic proto-oncoprotein PAX3.
Studies from murine embryogenesis and cancer cells derived from human melanomas have identified a critical role for the transcription factor PAX3 in the suppression of p53 protein accumulation and p53-dependent apoptosis. Here we show, using a well-defined over-expression system, that PAX3 suppresses p53-dependent transcription from promoters of p53-responsive genes, notably BAX and HDM2-P2, and reduces p53 protein abundance by promoting its degradation. We define the functional domains of PAX3 required for this activity, and furthermore present evidence that PAX3-dependent inhibition of p53 is independent of binding of the N-terminal domain of p53 to HDM2, the primary negative regulator of cellular p53 activity.
Cancer Sciences Division, School of Medicine, University of Southampton, UK.
Timothy J
TJ
Underwood
Jay
J
Amin
Karen A
KA
Lillycrop
Jeremy P
JP
Blaydes
D000818:Animals; D050437:Genes, Developmental; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2