AP2α alters the transcriptional activity and stability of p53

• Published in: Oncogene Vol. 25; no. 15; pp. 2148 - 2159
• Main Authors: STABACH, P. R, THIYAGARAJAN, M. M, WOODFIELD, G. W, WEIGE, R. J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 06-04-2006; Nature Publishing Group
• Subjects: Alleles; Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cyclin-dependent kinase inhibitor p21; Fundamental and applied biological sciences. Psychology; Metastases; Molecular and cellular biology; Molecular genetics; p53 Protein; Point mutation; Transcription; Transcription. Transcription factor. Splicing. Rna processing; Tumors; AP2α; TP53 Gene; Stability; Transcription; CDKN1A Gene; AP-2; Carcinogenesis; P21; Tumor suppressor gene; P53
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209250

AP2α and p53 form nuclear complexes that establish a functional partnership, which regulates the expression of certain genes involved in cell growth and metastasis. The growth effects of AP2α are mediated through p21WAF1/CIP1 and the ability for AP2α to coactivate p21 requires p53. Herein, we have localized the AP2-binding region of p53 to amino acids 305–375. Analysis of 26 distinct p53 alleles established a correlation between AP2α binding and transcriptional coactivation. The L350P point mutation was the only nonbinding allele that retained normal transcriptional activity by reporter assay. Although both wild-type and L350P alleles facilitated binding of AP2α to the p21 promoter, the L350P allele was significantly reduced in its ability to induce the endogenous p21 gene, demonstrating a striking difference in activity comparing reporter assays with activation of endogenous p53 target genes. Interestingly, expression of AP2 in the absence of radiation repressed p53-mediated induction of p21 and this effect was explained by a reduction in p53 stability induced by AP2α overexpression. We conclude that AP2α has competing effects on p53 activity through coactivation and decreased stability. These findings may provide a mechanism to account for the discrepancies reported for the association between AP2 and p21 expression in tumor tissue.