AP2α alters the transcriptional activity and stability of p53

Abstract

AP2a 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 AP2a are mediated through p21 WAF1/CIP1 and the ability for AP2a 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 AP2a 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 AP2a 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 AP2a overexpression. We conclude that AP2a 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.

Dual association by TFAP2A during activation of the p21cip/CDKN1A promoter

“…3 and lanes 3, 5 and 7). Overall therefore, these findings argue against an absolute dependence on p53 by TFAP2A in upregulating p21cip expression 15,16 and instead agree with observations in HeLa cells, which are functionally null for p53, where CDKN1A was also shown to be positively regulated by TFAP2A.…”

“…Our ChIP data examining the binding of endogenous factors, therefore, provides some support for previous observations using exogenous protein expression which suggested that TFAP2A needs to interact with p53 site 1 to activate CDKN1A. 16 However, in that study the authors omitted to investigate interaction at the proximal promoter and implied that TFAP2A is wholly dependent on p53 to activate CDKN1A. Comparing our ChIP data at 24 and 48 hours, demonstrates that, while the TFAP2A interaction at the -2,250 region was observed at early stages of induction, continued expression of p21cip was associated with increased TFAP2A binding at the proximal promoter, especially in vinblastine treated cells.…”

“…15,16 Partial support for these data has come from an independent study looking at CDKN1A induction following adenovirus mediated overexpression of TFAP2A in derivatives of the HCT116 colon carcinoma line. The degree of p21cip induction upon TFAP2A overexpression in HCT116 p53 -/-cells was significantly reduced compared to that seen with wild-type cells.…”

Activator protein‐2 in carcinogenesis with a special reference to breast cancer—A mini review

“…74,85 This may be explained by the observation that only wt p53 seems to be capable to properly facilitate AP-2a binding and coactivation of the p21 WAF1 gene expression, whereas the activity using mutant p53 is reduced or nonexisting. 86 In addition, AP-2a has competing effects on p53 activity through coactivation and decreased stability. 86 Recently, AP-2a expression, for example, in breast and lung cancers has been related to high sensitiveness to chemotherapeutic drugs due to massive induction of apoptosis in AP-2a highly expressing cells.…”

The determination of changes in the expression of genes for selected specific transcriptional factors in in vitro ductal breast cancer cells under the influence of paclitaxel

“…In our study, the expression of AP2A was 3.86-fold and AP2C 2.02-fold higher in the breast cancer cells treated with 60 ng/ml doses of paclitaxel than in the control cells. Expression microarray results in human breast carcinoma cells indicate that genes for activating enhancer-binding protein 2alpha (AP-2alpha) and activating enhancer-binding protein 2gamma (AP-2gamma) are targets for transcriptional activation by p53, and suggest that AP-2 proteins may mediate some of the downstream effects of p53 expression, such as inhibition of proliferation [21,22]. Expression of either AP-2alpha or AP-2gamma inhibits growth of human breast carcinoma cells in vitro.…”