Tumor Suppressor Activity of AP2α Mediated through a Direct Interaction with p53

Abstract

The AP2 transcription factor family is a set of developmentally regulated, retinoic acid inducible genes composed of four related factors, AP2␣, AP2␤, AP2␥, and AP2␦. AP2 factors orchestrate a variety of cell processes including apoptosis, cell growth, and tissue differentiation during embryogenesis. In studies of primary malignancies, AP2␣ has been shown to function as a tumor suppressor in breast cancer, colon cancer, and malignant melanoma. In cell culture models, overexpression of AP2␣ inhibits cell division and stable colony formation, whereas, a dominant-negative AP2␣ mutant increases invasiveness and tumorigenicity. Here we show that AP2␣ targets the p53 tumor suppressor protein.Studies with chromatin immunoprecipitation demonstrate that AP2␣ is brought to p53 binding sites in p53-regulated promoters. The interaction between AP2␣ and p53 augments p53-mediated transcriptional activation, which results in up-regulation of the cyclin-dependent kinase inhibitor p21 WAF1/CIP1 . AP2␣ is able to induce G 1 and G 2 cell cycle arrest only in the presence of wild-type p53. Thus, we conclude that the tumor suppressor activity of AP2␣ is mediated through a direct interaction with p53. These results also provide a mechanism to explain patterns of gene expression in cancers where AP2␣ is known to function as a tumor suppressor.The AP2 transcription factor family is a set of developmentally regulated, retinoic acid inducible genes composed of four related factors-AP2␣, AP2␤, AP2␥, and AP2␦ (1-4). AP2 factors orchestrate a variety of cell processes including apoptosis, cell growth, and tissue differentiation during embryogenesis (5, 6). Studies in AP2 knock-out mice have indicated an important role for AP2 factors in the development of neural crest, epidermal, and urogenital tissues (5-9). AP2 factors have been shown to regulate the expression of genes in various tissues and tumors. In melanoma cells, AP2 has been shown to regulate the MUC18 and c-KIT promoters (10). AP2␣ and AP2␥ appear to be coordinately involved in regulating the basal and cAMP-induced expression of human chorionic gonadotropin in the placenta (11). In breast cancer, the AP2 factors have been implicated in the regulation of the ErbB2 (3, 12) and ER␣ genes (13,14).Several lines of investigation have led to the conclusion that AP2␣ is a tumor suppressor gene. Studies of primary breast tumors using immunohistochemistry demonstrated a progressive loss of AP2␣ expression with tumor progression from normal mammary epithelium, to DCIS, and to invasive cancer (15). Similar findings have been reported for colon carcinomas evaluated by immunohistochemistry, which demonstrated a decrease in AP2␣ expression in advanced Duke's stage carcinomas (16). Interestingly, there was an increase in AP2␣ mRNA in advanced stage colon tumors as determined by in situ hybridization indicating that the loss of AP2␣ was at the level of protein synthesis or stability. Loss of AP2␣ expression has also been reported to occur with malignant transformation and tumor progression in cuta...

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.…”

“…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.…”

AP-2α and AP-2γ are transcriptional targets of p53 in human breast carcinoma cells

“…AP-2a and AP-2g, two members of the AP-2 family, are transcription factors with high homology to each other. It has been reported that there is a physical interaction between p53 and AP-2 proteins (McPherson et al, 2002;Modugno et al, 2002). Most importantly, the functional interaction between these two proteins was discovered and it was demonstrated that both the p53 and AP-2 transcription factors can upregulate p21, arrest cell cycle progression, induce apoptosis and promote tumor death (McPherson et al, 2002;Wajapeyee and Somasundaram, 2003).…”

“…As a DNA-bindingdefective mutant failed to elicit a comparable effect, p53 DNA-binding ability was essential to exhibit the characteristics of tumor-suppressing function described herein. Even though the presence of p53 can improve AP-2-induced cell killing, AP-2 alone can greatly induce breast carcinoma cell death (McPherson et al, 2002;Wajapeyee and Somasundaram, 2003). Indeed, the fact that AP-2 expression decreased MDA MB-231 cell growth (Supplementary Figure 11) implies that AP-2 may mediate part of p53 function in growth inhibition.…”

“…It is reported that there is a physical and functional interaction between p53 and AP-2 proteins (McPherson et al, 2002;Modugno et al, 2002). The presence of p53 and p21 can enhance AP-2a-induced cell cycle arrest and AP-2a-decreased DNA synthesis (McPherson et al, 2002;Wajapeyee and Somasundaram, 2003).…”