P53 Activates Fanconi Anemia Group C Gene Expression

Abstract

The tumor suppressor protein p53 (wtp53) can bind to specific target sequences and activate transcription of genes adjacent to these DNA elements. Two p53 binding sites are present in the gene coding for the Fanconi anemia complementation group C (FAC), one in the promoter region (from -1295 to -1266) and one in the coding region of FAC (from +1828 to +1848). Gel shift experiments show that wtp53 binds to the p53 target sequence in the promoter region of the FAC gene. We have investigated whether binding of p53 to these target sites may affect expression of the FAC gene. Transfection experiments show that overexpression of wtp53 in human diploid fibroblasts and lymphoblasts augments transcription of the FAC gene up to three-fold. The transfection efficacy was approximately 15% for both cell types. The FAC expression activity per transformed cell was stimulated to an estimated level of 18- to 21-fold upon overexpression of p53. The tumor-derived p53 mutants, His175 and His273, that fail to bind DNA showed only a reduced stimulatory activity on FAC transcription. Luciferase assays demonstrated that interaction of p53 with its target site in the FAC promoter does not modulate the promoter activity. We suggest that the p53 binding site contributes to, but may not be an absolute prerequisite for p53-directed transcriptional activation. We conclude that the FAC gene can be added to the list of genes that interact with p53.

Systems Biology-Based Identification of Crosstalk between E2F Transcription Factors and the Fanconi Anemia Pathway

“…Promoter analyses for mutations and the methylation status of FA genes have been well characterized; these statuses are known to affect the FA/BRCA pathway (Taniguchi et al 2003). Among FA genes, the promoter of FANCC has been cloned and shown to be regulated by p53 (Savoia et al 1995; Liebetrau et al 1997). Once functional links between the E2F1 and FA/BRCA pathways have been established, the complete system biology of the FA/BRCA pathway could be analyzed by examining their promoter regulation by cell cycle-associated key transcriptional regulators, including p53.…”

Fanconi anemia proteins and endogenous stresses

“…Early work from the Hoehn group showed that oxidative stress altered p53 expression and function in cultured FA cells [100-102]. Recently, studies from several other groups demonstrated that Fancd1 -/- , Fancd2 -/- and Fancc -/- mice have accelerated tumor development in a Trp53 -deficient background [103-105], and that p53 knockdown in FANCD2-deficient zebrafish leads to increased apoptosis and developmental defects [106].…”

The ubiquitin‐proteasome system in cancer, a major player in DNA repair. Part 2: transcriptional regulation

“…The establishment of p53 contribution to the expression of FAC was based on the description of two p53‐binding sites in the promoter and coding region of the gene, respectively. Also, p53 overexpression led to significant enhancement of transcription of FAC gene, although luciferase assays disclosed no modulation of the promoter activity (leading to the conclusion that p53‐binding is not directly responsible for activation of FAC transcription) [94].…”