Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-κB and Myc/Max

Abstract

Transcriptional control of p53 expression participates in the generation of appropriate levels of active p53 in response to mitogenic stimulation. This prompted us to study the role of a putative AP-1 and a NF-kB motif in the human p53 promoter for transcriptional regulation. We show that mutation of the AP-1 or the NF-kB motif abolishes transcription from the human p53 promoter in HeLa, HepG2 and adenovirus type 5 E1-transformed 293 cells. In comparison, mutation of the previously characterized Myc/Max/USF binding site in the human p53 promoter reduces the transcription rate ®vefold. The AP-1 motif in the human p53 promoter binds c-Fos and c-Jun and the NF-kB motif binds p50 NF-kB1 and p65 RelA . The cooperative nature of transcriptional activation by these factors was documented by repression of c-fos or NF-kB1 translation: Pretreatment of the cells with a cfos or p50 NF-kB1 antisense oligonucleotide suppresses transcription from the human p53 promoter completely. In addition, we show that (a) the level of endogenous p53 mRNA and (b) transcription from the strictly p53-dependent human mdm2 promoter are reduced in the presence of c-fos, c-jun, p50 NF-kB1 , p65 RelA or c-myc antisense oligonucleotides, underscoring the importance of these transcription factors for the expression of functional p53.

Hammerhead ribozyme against γ-glutamylcysteine synthetase sensitizes human colonic cancer cells to cisplatin by down-regulating both the glutathione synthesis and the expression of multidrug resistance proteins

“…64 It is interesting to know if GSH participates in the expression of ABC transporters through the regulation by p53. A role for GSH in the redox regulation of transcriptional factors and intracellular signal transduction pathways has been suggested.…”

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

“…However, transcriptional and translational modulation also seems to be involved in the control of p53 activity (reviewed in Hansen and Oren, 1997;Oren, 1999). Several transcriptional factors (AP-1, NF-kB, Myc/Max) as well as p53 itself have indeed been reported to interact with the p53 gene promoter (Kirch et al, 1999). However, there is no consensus regarding the role of p53 in the regulation of its own transcription.…”

“…These structural changes dramatically increase the half-life of p53, which accumulates rapidly in the nucleus. Moreover, the level of p53 can also be modulated at the transcriptional level after mitogenic stimulation, di erentiation induction and genotoxic stress (Reich and Levine, 1984;Sun et al, 1995;Balint and Reisman, 1996;Kirch et al, 1999). The WT-activated p53 acts as a transcriptional factor and regulates the expression of target genes including p21(WAF1/CIP1), gadd45, bax or bcl2, which in turn control cell cycle checkpoints, DNA repair and apoptosis (Kern et al, 1991;Farmer et al, 1992;Miyashita et al, 1994).…”

Activation and activities of the p53 tumour suppressor protein

“…The NF-κB transcription factor has lately been shown to play an important role in p53-mediated apoptosis (Ryan et al, 2000), in contrast to the anti-apoptotic effect of NF-κB induced in response to TNF (Van Antwerp et al, 1996;Phillips et al, 1999). However, in other systems p53 expression has been shown to be dependent on NF-κB (Wu and Lozano, 1994;Kirch et al, 1999), and the contribution of NF-kB to the p53 apoptotic pathway remains unclear.…”