Transcription factors that interact with p53 and Mdm2

Abstract

The tumor suppressor p53 is activated upon cellular stresses such as DNA damage, oncogene activation, hypoxia, which transactivates sets of genes that induce DNA repair, cell cycle arrest, apoptosis, or autophagy, playing crucial roles in the prevention of tumor formation. The central regulator of the p53 pathway is Mdm2 which inhibits transcriptional activity, nuclear localization, and protein stability. More than 30 cellular p53-binding proteins have been isolated and characterized including Mdm2, Mdm4, p300, BRCA1/2, ATM, ABL, and 53BP-1/2. Most of them are nuclear proteins; however, not much is known about p53-binding transcription factors. In this review, we focus on transcription factors that directly interact with p53/Mdm2 through direct binding including Dmp1, E2F1, YB-1, and YY1. Dmp1 and YB-1 bind only to p53 while E2F1 and YY1 bind to both p53 and Mdm2. Dmp1 has been shown to bind to p53 and block all the known functions for Mdm2 on p53 inhibition, providing a secondary mechanism for tumor suppression in Arf-null cells. Although E2F1-p53 binding provides a checkpoint mechanism to silence hyperactive E2F1, YB-1 or YY1 interaction with p53 subverts the activity of p53, contributing to cell cycle progression and tumorigenesis. Thus, the modes and consequences for each protein-protein interaction vary from the viewpoint of tumor development and suppression.

Aberrant expression of p16INK4a in human cancers – a new biomarker?

“…The DMP1 consensus is located −2.3 kb and −0.31 kb of ARF and −4.04 kb and −1.40 kb of INK4a in humans. Both of these are Dmp1 target genes (Dmp1 reviewed in 7, 96–98) although the mode of regulation is different (36). …”

From General Aberrant Alternative Splicing in Cancers and Its Therapeutic Application to the Discovery of an Oncogenic DMTF1 Isoform

“…The human DMTF1 gene is located on chromosome 7p21, a region frequently deleted in breast cancer, acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS) [8,67,68,69]. DMTF1 is highly conserved between humans and mice, with 95% similarity in amino acid sequences.…”

Stabilization of the p53-DNA Complex by the Nuclear Protein Dmp1α

“…Of note, both Dmp1 +/− and Dmp1 −/− mice showed acceleration of oncogene-induced tumor development with no significant differences in survival between the two cohorts, suggesting that Dmp1 is haplo-insufficient for tumor suppression (19, 34, 35; reviewed in 46). We recently reported that Dmp1 physically interacts with p53 to neutralize the known functions of Mdm2 (or HDM2), namely ubiquitination, nuclear-cytoplasmic transport, and suppression of transport (47), a very unique property among p53/Mdm2-binding transcription factors (48). The h DMP1 locus encodes at least three splicing variants -h DMP1α, β, and γ with antagonizing functions (49–51, reviewed in 52).…”