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

Abstract

We recently reported the existence of a physical interaction between the Myb-like transcription factor Dmp1 (Dmtf1) and p53 in which Dmp1 antagonized polyubiquitination of p53 by Mdm2 and promoted its nuclear localization. Dmp1 significantly stabilized p53-DNA complexes on promoters that contained p53-consensus sequences, which were either supershifted or disrupted with antibodies to Dmp1. Lysates from mice injected with doxorubicin showed that Dmp1 bound to p21Cip1, Bbc3, and Thbs1 gene regulatory regions in a p53-dependent fashion. Our data suggest that acceleration of DNA-binding of p53 by Dmp1 is a critical process for Dmp1 to increase the p53 function in Arf-deficient cells.

Tumor suppression by the EGR1, DMP1, ARF, p53, and PTEN Network

“…Our study shows that the Dmp1 protein directly interacts with p53 and blocks the activities of Mdm2, especially in epithelial cells and T lymphocytes (42). Dmp1 also stabilizes p53 binding to transcriptional target genes (43). These two mechanisms will act synergistically to boost the p53 activity to prevent tumorigenesis.…”

“…Dmp1α expression antagonized p53's ubiquitination by HDM2 both in cell and in vitro, and restores p53's nuclear localization that was lost with HDM2 expression (42). Moreover, Dmp1α stabilized p53-DNA complexes on genomic DNA that contained p53-consensus sequences, which were either supershifted or disrupted with antibodies to Dmp1 (43). Dmp1α-p53 interaction significantly increased the levels of p53 independent of Dmp1's DNA-binding, and hence the p21 Cip1 promoter activity was synergistically induced by co-expression of Dmp1α and p53 in p53 −/− ;Arf −/− double knockout cells (42).…”

“…The induction of p21 Cip1 and Bbc3 (Puma) by genotoxic doxorubicin treatment was more seriously affected in Dmp1 −/− and p53 −/− tissues than in Arf −/− (42). Lysates from mice injected with doxorubicin showed that Dmp1 bound to p21 Cip1 , Bbc3, and Thbs1 genomic regulatory regions in a p53-dependent fashion (43). These data indicate that Dmp1, but not Arf, is actively involved in DNA damage response, justifying further investigation of the role.…”

“…Both promoters are repressed by and genotoxic signals mediated mainly the p65 subunit of by NF-κB (41). Dmp1 (Dmp1α) physically interacts with p53 to neutralize all the activities of Mdm2 on p53, indicating that this is the secondary mechanism of tumor surveillance in Arf-deficient cells (42,43). Recent studies show that Dmp1 also transactivates p16 Ink4a although the effect is less than stimulation of Arf (44,45).…”

Aberrant expression of ETS1 and ETS2 proteins in cancer

“…In contrast to ETS1 , loss of the Myb-like transcription factor DMP1α ( DMTF1α ) binds to the Ets site in the Arf promoter (91) is associated with low Ki67 and is associated with favorable prognosis (92) for Dmp1 original articles; 93–101; 67, 102–106 for reviews). Dmp1α also binds directly to p53 for activation in Arf -deficient cells (100, 101). It was reported that expression of neuNT, but not normal neu, caused transcriptional activation of Ets, AP1, or NF-κB-dependent reporter genes (107).…”