Critical Roles of DMP1 in Human Epidermal Growth Factor Receptor 2/neu-Arf-p53 Signaling and Breast Cancer Development

Abstract

Human epidermal growth factor receptor 2 (HER2) overexpression stimulates cell growth in p53-mutated cells while it inhibits cell proliferation in those with wild-type p53, but the molecular mechanism is unknown. The Dmp1 promoter was activated by HER2/neu through the phosphatidylinositol-3′-kinaseAkt-NF-κB pathway, which in turn stimulated Arf transcription. Binding of p65 and p52 subunits of NF-κB was shown to the Dmp1 promoter and that of Dmp1 to the Arf promoter on HER2/neu overexpression. Both Dmp1 and p53 were induced in premalignant lesions from mouse mammary tumor virus-neu mice, and mammary tumorigenesis was significantly accelerated in both Dmp1 +/− and Dmp1 −/− mice. Selective deletion of Dmp1 and/or overexpression of Tbx2/Pokemon was found in >50% of wild-type HER2/neu carcinomas, although the involvement of Arf, Mdm2, or p53 was rare. Tumors from Dmp1, and wild-type neu mice with hemizygous Dmp1 deletion showed significant downregulation of Arf and p21 Cip1/WAF1, showing p53 inactivity and more aggressive phenotypes than tumors without Dmp1 deletion. Notably, endogenous hDMP1 mRNA decreased when HER2 was depleted in human breast cancer cells. Our study shows the pivotal roles of Dmp1 in HER2/neu-p53 signaling and breast carcinogenesis.

Direct promoter induction of p19Arf by Pit-1 explains the dependence receptor RET/Pit-1/p53-induced apoptosis in the pituitary somatotroph cells

“…The low basal levels of p19Arf (p14ARF) explain that its expression is commonly regulated through transcriptional activation (Bates et al, 1998;Robertson and Jones, 1998;de Stanchina et al, 1998;Inoue et al, 1999;del Arroyo et al, 2007;Taneja et al, 2010). However, ARF expression also could be regulated through proteasomal inhibition (Kuo et al, 2004;Chen et al, 2010).…”

Aberrant expression of ETS1 and ETS2 proteins in cancer

“…Co-transfection of dominant inhibitory Ets2 mutants specifically blocked neuNT-mediated activation of Ets-dependent reporter genes (107). Thus Ets activation is required for neuNT-mediated cellular transformation (for neuNT see 105, 108–110). …”

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

“…It has been theorized that the Dmp1 protein acts as a tumor suppressor by directly transactivating the Arf promoter, thereby inducing Arf-, p53-dependent cell cycle arrest (20, 33, 34, 43). Eµ - Myc, K-ras LA , HER2/neu, and cyclin D1 -driven tumor development was significantly accelerated in Dmp1 -deficient mice (19, 34, 35, 44, 45). 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).…”

“…p19 Arf directly binds to Mdm2, thereby stabilizing and activating p53. Arf is induced by all the reported oncogenic stresses triggered by mutant Ras, c-Myc, E2F1, or HER2 overexpression (16–19). The Arf promoter is directly activated by E2F1 or Dmp1 (20) while the protein is stabilized by c-Myc or nucleophosmin through abrogation of Ulf-mediated Arf ubiquitylation (21).…”

“…Mitogenic signals from oncogenic Ras (39) and HER2/neu (19, 40) have been shown to activate the Dmp1 promoter (39, 41) while physiological mitogens as well as genotoxic stimuli mediated by NF-κB cause repression (42). It has been theorized that the Dmp1 protein acts as a tumor suppressor by directly transactivating the Arf promoter, thereby inducing Arf-, p53-dependent cell cycle arrest (20, 33, 34, 43).…”