Figure 2: Oncogenic and tumor suppressive signaling pathways involving Dmp1. Arf is induced by potentially oncogenic signals stemming from overexpression of oncogenes such as c-Myc, E2F1, and activated Ras, which quenches inappropriate mitogenic signaling by diverting incipient cancer cells to undergo p53-dependent growth arrest or cell death.,, Positive input signals for Arf have been shown in red (our own research) or pink (research from other labs). Conversely, negative signals have been shown in T in black. The output signals for Arf have been shown in striped arrows. Both Dmp1-/- and Dmp1+/- mice show hypersensitivity to develop tumors in response to carcinogen or γ-irradiation., D-type cyclins inhibit Dmp1's activity in a Cdk-independent fashion in promoters lacking E2F sites; however, it cooperates with Dmp1α to activate the Ink4a and Arf promoters, to eliminate incipient tumor cells. The Dmp1 promoter is activated by the oncogenic Ras-Raf-Mek-Erk-Jun and HER2-Pi3k-Akt-NF-κB pathways, and thus Ras or HER2-driven carcinogenesis is accelerated in Dmp1-deficient mice.,, The human DMP1 locus generates three splice variants, namely DMP1 α, β, and γ with antagonizing activity between DMP1α and β. DMP1 β and γ transcripts have not been reported in mice. Dmp1α physically interacts with the epigenetic modifier YY1 that affects EZH2 activity. YY1 binds to HDM2 and Dmp1α to accelerate HDM2-mediated polyubiquitination of p53. Our study shows that Dmp1α physically interacts with p53 through p53's carboxyl-terminal and Dmp1's DNA-binding domain. Dmp1α antagonized p53's ubiquitination by HDM2 both in vitro and in cell and restored p53's nuclear localization that had been lost with HDM2 expression; Dmp1 also stabilized p53 binding to transcriptional target genes. Dmp1α-p53 interaction increases the levels of p53 independent of Dmp1's DNA-binding, and hence both p21Cip1and Bbc3 promoters were synergistically activated by co-expression of Dmp1α and p53 in p53-/-; Arf-/-cells. In accordance, the induction of p21Cip1and Bbc3 by genotoxic drug treatment was more seriously affected in Dmp1-/- and p53-/- tissues than in Arf-/-. In summary, Dmp1α stimulates the p53 pathway by direct transactivation of the Arf promoter in response to oncogenic stresses,,, and direct physical interaction with p53 in DNA damage response (DDR)., Mekk1 is activated by a variety of oxidative stress signaling, such as dsDNA breaks, UV, cytokines, osmotic stress, and oncogenes. Activation of MEKK1 by c-Abl in DDR has been reported. MEKK1 is cleaved by caspase 3 following DNA damage to generate ΔMEKK1, which increases the Dmp1α protein by phosphorylation., Loss of PTEN is found in 70% of advanced prostate cancer (PCa), resulting in activation of the Pi3k-Akt pathway that promotes survival by inhibiting apoptosis and causing genomic instability. The tumor suppressor Pten accelerates the conversion of Pip3 to Pip2, and thus is a negative regulator of Pi3k signaling pathway. In PCa, loss of PTEN drives cell cycle arrest and senescence as a tumor suppressive mechanism mediated by upregulation of p53 expression. Accumulating studies show that RNA splicing is affected by DDR, and also roles of YY1 and PTEN in DDR.