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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.[1],[2],[3] 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.[39],[40] D-type cyclins inhibit Dmp1's activity in a Cdk-independent fashion in promoters lacking E2F sites;[38] however, it cooperates with Dmp1α to activate the Ink4a and Arf promoters[30],[47] 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.[41],[44],[46] The human DMP1 locus generates three splice variants, namely DMP1 α, β, and γ with antagonizing activity between DMP1α and β.[56] 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.[48] 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;[48] Dmp1 also stabilized p53 binding to transcriptional target genes.[51] 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.[48] In accordance, the induction of p21Cip1and Bbc3 by genotoxic drug treatment was more seriously affected in Dmp1-/- and p53-/- tissues than in Arf-/-.[48] In summary, Dmp1α stimulates the p53 pathway by direct transactivation of the Arf promoter in response to oncogenic stresses[30],[41],[44],[46] and direct physical interaction with p53 in DNA damage response (DDR).[48],[51] 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.[65],[66] 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.

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.<sup>[1],[2],[3]</sup> 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 <i>Dmp1</i><sup>-/-</sup> and <i>Dmp1</i><sup>+/-</sup> mice show hypersensitivity to develop tumors in response to carcinogen or <i>γ</i>-irradiation.<sup>[39],[40]</sup> D-type cyclins inhibit Dmp1's activity in a Cdk-independent fashion in promoters lacking E2F sites;<sup>[38]</sup> however, it cooperates with Dmp1α to activate the <i>Ink4a</i> and <i>Arf</i> promoters<sup>[30],[47]</sup> to eliminate incipient tumor cells. The <i>Dmp1</i> 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 <i>Dmp1</i>-deficient mice.<sup>[41],[44],[46]</sup> The human <i>DMP1</i> locus generates three splice variants, namely <i>DMP1</i> α, β, and <i>γ</i> with antagonizing activity between DMP1α and β.<sup>[56]</sup> <i>DMP1 β</i> and <i>γ</i> 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.<sup>[48]</sup> Dmp1α antagonized p53's ubiquitination by HDM2 both <i>in vitro</i> and <i>in cell</i> and restored p53's nuclear localization that had been lost with HDM2 expression;<sup>[48]</sup> Dmp1 also stabilized p53 binding to transcriptional target genes.<sup>[51]</sup> Dmp1α-p53 interaction increases the levels of p53 independent of Dmp1's DNA-binding, and hence both <i>p21</i><sup>Cip1</sup>and <i>Bbc3</i> promoters were synergistically activated by co-expression of Dmp1α and p53 in <i>p53</i><sup>-/-</sup>; <i>Arf</i><sup>-/-</sup>cells.<sup>[48]</sup> In accordance, the induction of <i>p21</i><sup>Cip1</sup>and <i>Bbc3</i> by genotoxic drug treatment was more seriously affected in <i>Dmp1</i><sup>-/-</sup> <i>and p53</i><sup>-/-</sup> tissues than in <i>Arf</i><sup>-/-</sup>.<sup>[48]</sup> In summary, Dmp1α stimulates the p53 pathway by direct transactivation of the <i>Arf</i> promoter in response to oncogenic stresses<sup>[30],[41],[44],[46]</sup> and direct physical interaction with p53 in DNA damage response (DDR).<sup>[48],[51]</sup> 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.<sup>[65],[66]</sup> Loss of <i>PTEN</i> 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 <i>Pten</i> accelerates the conversion of Pip3 to Pip2, and thus is a negative regulator of Pi3k signaling pathway. In PCa, loss of <i>PTEN</i> 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.