The discussed in chapter 3.4. Furthermore, Myc is downstream

The mechanism behind the tumorigenic function of Myc considers proliferation anddifferentiation, but also the ability of Myc to increase cell growth (cell mass in size). Thisoccurs by increasing protein synthesis and reprogramming cell metabolism (Iritani andEisenman, 1999). In accordance, enforced expression of the Drosophila c-Myc ortholog inwing imaginal disc results in increased cell size (Johnston et al., 1999). Importantly,genomic instability and amplification are increased in Myc-expressing cells, for exampleby ROS generation or overcoming the p53 checkpoint (Felsher and Bishop, 1999). Morerecently, Myc was suggested to regulate angiogenesis by inducing angiogenic switch viamiR17-92 microRNA cluster or interleukin 1? (Dews et al., 2010; Shchors et al., 2006).Additionally, Myc can induce immortalization of a cell, however, the mechanisms arevery controversial (Lutz et al., 2002). Specific metabolic pathways are also targeted byMyc, as discussed in chapter 3.4. Furthermore, Myc is downstream from many signaltransduction pathways like MEK-ERK and PI3K that are responsive to growth factors orthe cellular microenvironment (Lee et al., 2008). Conversely, Myc tumors have beenshown to be resistant to anti-mitogenic TGF-? signaling (Meyer and Penn, 2008).Several transgenic mouse models have been developed to decipher the mechanism howderegulated Myc induce tumorigenesis. The mouse data has provided the evidence thatderegulated expression of Myc is sufficient to drive tumorigenesis in a number oftransgenic mouse tissues, but not all (Adams et al., 1985; Leder et al., 1986). For instance,Myc induced tumor in mammary mouse tissue under Wap- or MMTV-promoter and inmouse prostate tissue, however, with delayed onset of tumors (Ellwood-Yen et al., 2003;Schoenenberger et al., 1988; Stewart et al., 1984). Importantly, in each of these casesadditional mutagenic events are necessary for Myc to enable its tumorigenic potential.Importantly, using inducible systems (tTA Tet-O-Myc, pIns-MycERtm) it has becomeevident that withdrawal of Myc ectopic expression is required to maintain tumor, orotherwise the tumor will regress (Arvanitis and Felsher, 2006; Karlsson et al., 2003).Importantly, these tumors are considered to be addicted to Myc. Furthermore, increasingdata on mouse models suggest that evading Myc-apoptosis is one of the majormechanisms behind the oncogenic function of Myc (Dang et al., 2005).Several laboratories made an intriguing discovery in the early 90´s that oncogenes such asMyc and the adenovirus E1A, which are both potent inducers of cell proliferation, inducealso apoptosis. The early view of oncogene-induced apoptosis was that it was indirect ordistal response of the cell to an enforced cell cycle entry or to an inappropriate growthsignal generated by Myc. Currently it is evident that Myc-induced apoptosis has a closelink to the Bcl-2-mediated mitochondrial apoptosis pathway. Originally Bcl-2 was foundto cooperate with Myc in tumorigenesis by inhibiting Myc-induced apoptosis (Fanidi et al.,1992). Similarly, acceleration of lymphomagenesis is found in transgenic mice thatexpress both Myc and Bcl-2 compared with transgenic mice that harbor just the Myctransgene (Strasser et al., 1990). Also Myc-null cells were resistant to diverse apoptoticstimuli. Furthermore, ectopic expression of Myc in the absence of specific survival factorslead to apoptosis (Askew et al., 1991; Evan et al., 1992). Later Myc was shown to inducethe release of cytochrome c from mitochondria during apoptosis (Juin et al., 1999).Several studies suggest an important role for Bax in Myc-mediated engagement of themitochondrial pathway. For instance, Myc was shown to be required for DNA damageinducedBax conformational change and activation and also to Bax oligomerization atmembranes. (Annis et al., 2005; Soucie et al., 2001). Interestingly, in the pIns-MycERtmpancreas model, the Myc overexpression is able to induce apoptosis of ?-cellssimultaneously with the proliferation. However, expression of Bcl-xL or loss-of Bax areshown to enable Myc-tumorigenesis in these ?-cells (Dansen et al., 2006; Pelengaris et al.,2002). Also, in the MMTV-Myc mammary transgenic mouse model, Myc inducesapoptosis in a Bax-dependent manner. Additionally, Myc has been shown to up-regulateBax in growth factor-deprived human cancer cell lines (Mitchell et al., 2000). In nonepithelialcell tumor models, Myc can co-operate with Bcl-2 and Bcl-xL overexpression in??-Myc lymphoma and with loss of Bim in ??-Myc B-cell leukemia (Egle et al., 2004).Some studies have shown evidence that Myc suppresses Bcl-2 or Bcl-xL expression bothin MEFs and primary hematopoietic cells (Eischen et al., 2001b; Kelly et al., 2011).Furthermore, Myc has been proposed to affect the Bcl-2 family network controlling themitochondrial pathway, yet the mechanisms by which Myc actually increase the activationof Bax and Bak remain unknown.Importantly, tumor suppressor p53 seems to have an essential for Myc-induced apoptosis(Hermeking and Eick, 1994). For instance, elevated expression of p53 appears to beassociated with apoptosis occurring by Myc (Hermeking and Eick, 1994). Myc-inducedphosphorylation of Serine 15 (murine homologue 18) inhibits Myc tumorigenesis in ??-Myc mice (Sluss et al., 2010). Furthermore, p53 phosphorylated by ATM promotes Mycapoptosis in squamous epithelial cells (Pusapati et al., 2006). Likewise, Myc co-operatesin tumorigenesis with loss of p53 or ARF in variety of models like in lymphomas, but not,for example, in mammary carcinomas (Eischen et al., 1999; Elson et al., 1995).Conversely, existing data in several systems suggest that elevated Myc can induceapoptosis in the absence of p53, for example, by suppressing Bcl-xL. Thus, Myc-inducedapoptosis is not always dependent on p53 (Hsu et al., 1995; Maclean et al., 2003).