EXCEED THE SPACE PROVIDED. Activation of the MYC and/or the E2F families of transcription factors are common denominators of human cancer. Their selective activation is driven by their ability to promote continuous cell cycle progression, block differentiation and induce angiogenesis. However, c-Myc or E2F- 1 activation also overrides the protective effects of survival factors to induce apoptosis. We have demonstrated that c-Myc and E2F-1 trigger two apoptotic pathways in hematopoietic cells. First, they indirectly activate the p53 apoptotic program by inducing the expression of the ARF tumor suppressor, which sequesters p53's natural inhibitor Mdm2. Second, c-Myc and E2F-1 rapidly suppress the expression of the anti- apoptotic genes bel-2 or bel-X. Analysis of lymphomas arising in E_t-myc transgenic mice has established that both apoptotic pathways are disabled during tumorigenesis and crossing E_t-myc transgenics to ARF-deficient mice, or to mice deficient in Bax, a pro-apoptotic Bcl-2 family member inhibited by Bcl-2 or BcI-XL, dramatically accelerates lymphomagenesis. These studies have established the relevance of these apoptotic pathways during Myc-induced tumorigenesis, but the mechanism(s) by which Myc triggers these pathways is not resolved. Therefore, experiments of Aim #1 will identify mediators of the bcl-2/bcl-X suppression pathway triggered by c-Myc. Interestingly, our studies have linked Myc- and E2F-l-mediated suppression of bcl-2/bcl-X to the regulation of the p27gaPl-Cdk2 pathway. p27 Kiplfunctions as a tumor suppressor, and therefore the experiments of Aim #1 will also determine the role of p27 I_pl in regulating the Myc-indueed suppression of bcl-2/bcl-X, apoptosis and lymphomagenesis. We have shown that the suppression of bcl-2/bcl-X by e-Myc or E2F-1 is independent of ARF or p53, yet it is not resolved whether the converse is true. Our analyses have also demonstrated that the bcl-2/bcl-X suppression pathway is disabled at equal frequency in wild type and ARF-null Elx-myc transgenics. Thus, experiments of Aim #2 will test the hypothesis that disabling the bcl-2/bcl-X suppression pathway may be necessary for Myc to induce and maintain tumor development. Finally our data indicate that loss ofARF and/orp53 selectively up-regulates the basal levels of Bcl-2 in hematopoietic cells. This suggests that loss of ARF and/or p53 impairs c-Myc-induced apoptosis at least in part through up-regulation of Bcl-2, and that there is cross-talk between the bcl-2/bcl-X and ARF-p53 apoptotic pathways. Experiments in Aims #3 therefore include genetic tests to determine whether this cross-talk occurs in vivo in E_t-myc transgenics, and will evaluate whether there is a hierarchy in these apoptotic pathways. Elucidating the pathway(s) by which Myc suppresses the expression of bcl-2 or bcl-X may provide new therapeutic targets for the treatment of cancer. PERFORMANCE SITE ========================================Section End===========================================
| Huang, Qingling; Chen, Lihong; Yang, Leixiang et al. (2018) MDMX acidic domain inhibits p53 DNA binding in vivo and regulates tumorigenesis. Proc Natl Acad Sci U S A 115:E3368-E3377 |
| Lu, Yuanzhi; Wu, Yongsheng; Feng, Xiaoling et al. (2014) CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis. J Clin Invest 124:1672-84 |
| Doherty, Joanne R; Yang, Chunying; Scott, Kristen E N et al. (2014) Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis. Cancer Res 74:908-20 |
| Valentin-Vega, Yasmine A; Maclean, Kirsteen H; Tait-Mulder, Jacqueline et al. (2012) Mitochondrial dysfunction in ataxia-telangiectasia. Blood 119:1490-500 |
| Joo, Joung Hyuck; Dorsey, Frank C; Joshi, Aashish et al. (2011) Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy. Mol Cell 43:572-85 |
| Ji, Hongkai; Wu, George; Zhan, Xiangcan et al. (2011) Cell-type independent MYC target genes reveal a primordial signature involved in biomass accumulation. PLoS One 6:e26057 |
| den Hollander, Jurgen; Rimpi, Sara; Doherty, Joanne R et al. (2010) Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116:1498-505 |
| Old, Jennifer B; Kratzat, Susanne; Hoellein, Alexander et al. (2010) Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc-driven lymphomagenesis. Mol Cancer Res 8:353-62 |
| Keller, Ulrich; Huber, Jurgen; Nilsson, Jonas A et al. (2010) Myc suppression of Nfkb2 accelerates lymphomagenesis. BMC Cancer 10:348 |
| Zhang, Ji; Randall, Mindy S; Loyd, Melanie R et al. (2009) Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation. Blood 114:157-64 |
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