The majority of leukemia harbor lesions which directly or indirectly activate the expression or activity of the c-Myc or E2F oncogenes which function as master regulators of the cell cycle. However, enforced expression of c-Myc or E2F-1 in hematopoietic progenitors also activates the apoptotic program and rapidly induce cell death when cells are deprived of survival factors. We have demonstrated that expression of Bcl-2, an oncogene which specifically functions to suppress apoptosis, is tightly regulated by pathways which suppress or activate apoptosis. Overexpression of oncogenes which trigger apoptosis leads to suppression of Bcl-2 protein and RNA expression and the experiments in Aim number 1 will determine the mechanism of Bcl-2 suppression. Modulating Bcl-2 levels in cells overexpressing c-Myc orE2F-1 demonstrated that specific thresholds of Bcl-2 are critical in regarding cell survival. Therefore, the experiments of Aim number 2 will determine, in agenetic fashion, the requirement for Bcl-2, and for its dimerization partner Bax, in c- Myc mediated transformation and apoptosis. Finally, we have demonstrated that Bcl-2 is also targeted by pathways which suppress apoptosis. Specifically, overexpression of another Bcl-2 family member, Bcl-XL, which is also a cell death antagonist and is selectively activated (by retroviral inssertions) in cytokine-independent murine leukemia also suppresses Bcl-2 expression. By contrast, overexpression of Bcl-2 does not influence levels of Bcl-XL or other family members. Therefore, this suggests that there is hierarchical regulation on Bcl-2 family members. Experiments of Aim number 3 will address the mechanism by which Bcl-2 is suppressed by Bcl-XL and determine the hierarchical relationships of Bcl-2 family members. Thus, our studies suggest that although Bcl-2 and Bcl-XL are structurally related, they are differentially regulated and are selectively targeted by unique pathways during myelopoiesis and leukemogenesis. In particular, our results suggest the hypothesis that levels of Bcl-2 are dynamically regulated by pathways that activate or suppress apoptosis and that this may play a critical role in the deletion of cells in hematopoiesis and leukemia.
| 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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