The MYC family of oncogenes is common targets of most cancers and their selective activation reflects their ability to promote continuous cell proliferation, and to provoke transformation and tumor angiogenesis. How c-Myc triggers these processes is not clear, although they all require Myc's transcription functions. Our work established that ornithine decarboxylase (ODC), the key regulator of polyamine biosynthesis, is a Myc transcription target and that MYC activation in cancer results in highly elevated levels of ODC. However, how c-Myc activates ODC transcription is not resolved. c-Myc is a basic-helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor and the conventional model posits that Myc dimerizes with Max, another bHLH-Zip protein, and that Myc:Max dimers bind to consensus CACGTG elements in target genes and activate transcription. Our creation of a knockin allele of ODC in mice, in which both Myc:Max binding sites are mutated, suggest a paradigm shift in how Myc may regulate its target genes. These studies indicate that these CACGTG elements are rather important for transcriptional repression, and support a model whereby c-Myc activates ODC by sequestering Max from the Mnt:Max complex, which actively represses ODC transcription. Therefore, in Aim 1 experiments are proposed to determine the mechanism by which c-Myc regulates ODC, to confirm the relevance of the ODC intron 1 CACGTG elements to transcriptional regulation by creating additional knock-in mice, and to define the role of Mnt in regulating ODC, again using mouse models. Myc activation in normal cells is held in check by triggering the apoptotic program. We have established this involves the induction of the ARF-p53 checkpoint and the suppression of the anti-apoptotic genes, bcl-2 or bcI-X, and that both of these pathways are disrupted during Myc-induced tumorigenesis. Our studies have established that ODC loss or overexpression induces apoptosis and that ODC overexpression also suppresses the expression of bcl-2. Therefore, a second goal of the proposed studies is to determine the physiological role of ODC in Myc-induced apoptosis and tumorigenesis.
In Aim #2 we will evaluate whether ODC is sufficient to trigger the """"""""Myc"""""""" apoptotic pathways, and whether ODC loss, using a conditional ODC knockout, impairs Myc-induced apoptosis. Finally, in Aim #3 we address whether ODC is necessary as a regulator of Myc-induced tumorigenesis and angiogenesis by evaluating effects of ODC loss on Myc-induced lymphomagenesis in Emu-myc transgenic mice, and of ODC overexpression in c-myc-/- embryonic stem cells, which are defective in ODC expression, and tumor angiogenesis. The creation of the conditional ODC knockout provides an important pre-clinical mouse model to test the efficacy in targeting ODC in tumor development, maintenance and angiogenesis.
|Singh, Kshipra; Coburn, Lori A; Asim, Mohammad et al. (2018) Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses. Cancer Res 78:4303-4315|
|Amelio, Antonio L; Fallahi, Mohammad; Schaub, Franz X et al. (2014) CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement. Proc Natl Acad Sci U S A 111:E3260-8|
|Hoellein, Alexander; Fallahi, Mohammad; Schoeffmann, Stephanie et al. (2014) Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma. Blood 124:2081-90|
|Doherty, Joanne R; Cleveland, John L (2013) Targeting lactate metabolism for cancer therapeutics. J Clin Invest 123:3685-92|
|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|
|Rounbehler, Robert J; Li, Weimin; Hall, Mark A et al. (2009) Targeting ornithine decarboxylase impairs development of MYCN-amplified neuroblastoma. Cancer Res 69:547-53|
|Carew, Jennifer S; Nawrocki, Steffan T; Reddy, Venudhar K et al. (2008) The novel polyamine analogue CGC-11093 enhances the antimyeloma activity of bortezomib. Cancer Res 68:4783-90|
|Rodrigues, Claudia O; Nerlick, Steve T; White, Elsie L et al. (2008) A Myc-Slug (Snail2)/Twist regulatory circuit directs vascular development. Development 135:1903-11|
|Guo, Yongjun; Cleveland, John L; O'Brien, Thomas G (2005) Haploinsufficiency for odc modifies mouse skin tumor susceptibility. Cancer Res 65:1146-9|
|Nilsson, Jonas A; Cleveland, John L (2004) Mnt: master regulator of the Max network. Cell Cycle 3:588-90|
Showing the most recent 10 out of 11 publications