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TROY BAUDINO
Nilsson JA, Keller UB, Baudino TA, Yang C, Norton S, Old
JA, Nilsson LM, Neale G, Kramer DL, Porter CW, Cleveland JL.
Targeting ornithine decarboxylase in Myc-induced
lymphomagenesis prevents tumor formation. Cancer Cell. 2005
May;7(5):433-44
Checkpoints that control Myc-mediated
proliferation and apoptosis are bypassed during
tumorigenesis. Genes encoding polyamine biosynthetic enzymes
are overexpressed in B cells from E mu-Myc transgenic mice.
Here, we report that disabling one of these Myc targets,
Ornithine decarboxylase (Odc), abolishes Myc-induced
suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1),
thereby impairing Myc's proliferative, but not apoptotic,
response. Moreover, lymphoma development was markedly
delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc
mice treated with the Odc inhibitor difluoromethylornithine
(DFMO). Strikingly, tumors ultimately arising in E
mu-Myc;Odc(+/-) transgenics lacked deletions of Arf,
suggesting that targeting Odc forces other routes of
transformation. Therefore, Odc is a critical Myc
transcription target that regulates checkpoints that guard
against tumorigenesis and is an effective target for cancer
chemoprevention.
Davidoff AM, Ng CY, Zhang Y, Streck CJ, Mabry SJ, Barton SH,
Baudino T, Zhou J, Kerbel RS, Vanin EF, Nathwani AC. Careful
decoy receptor titering is required to inhibit tumor
angiogenesis while avoiding adversely altering VEGF
bioavailability. Mol Ther. 2005 Feb;11(2):300-10
To inhibit tumor-induced angiogenesis, the VEGF signaling
pathway was targeted using AAV vectors encoding a VEGF decoy
receptor, a truncated, soluble form of the murine VEGF
receptor-2 (tsFlk-1). This approach initially had
significant anti-neuroblastoma efficacy in murine xenograft
models of local and metastatic disease, but when higher
circulating levels of tsFlk-1 were established, tumor growth
was more aggressive than even in control mice. Part of the
mechanism for this apparent tumor resistance was increased
human VEGF expression by the tumor cells. However, further
investigation revealed that although a greater amount of
VEGF could be bound by higher levels of tsFlk-1, more VEGF
also existed in an unbound state and was, therefore,
available to support angiogenesis. This novel,
tumor-independent mechanism for resistance to antiangiogenic
strategies suggests that careful titering of angiogenesis
inhibitors may be required to achieve maximal antitumor
efficacy and avoid therapy resistance mediated, in part, by
ligand bioavailability. This has important implications for
therapeutic strategies that use decoy receptors and other
agents, such as antibodies, to bind angiogenic factors, in
an attempt to inhibit tumor neovascularization.
Nilsson JA, Maclean KH, Keller UB, Pendeville H, Baudino TA,
Cleveland JL. Mnt loss triggers Myc transcription targets,
proliferation, apoptosis, and transformation. Mol Cell Biol.
2004 Feb;24(4):1560-9
Myc oncoproteins are overexpressed in most cancers and are
sufficient to accelerate cell proliferation and provoke
transformation. However, in normal cells Myc also triggers
apoptosis. All of the effects of Myc require its function as
a transcription factor that dimerizes with Max. This complex
induces genes containing CACGTG E-boxes, such as Ornithine
decarboxylase (Odc), which harbors two of these elements.
Here we report that in quiescent cells the Odc E-boxes are
occupied by Max and Mnt, a putative Myc antagonist, and that
this complex is displaced by Myc-Max complexes in
proliferating cells. Knockdown of Mnt expression by stable
retroviral RNA interference triggers many targets typical of
the "Myc" response and provokes accelerated proliferation
and apoptosis. Strikingly, these effects of Mnt knockdown
are even manifest in cells lacking c-myc. Moreover, Mnt
knockdown is sufficient to transform primary fibroblasts in
conjunction with Ras. Therefore, Mnt behaves as a tumor
suppressor. These findings support a model where Mnt
represses Myc target genes and Myc functions as an oncogene
by relieving Mnt-mediated repression.
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