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ERK and JNK activation is essential for transformation by v-RelSheely, Juliana Irene 23 October 2009 (has links)
v-Rel is the acutely oncogenic member of the NF-[kappa]B family of transcription
factors and transforms cells through the altered regulation of pathways normally
controlled by cellular NF-[kappa]B. Initial studies revealed that expression of v-Rel results in
the strong and sustained activation of the ERK and JNK MAP kinases. This induction is
critical for the v-Rel transformed phenotype, as suppression of MAPK activity with
chemical inhibitors or siRNA severely limited colony formation of v-Rel transformed cell
lines of hematopoietic origin. However, signaling must be maintained within a certain
range in these cells, as strong additional activation of either pathway through expression
of constitutively active MKK mutants also attenuated the transformed phenotype.
Studies in primary spleen cells revealed that MAPK signaling is also required for the
early stages of v-Rel-mediated transformation. However, constitutive MAPK activity
further enhanced the transformation efficiency of v-Rel in primary cells. These studies,
as well as analogous experiments in DT40 cells, indicate distinct requirements for MAPK activity at different stages of v-Rel-mediated transformation. The proto-oncoprotein, c-Rel, only weakly activates ERK and JNK signaling compared to v-Rel. Importantly,
elevated MAPK activity enhanced transformation by c-Rel, indicating that the ability of
v-Rel to induce MAPK signaling is a major contributor to its oncogenic potential. Taken
together, this work demonstrates an important role for ERK and JNK activity in
transformation by v-Rel.
Additional studies examined mechanisms through which MAPK activity is
regulated in v-Rel transformed cells. Feedback regulation of the ERK activator, MKK1,
at T292 was shown to limit ERK activation in v-Rel transformed cells, preventing the
detrimental effects of constitutive activity. This result is the first indication that this
regulation may have a role in the maintenance of transformation. Further, several v-Rel induced
cytokines were identified that activate ERK and JNK signaling in v-Rel
transformed cells, revealing one means by which v-Rel-dependent transcriptional changes
lead to MAPK activation. These studies demonstrate the integration of multiple
mechanisms in achieving the optimal levels of MAPK activity that are essential for v-Rel-mediated transformation. / text
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Drosophila Eye Model to Study Dorso-Ventral (DV) Patterning and Neurodegenerative DisordersGogia, Neha January 2019 (has links)
No description available.
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Drosophila Eye Model to Study Genetic Modifiers of Alzheimer's DiseaseDeshpande, Prajakta Dhumraketu 07 August 2023 (has links)
No description available.
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Death is Not the End: The Role of Reactive Oxygen Species in Driving Apoptosis-induced ProliferationFogarty, Caitlin E. 02 June 2015 (has links)
Apoptosis-induced proliferation (AiP) is a compensatory mechanism to maintain tissue size and morphology following unexpected cell loss during normal development, and may also be a contributing factor to cancer growth and drug resistance. In apoptotic cells, caspase-initiated signaling cascades lead to the downstream production of mitogenic factors and the proliferation of neighboring surviving cells. In epithelial Drosophila tissues, the Caspase-9 homolog Dronc drives AiP via activation of Jun N-terminal kinase (JNK); however, the specific mechanisms of JNK activation remain unknown. Using a model of sustained AiP that produces a hyperplastic phenotype in Drosophila eye and head tissue, I have found that caspase-induced activation of JNK during AiP depends on extracellular reactive oxygen species (ROS) generated by the NADPH oxidase Duox. I found these ROS are produced early in the death-regeneration process by undifferentiated epithelial cells that have initiated the apoptotic cascade. I also found that reduction of these ROS by mis-expression of extracellular catalases was sufficient to reduce the frequency of overgrowth associated with our model of AiP. I further observed that extracellular ROS attract and activate Drosophila macrophages (hemocytes), which may in turn trigger JNK activity in epithelial cells by signaling through the TNF receptor Grindelwald. We propose that signaling back and forth between epithelial cells and hemocytes by extracellular ROS and Grindelwald drives compensatory proliferation within the epithelium, and that in cases of persistent signaling, such as in our sustained model of AiP, hemocytes play a tumor promoting role, driving overgrowth.
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