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
| Identifer | oai:union.ndltd.org:UTEXAS/oai:repositories.lib.utexas.edu:2152/6647 |
| Date | 23 October 2009 |
| Creators | Sheely, Juliana Irene |
| Source Sets | University of Texas |
| Language | English |
| Detected Language | English |
| Format | electronic |
| Rights | Copyright is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works. |
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