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Transcriptional repression by the dominant negative oncogene v-erba

Objective



Research objectives and content
Cancer is commonly linked to aberrant proliferation and a failure of the transformed cells to differentiate. Activated proto-oncogenes are thought to provide continuous proliferation signals that enhance the growth of transformed cells. Conversely, transformation can also be achieved by preventing transactivation of genes or gene network that regulate cell growth and/or differentiation. A prototypic example is the dominant negative oncogene, v-erbA, a mutated thyroid hormone receptor (T3R) variant encoded by the avian erythroblastosis virus (AEV). V-erbA is thought to antagonize T3R function through constitutive binding to T3-response elements and occlusion of the endogenous receptor and/or by actively repressing (silencing) transcription. Whether and how v-erbA represses natural genes within their chromosomal loci is largely obscure due to the lack of model systems. Recently, the Stunnenberg lab has been able to demonstrate that v-erbA silences expression of the chicken Carbonic Anhydrase II (CAII) gene through a novel v-erbA response element (VRE) located in an erythroid-specific enhancer. By using in vivo and in vitro approaches, I propose to use this model system to unravel the molecular mechanisms by which v-erbA and its cellular counterpart c-erbA/T3R silence transcription and to assess the role of putative co- repressor proteins in his process. This system affords a unique opportunity to investigate not only the molecular basis of erythroleukemia but also the regulation of the targeted gene by wild type and mutated nuclear receptors. Training content (objective, benefit and expected impact)
The Stunnenberg group is among the leading in the receptor field. This study will provide novel insight in how gene transcription is regulated by Class II nuclear receptors, and in particular the role of v-erbA and T3R in repression and chromatin opening. Moreover, this system provides the opportunity to unravel the molecular basis of the erythroleukemia.

Funding Scheme

RGI - Research grants (individual fellowships)

Coordinator

Katholieke Universiteit Nijmegen - Stichting Katholieke Universiteit
Address
1,Toernooiveld
6525 ED Nijmegen
Netherlands

Participants (1)

Not available
France