Function of the TRAP/SMCC mediator in nuclear receptor transcription regulation of differentiation programms

• Applicant: Dr. Arndt Benecke, Ph.D.
• Subject Area: Cell Biology
• Term: from 2001 to 2003
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5307456

Thyroid hormone and retinoic acid are small hydrophobic signaling substances required for embryogenesis and maintenance of the complex body plan during adulthood. They are specifically bound by the thyroid hormone and retinoid receptors, closely related transcription factors belonging to the family of nuclear receptors. The recent identification of a mammalian mediator complex (TRAP/SMCC) as a thyroid hormone receptor coactivator has set the grounds to understand transcription activation by nuclear receptors in biochemical defined transcription systems. Furthermore, the genetic engineered TRAP220 mouse null-mutant provides a means of dissecting the nuclear receptor signaling pathway in a dynamic, physiologic system. We will analyze TRAP220 knock-out (KO or -/-) embryonic stem cells als well as hematopoietic cells derived from the TRAP220 -/- mice for defects in nuclear receptor differentiation pathways. Furthermore, we attempt to reconstitute transcription activation from suitable natural retinoid target promoters in vitro. These complementary approaches will ultimately lead to the understanding of transcription regulation by nuclear receptors at both, the physiologic and the mechanistic level, and thus allow specific interference into pathologic processes involving the nuclear receptor signaling cascade.

• DFG Programme: Research Fellowships
• International Connection: France, USA
• Cooperation Partner: Professor Dr. Robert Roeder