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Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid
1Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10021, USA.
Abstract:
The TRAP220 component of the TRAP/SMCC complex, a mammalian homologof the yeast Mediator that shows diverse coactivation functions, interacts directly with nuclear receptors. Ablation of the murine Trap220 gene revealed that null mutants die during an early gestational stage with heart failure and exhibit impaired neuronal development with extensive apoptosis. Primary embryonic fibroblasts derived from null mutants show an impaired cell cycle regulation and a prominent decrease of thyroid hormone receptor function that is restored by ectopic TRAP220 but no defect in activation by Gal4-RARalpha/RXRalpha, p53, or VP16. Moreover, haploinsufficient animals show growth retardation, pituitary hypothyroidism, and widely impaired transcription in certain organs. These results indicate that TRAP220 is essential for a wide range of physiological processes but also that it has gene- and activator-selective functions.
Insights
TRAP220 is crucial for development, regulating gene transcription and thyroid hormone receptor function. Its absence causes embryonic lethality, heart failure, and impaired neuronal growth, highlighting its essential physiological roles.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- The TRAP220 protein is a key component of the TRAP/SMCC complex, a mammalian Mediator involved in coactivation.
- This complex interacts with nuclear receptors, playing a role in transcriptional regulation.
Purpose of the Study:
- To investigate the physiological functions of TRAP220 in mammalian development.
- To determine the role of TRAP220 in nuclear receptor-mediated gene activation.
Main Methods:
- Gene ablation in mice to create null mutants.
- Analysis of embryonic development, cell cycle regulation, and apoptosis in primary fibroblasts.
- Assessment of transcriptional activity using various activators and receptors.
Main Results:
- TRAP220 null mutants exhibit embryonic lethality due to heart failure and impaired neuronal development.
- Primary fibroblasts show cell cycle defects and reduced thyroid hormone receptor function.
- Haploinsufficiency leads to growth retardation, hypothyroidism, and widespread transcriptional defects.
Conclusions:
- TRAP220 is essential for multiple physiological processes, including embryonic development and organ function.
- TRAP220 exhibits selective functions, impacting specific genes and activators, particularly thyroid hormone receptors.