Date of Degree
PhD (Doctor of Philosophy)
Robert A. Philibert
MED12 is an X– chromosome member of the Mediator complex that is a key regulator of tissue specific gene expression and moderates intracellular signaling via multiple developmental pathways. Sequence variation in the carboxy– terminus of MED12, which contains a PQL and Opa domain, is associated with X– linked mental retardation behavioral syndromes and schizophrenia. Unfortunately, the mechanism(s) through which sequence variation in the carboxy– terminus could alter vulnerability to neurodevelopmental and neuropsychiatric illnesses is yet unclear.
In order to elucidate a better understanding of this process, we examined the role of the MED12 carboxy– terminus in cell cycle and gene expression with a full– length overexpression construct, domain deleted overexpression constructs and RNA interference using a HEK293 cell model. Our results show that MED12 overexpression leads to G1 cell cycle exit, whereas deletion of the PQL domain and MED12 RNA interference results in cell cycle progression. Our data also show that MED12 expression level differentially affects early response antiviral gene expression and stress response mechanisms. These results are consistent with prior studies showing that MED12 has a key role in determining neuronal cell fate and with the theoretical understanding of the biological basis of psychosis. These results also lend further insight upon the pathways through which MED12 exerts its effects upon differentiation and disease pathogenesis, which may lead to new approaches to the treatment of MED12– related disorders.
2, x, 116 pages
Includes bibliographical references (pages 104-116).
Copyright 2011 Pamela Joy Wernett