The Serum Response Factor (SRF) is likely to function as a regulator of activity-dependent gene expression in neurons. The SRF pathway activates gene expression in response to calcium influx through both L-type voltage sensitive calcium channels (VSCCs) and N-methyl D-aspartate (NMDA) receptor subtypes. In neurons, SRF appears to be a regulator of NMDA receptor-mediated gene expression. Experiments are proposed to elucidate the mechanism by which SRF mediates activity-dependent gene expression, using the c-fos gene as a model system. In the first aim, structure/function analyses of SRF mutants will be used to identify and characterize calcium-responsive domain(s) in response to activation of VSCCs in PC12 cells. In the second aim, c-fos/beta-globin chimeric genes will be used to identify coding region sequence determinants involved in regulating the calcium response and to characterize their mechanism of action. In the third aim, the involvement of SRF in calcium-dependent regulation of c-fos activity will be examined in cultured neurons when NMDA receptors are activated by either synaptic activity or by the neurotransmitter glutamate.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29NS036256-01A1
Application #
2488247
Study Section
Neurology C Study Section (NEUC)
Program Officer
Baughman, Robert W
Project Start
1997-09-30
Project End
2002-05-31
Budget Start
1997-09-30
Budget End
1998-05-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Major, Michael L; Cheung, Herman S; Misra, Ravi P (2007) Basic calcium phosphate crystals activate c-fos expression through a Ras/ERK dependent signaling mechanism. Biochem Biophys Res Commun 355:654-60
Misra, R P; Bronson, S K; Xiao, Q et al. (2001) Generation of single-copy transgenic mouse embryos directly from ES cells by tetraploid embryo complementation. BMC Biotechnol 1:12
Miano, J M; Carlson, M J; Spencer, J A et al. (2000) Serum response factor-dependent regulation of the smooth muscle calponin gene. J Biol Chem 275:9814-22
Misra, R P (2000) Calcium and disease: molecular determinants of calcium crystal deposition diseases. Cell Mol Life Sci 57:421-8
Spencer, J A; Misra, R P (1999) Expression of the SRF gene occurs through a Ras/Sp/SRF-mediated-mechanism in response to serum growth signals. Oncogene 18:7319-27
Spencer, J A; Major, M L; Misra, R P (1999) Basic fibroblast growth factor activates serum response factor gene expression by multiple distinct signaling mechanisms. Mol Cell Biol 19:3977-88