FE65 is an adapter protein composed of three protein-protein interaction domains. It contains a WW domain and two PI domains. FE65 binds to APP through its carboxy-terminal PI domain (PID2). FE65 was initially described as a transcriptional activator, which can be found both in the nucleus and the cytoplasm. It was later shown to bind the cytoplasmic domain of APP and to profoundly alter APP processing and trafficking. Recent reports have shown that FE65 can localize to the nucleus and that full-length APP serves as a cytosolic anchor for FE65. FE65 PID1 can bind the transcription factor CP2/LSF/LBP1 and can also bind the histone acetyl transferase Tip60 in the nucleus and modulate transcription. In analogy to the notch intracellular domain (NICD), it is suggested that FE65 binds to the gamma-cleaved cytoplasmic tail of APP (gamma-CTF) and translocates to the nucleus where it binds Tip60 and activates transcription. The central hypothesis of this proposal is that a complex, including the gamma-CTF fragment of APP and the adaptor FE65, is a regulator of transcription.
The specific aims of this proposal are:
Specific Aim 1. To identify the nuclear macromolecular complex that involves FE65 and the gamma-cleaved cytoplasmic tail of APP.
Specific Aim 2. To discover genes whose transcription is regulated by the FE65/gamma-CTF complex.
Specific Aim 3. To elucidate signals that regulate the formation and nuclear translocation of the FE65/gamma-CTF complex.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021792-03
Application #
6923619
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Snyder, Stephen D
Project Start
2003-09-01
Project End
2008-07-31
Budget Start
2005-08-15
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$339,000
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Kajiwara, Yuji; Akram, Afia; Katsel, Pavel et al. (2009) FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4. PLoS One 4:e5071
Zaidi, Nikhat F; Kuplast, Kristy G; Washicosky, Kevin J et al. (2006) Calsenilin interacts with transcriptional co-repressor C-terminal binding protein(s). J Neurochem 98:1290-301