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J. Biol. Chem., Vol. 277, Issue 38, 35481-35488, September 20, 2002
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From the The functions of the Alzheimer's
Fe65, a Ligand of the Alzheimer's
-Amyloid Precursor Protein,
Blocks Cell Cycle Progression by Down-regulating Thymidylate Synthase
Expression*
§,§,,,,
, and**
Dipartimento di Biochimica e Biotecnologie
Mediche, Università di Napoli Federico II, 80131 Napoli, Italy,
¶ Istituto Nazionale dei Tumori "Fondazione Pascale," 80131 Napoli, Italy, and the Department of Biology, Boston
University, Boston, Massachusetts 02215
-amyloid precursor protein (APP) and of its complex with the adaptor
protein Fe65 are still unknown. We have demonstrated that Fe65 is also
a nuclear protein and APP functions as an extranuclear anchor, thus
preventing Fe65 nuclear translocation. According to this finding, it
was also demonstrated that Fe65 could play a role in the regulation of transcription. In the present paper we show that the overexpression of
Fe65 prevents G1 
S cell cycle progression of
serum-stimulated fibroblasts and that the contemporary overexpression
of APP abolishes this effect of Fe65. The overexpression of Fe65
completely abolishes the activation of a key S phase gene, the
thymidylate synthase (TS) gene, driven by the transcription factor
LSF/CP2/LBP1 (LSF). This phenomenon is observed only in experimental
conditions leading to the accumulation of Fe65 in the nucleus.
Similarly, the two other members of the Fe65 protein family, Fe65L1 and
Fe65L2, have been found to translocate into the nucleus and to prevent
the activation of the TS gene promoter induced by LSF. Two results support the hypothesis that the inhibitory effect of Fe65 on cell cycle
progression in fibroblasts is the result of the inhibition of TS gene
expression: (i) Fe65 overexpression, but not Fe65 and APP
co-expression, prevents the accumulation of endogenous TS upon the
exposure of cells to serum, and (ii) thymidine addition to the culture
medium completely overcomes the growth arrest caused by Fe65. In
neuronal PC12 cells, the overexpression of Fe65 or of Fe65L1 and Fe65L2
blocks cell cycle, as observed in fibroblasts, but thymidine
supplementation to culture medium does not revert this block,
thus suggesting that Fe65 proteins induce in neuronal cells a gene
expression program different from that activated in fibroblasts.
*
This work was supported in part by V Framework Program Grant
QLK6-1999-02238 of the European Union, Biogem-Italy, the Consiglio Nazionale delle Ricerche-Italy, "Programma Biotecnologie MURST L. 95/95"; by a grant from the Ministero della Sanità
"Progetto Alzheimer" (to T. R.); and a grant from
MURST-PRIN2000 (to N. Z.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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