Fe65, a ligand of the Alzheimer's β-amyloid precursor protein, blocks cell cycle progression by down-regulating thymidylate synthase expression

Paola Bruni, Giuseppina Minopoli, Tiziana Brancaccio, Maria Napolitano, Raffaella Faraonio, Nicola Zambrano, Ulla Hansen, Tommaso Russo

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

The functions of the Alzheimer's β-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.

Original languageEnglish
Pages (from-to)35481-35488
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number38
DOIs
Publication statusPublished - Sep 20 2002

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Thymidylate Synthase
Amyloid beta-Protein Precursor
Fibroblasts
Cell Cycle
Cells
Ligands
Genes
Gene expression
Thymidine
Culture Media
Chemical activation
Amyloidogenic Proteins
Gene Expression
Proteins
Protein Precursors
PC12 Cells
Transcription
Nuclear Proteins
Anchors
Serum

ASJC Scopus subject areas

  • Biochemistry

Cite this

Fe65, a ligand of the Alzheimer's β-amyloid precursor protein, blocks cell cycle progression by down-regulating thymidylate synthase expression. / Bruni, Paola; Minopoli, Giuseppina; Brancaccio, Tiziana; Napolitano, Maria; Faraonio, Raffaella; Zambrano, Nicola; Hansen, Ulla; Russo, Tommaso.

In: Journal of Biological Chemistry, Vol. 277, No. 38, 20.09.2002, p. 35481-35488.

Research output: Contribution to journalArticle

Bruni, Paola ; Minopoli, Giuseppina ; Brancaccio, Tiziana ; Napolitano, Maria ; Faraonio, Raffaella ; Zambrano, Nicola ; Hansen, Ulla ; Russo, Tommaso. / Fe65, a ligand of the Alzheimer's β-amyloid precursor protein, blocks cell cycle progression by down-regulating thymidylate synthase expression. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 38. pp. 35481-35488.
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AU - Napolitano, Maria

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AU - Hansen, Ulla

AU - Russo, Tommaso

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AB - The functions of the Alzheimer's β-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.

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