Identification and Characterization of a κB/Rel Binding Site in the Regulatory Region of the Amyloid Precursor Protein Gene

Grilli, Mariagrazia; Ribola, Marina; Alberici, Antonella; Valerio, Alessandra; Memo, Maurizio; Spano, PierFranco

doi:10.1074/jbc.270.45.26774

Cited by 86 publications

(47 citation statements)

References 34 publications

(24 reference statements)

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“…We now show that an APP B binding activity is constitutively present in neuronal primary cultures from rat cerebellum. As far as specificity, affinity, and immunogenicity, the nuclear complex is identical to the one previously identified in rat brain, in T lymphocytes and cell lines of various origin (20). As postulated previously, also in neuronal cultures the APP B binding complex appears likely to correspond to a p50 homodimer.…”

Section: Discussionsupporting

confidence: 78%

“…Specificity of results was confirmed with preimmune serum or by incubating the antisera with the peptides against which they were raised (not shown). In conclusion, an APP B binding activity, with the same affinity properties and immunogenicity as the one previously identified from rat brain areas and cell lines of various origin (20), is also present in primary neurons.…”

Section: The App B Binding Complex From Cerebellar Granule Cells Is Isupporting

confidence: 73%

“…We have recently reported the identification of two identical sequences located in the 5Ј-regulatory region of the APP gene which are specific binding sites for regulatory members of the NF-B/Rel family of transcription factors (20). The NF-B family is composed of several distinct DNA binding subunits (including p50, p52, or p50B, p65 or RelA, c-Rel, RelB) which can hetero-and homodimerize, thereby forming complexes with distinct cell type distribution, DNA sequence specificity, and transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

“…In most cell types, these regulators mediate an early pathogen response by coordinately initiating transcription of genes involved in inflammatory, immune, and acute phase responses (21,22). In particular, we demonstrated that two identical decameric sequences corresponding to 5Ј-GGGGTTTCAC-3Ј, located in the 5Ј-regulatory region of the APP gene, are able to specifically bind NF-B/Rel proteins (20). The sites, which we referred to as APP B sites, interact with a B complex which is constitutively expressed in different rat brain areas and in several cell lines, where levels of this DNA binding activity correlates with APP mRNA content.…”

mentioning

confidence: 90%

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Interleukin-1β and Glutamate Activate the NF-κB/Rel Binding Site from the Regulatory Region of the Amyloid Precursor Protein Gene in Primary Neuronal Cultures

Grilli

Goffi

Memo

et al. 1996

Journal of Biological Chemistry

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143

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We originally reported that members of the family of transcription factors NF-B/Rel can specifically recognize two identical sequences, referred to as APP B sites, which are present in the 5 -regulatory region of the APP gene. Here we show that the APP B sites interact specifically with a complex which contains one of the subunits of the family, defined as p50 protein, and that they act as positive modulators of gene transcription in cells of neural origin. Additionally, the nuclear complex specifically binding to the APP B sites is constitutively expressed in primary neurons from rat cerebellum and it is up-regulated in response to both the inflammatory cytokine interleukin-1␤ (IL-1␤) and the excitatory amino acid glutamate. Since IL-1, whose levels are known to be induced in brain of individuals affected by Alzheimer's disease, and glutamate, are stimuli which have been regarded as major actors on the stage of neurodegenerative processes, we believe our evidence as potentially relevant for understanding the neuropathology associated with Alzheimer's disease.Alzheimer's disease (AD) 1 is a neurodegenerative disorder characterized by abnormal deposition of extracellular congophilic plaques in the brain. The main constituent of plaques is a 39-to 43-amino acid peptide, named ␤-amyloid, which is a proteolytic fragment of the amyloid precursor protein (APP) (1). In recent years, most experimental studies have been aimed at understanding the mechanisms of ␤-amyloid formation and deposition and at identifying potential risk factors which may favor these processes. In particular, APP gene mutations occurring in families with Familial AD have been correlated with disturbance in protein processing, which in turn, may predispose to ␤ amyloid formation (2, 3). However, since APP gene mutations represent a minor percentage of AD cases, it is evident that other mechanisms may exist to account for ␤-amyloid deposition. In this regard, it should not be underestimated that overexpression of the APP gene may be involved in the pathogenetic mechanisms of amyloid formation, at least in some clinical forms of the disease. Several observations underscore the potential contribution of the APP gene overexpression to favoring AD neuropathology: (i) the marked accumulation of ␤-amyloid which correlates with increased levels of APP mRNA in trisomy 21 (Down's syndrome) (4); (ii) the increased levels of APP gene transcripts in specific areas of the AD brains (5-7); (iii) the increased APP mRNA transcription in cultured fibroblasts from the Familial Alzheimer's disease-1 family (8). In addition, post-mitotic neurons which overexpress full-length APP were shown to degenerate and accumulate large amounts of amyloidogenic C-terminal fragments (9). The promoter region of the APP gene (10) has been shown to contain binding sequences for several known transcription factors (11)(12)(13)(14)(15)(16)(17)(18)(19). We reported recently (20) that a novel regulatory pathway for APP gene control at the transcriptional level may involve members of the NF...

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Section: Discussionsupporting

confidence: 78%

Section: The App B Binding Complex From Cerebellar Granule Cells Is Isupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

See 2 more Smart Citations

Interleukin-1β and Glutamate Activate the NF-κB/Rel Binding Site from the Regulatory Region of the Amyloid Precursor Protein Gene in Primary Neuronal Cultures

Grilli

Goffi

Memo

et al. 1996

Journal of Biological Chemistry

Self Cite

143

View full text Add to dashboard Cite

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“…APP-BP1 was initially identified as a protein that interacts with APP. Interestingly, the expression of APP apparently is regulated by NF-jB (Grilli et al 1995). The APP gene is rapidly transcribed in the brain in response to a number of stress conditions, including head trauma, focal ischemia, neurotoxicity, and heat shock (reviewed in O'Neill and Kaltschmidt 1997; Ghosh et al 1998;Perkins 2000).…”

Section: Discussionmentioning

confidence: 99%

ASPP2 inhibits APP‐BP1‐mediated NEDD8 conjugation to cullin‐1 and decreases APP‐BP1‐induced cell proliferation and neuronal apoptosis

Chen

Liu

Naumovski

et al. 2003

Journal of Neurochemistry

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APP-BP1, first identified as a protein that interacts with the carboxyl (C) terminus of the amyloid precursor protein (APP), is one-half of the bipartite activating enzyme for the ubiquitinlike protein NEDD8. We report here that APP-BP1 also specifically interacts with apoptosis stimulating protein of p53 ASPP2 in non-transfected cells through the functional predominant N-terminal domain ASPP2(332-483). ASPP2 inhibits the ability of APP-BP1 to rescue the ts41 cell cycle mutation and inhibits APP-BP1 induced apoptosis in primary neurons. ASPP2 reduces the ability of NEDD8 to conjugate to Cullin-1, inhibits APP-BP1-dependent ts41 cell proliferation, and blocks the ability of APP-BP1 to cause apoptosis and to cause DNA synthesis in neurons. We also show that ASPP2 activates nuclear factor-jB (NF-jB) transcriptional activity, which seems to be inhibited by the neddylation pathway since the dominant negative NEDD8 activating enzyme causes enhanced NF-jB activity. Our data provide the first in vivo evidence that ASPP2 is a negative regulator of the neddylation pathway through specific interaction with APP-BP1 and suggest that dysfunction of the APP-BP1 interaction with APP may be one cause of Alzheimer's disease.

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Polymorphisms in the Promoter of the Human APP Gene

Athan¹,

Lee²,

Arriaga³

et al. 2002

Arch Neurol

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Identification and Characterization of a κB/Rel Binding Site in the Regulatory Region of the Amyloid Precursor Protein Gene

Cited by 86 publications

References 34 publications

Interleukin-1β and Glutamate Activate the NF-κB/Rel Binding Site from the Regulatory Region of the Amyloid Precursor Protein Gene in Primary Neuronal Cultures

Interleukin-1β and Glutamate Activate the NF-κB/Rel Binding Site from the Regulatory Region of the Amyloid Precursor Protein Gene in Primary Neuronal Cultures

ASPP2 inhibits APP‐BP1‐mediated NEDD8 conjugation to cullin‐1 and decreases APP‐BP1‐induced cell proliferation and neuronal apoptosis

Polymorphisms in the Promoter of the Human APP Gene

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