DNA microarray profiling of developing PS1-deficient mouse brain reveals complex and coregulated expression changes

Mirnics, Z. K.; Mirnics, Károly; Terrano, David; Lewis, David A.; Sisodia, Sangram S.; Schor, Nina F.

doi:10.1038/sj.mp.4001389

Cited by 30 publications

(20 citation statements)

References 88 publications

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“…Cleavage of p75NTR by this protease results in intracellular release of p75ICD (Jung et al, 2003;Kanninget et al, 2003). Finally, microarray analyses of the brains of presenilin-1-deficient or -mutant mice and of p75NTR-deficient PC12 cells exhibit the same set of genes with altered expression relative to the brains of wild-type mice and to wild-type PC12 cells, respectively (Mirnics et al, 2003;Yan et al, 2004).…”

Section: Fig 11mentioning

confidence: 99%

The intracellular domain of p75NTR as a determinant of cellular reducing potential and response to oxidant stress

et al. 2005

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SummaryThe low-affinity neurotrophin receptor, p75NTR, has been found to be pro-or anti-apoptotic depending upon the cell in which it is expressed. Reactive oxygen species play a major role in apoptosis induction and enactment. Using two polyclonal PC12 populations that, respectively, do or do not express p75NTR, this paper demonstrates that p75NTR expression confers resistance to oxidant stress upon PC12 cells maintained in serum-containing medium. The effect of p75NTR on cell survival is mimicked in p75-negative cells by expression of constructs that produce the p75NTR intracellular domain (ICD) or p75NTR with the extracellular domain deleted (∆ ∆ ∆ ∆ ECD), suggesting that binding of an extracellular ligand to p75NTR is not required. Our studies further document that the differential sensitivity to oxidant stress is serum-dependent and associated with differential oxidation of glutathione between p75-positive and p75-negative cells. These results suggest that the role of p75NTR in determining the consequences and treatment of age-related disorders and conditions in which reactive oxygen species are involved may require neither the extracellular receptor domain nor, by inference, the cognate extracellular ligands of this neurotrophin receptor.

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Section: Fig 11mentioning

confidence: 99%

The intracellular domain of p75NTR as a determinant of cellular reducing potential and response to oxidant stress

et al. 2005

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“…Over the last several years, we have seen a revolution in highthroughput expression profiling of diseased human brain tissue (Ginsberg et al, 2000;Ho et al, 2001;Loring et al, 2001;Colangelo et al, 2002;Mufson et al, 2002;Yao et al, 2003;Blalock et al, 2004) and various models of human brain disorders (Dickey et al, 2003(Dickey et al, , 2004Marcotte et al, 2003;Mirnics et al, 2003;Gan et al, 2004;Wang et al, 2004). Although the expression profiling of AD tissue continues to generate data of enormous potential, the interpretation of the postmortem findings is greatly complicated by the nature of AD disease progress (Mirnics et al, 2001a;Marcotte et al, 2003;Mirnics and Pevsner, 2004).…”

Section: Introductionmentioning

confidence: 99%

Presenilin-1-Dependent Transcriptome Changes

et al. 2005

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Familial forms of Alzheimer's disease (FADs) are caused by the expression of mutant presenilin 1 (PS1) or presenilin 2. Using DNA microarrays, we explored the brain transcription profiles of mice with conditional knock-out of PS1 (cKO PS1) in the forebrain. In parallel, we performed a transcription profiling of the hippocampus and frontal cortex of the FAD-linked ⌬E9 mutant transgenic (TG) mice and matched controls [TG mice expressing wild-type human PS1 (hPS1)]. When the TG and cKO datasets were cross-compared, the majority of the 30 common expression alterations were in opposite direction, suggesting that the FAD-linked PS1 variant produces transcriptome changes primarily by gain of aberrant function. Our microarray studies also revealed an unanticipated inverse correlation of transcript levels between the brains of mice that coexpress ⌬E9 hPS1ϩ amyloid precursor protein (APP) 695 Swe and ⌬E9 hPS1 single transgenic mice. The opposite directionality of these changes in transcript levels must be a function of APP and/or APP derivatives.

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“…It is sequentially unrelated to any structurally characterized protein and was originally found expressed in the lateral neocortex of rats. It is a marker of regionality and development in both central and peripheral rodent nervous systems and is down-regulated in the presenilin-1-deficient mouse brain, thus putatively playing a role in Alzheimer's disease (1,2). The identification of latexin as an inhibitor of carboxypeptidase (CP) A (CPA) in a series of non-pancreatic tissues led to its isolation from the rat brain (3,4).…”

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confidence: 99%

Structure of human carboxypeptidase A4 with its endogenous protein inhibitor, latexin

Pallarès

Bonet

García‐Castellanos

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The only endogenous protein inhibitor known for metallocarboxypeptidases (MCPs) is latexin, a 25-kDa protein discovered in the rat brain. Latexin, alias endogenous carboxypeptidase inhibitor, inhibits human CPA4 (hCPA4), whose expression is induced in prostate cancer cells after treatment with histone deacetylase inhibitors. hCPA4 is a member of the A͞B subfamily of MCPs and displays the characteristic ␣͞␤-hydrolase fold. Human latexin consists of two topologically equivalent subdomains, reminiscent of cystatins, consisting of an ␣-helix enveloped by a curved ␤-sheet. These subdomains are packed against each other through the helices and linked by a connecting segment encompassing a third ␣-helix. The enzyme is bound at the interface of these subdomains. The complex occludes a large contact surface but makes rather few contacts, despite a nanomolar inhibition constant. This low specificity explains the flexibility of latexin in inhibiting all vertebrate A͞B MCPs tested, even across species barriers. In contrast, modeling studies reveal why the N͞E subfamily of MCPs and invertebrate A͞B MCPs are not inhibited. Major differences in the loop segments shaping the border of the funnel-like access to the protease active site impede complex formation with latexin. Several sequences ascribable to diverse tissues and organs have been identified in vertebrate genomes as being highly similar to latexin. They are proposed to constitute the latexin family of potential inhibitors. Because they are ubiquitous, latexins could represent for vertebrate A͞B MCPs the counterparts of tissue inhibitors of metalloproteases for matrix metalloproteinases.metallocarboxypeptidase ͉ metalloprotease ͉ x-ray crystal structure

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DNA microarray profiling of developing PS1-deficient mouse brain reveals complex and coregulated expression changes

Cited by 30 publications

References 88 publications

The intracellular domain of p75NTR as a determinant of cellular reducing potential and response to oxidant stress

The intracellular domain of p75NTR as a determinant of cellular reducing potential and response to oxidant stress

Presenilin-1-Dependent Transcriptome Changes

Structure of human carboxypeptidase A4 with its endogenous protein inhibitor, latexin

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