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Gene expression profile in prion protein-deficient fibroblasts in culture.

ABSTRACT: To investigate the physiological function of the cellular isoform of prion protein (PrP(C)), the gene expression profile was studied by analyzing a cDNA expression array containing 597 clones of various functional classes in two distinct skin fibroblast cell lines designated SFK and SFH, established from PrP-deficient (PrP(-)(/-)) mice and PrP(+/+) mice, respectively. The cells were incubated in the culture medium with or without inclusion of basic fibroblast growth factor (bFGF). When SFK cells were compared with SFH cells in untreated conditions, the expression of 15 genes, including those essential for cell proliferation and adhesion, was reduced, whereas the expression of 27 genes, including those involved in the insulin-like growth factor-I (IGF-I) signaling pathway, was elevated. Northern blot analysis verified a significant down-regulation of the receptor tyrosine kinase substrate Eps8, cyclin D1, and CD44 mRNAs, and a substantial up-regulation of phosphatidylinositol 3-kinase p85, IGF-I, and serine protease inhibitor-2.2 mRNAs in SFK cells. The patterns of induction or reduction of gene expression after exposure to bFGF showed considerable overlap between both cell types. Furthermore, both Eps8 and CD44 mRNA levels were reduced greatly in the brain tissues of the cerebrum isolated from the PrP(-)(/-) mice. These results indicate that the disruption of the PrP gene resulted in an aberrant regulation of a battery of genes important for cell proliferation, differentiation, and survival, including those located in the Ras and Rac signaling pathways.

SUBMITTER: Satoh J

PROVIDER: S-EPMC1850192 | biostudies-literature | 2000 Jul

REPOSITORIES: biostudies-literature

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Gene expression profile in prion protein-deficient fibroblasts in culture.

Satoh J J Kuroda Y Y Katamine S S

The American journal of pathology 20000701 1

To investigate the physiological function of the cellular isoform of prion protein (PrP(C)), the gene expression profile was studied by analyzing a cDNA expression array containing 597 clones of various functional classes in two distinct skin fibroblast cell lines designated SFK and SFH, established from PrP-deficient (PrP(-)(/-)) mice and PrP(+/+) mice, respectively. The cells were incubated in the culture medium with or without inclusion of basic fibroblast growth factor (bFGF). When SFK cells ...[more]

PMID: 10880376

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Project description:Na+/H+ exchanger 3 (NHE3) provides a major route for intestinal Na+ absorption. NHE3 has been considered a target of proinflammatory cytokines and enteropathogenic bacteria, and impaired NHE3 expression and/or activity may be responsible for inflammation-associated diarrhea. However, the possibility of loss of NHE3 function reciprocally affecting gut immune homeostasis has not been investigated. In this report, we describe that NHE3-deficient mice spontaneously develop colitis restricted to distal colonic mucosa. NHE3(-/-) mice housed in a conventional facility exhibited phenotypic features such as mild diarrhea, occasional rectal prolapse, and reduced body weight. Genomewide microarray analysis identified not only a large group of transport genes that potentially represent an adaptive response, but also a considerable number of genes consistent with an inflammatory response. Histological examination demonstrated changes in the distal colon consistent with active inflammation, including crypt hyperplasia with an increased number of 5-bromo-2'-deoxyuridine-positive cells, diffuse neutrophilic infiltrate with concomitant 15-fold increase in matrix metalloproteinase 8 expression, an increased number of pSer276-RelA-positive cells, and a significant decrease in periodic acid-Schiff-positive goblet cells. Real-time PCR demonstrated elevated expression of inducible nitric oxide synthase (38-fold), TNF-alpha (6-fold), macrophage inflammatory protein-2 (48-fold), and IL-18 (3-fold) in the distal colon of NHE3(-/-) mice. NHE3(-/-) mice showed enhanced bacterial adhesion and translocation in the distal colon. Colitis was ameliorated by oral administration of broad-spectrum antibiotics. In conclusion, NHE3 deficiency leads to an exacerbated innate immune response, an observation suggesting a potentially novel role of NHE3 as a modifier gene, which when downregulated during infectious or chronic colitis may modulate the extent and severity of colonic inflammation.

Dataset Information

Gene expression profile in prion protein-deficient fibroblasts in culture.

Publications

Gene expression profile in prion protein-deficient fibroblasts in culture.

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