Differentially expressed genes in embryonic cardiac tissues of mice lacking Folr1gene activity

Zhu, Huiping; Cabrera, Robert M.; Wlodarczyk, Bogdan J.; Bozinov, Daniel; Wang, Deli; Schwartz, Robert J.; Finnell, Richard H.

doi:10.1186/1471-213x-7-128

Cited by 28 publications

(25 citation statements)

References 49 publications

(43 reference statements)

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“…The increase in levels of C 16 -, C 24 -, and C 24:1 -ceramides upon Aldh1l1 expression, observed in our experiments, suggested that the ceramide signaling pathways are involved in folate stress response. This increase could be a nonspecific postapoptotic accumulation of ceramide species.…”

Section: Discussionmentioning

confidence: 65%

“…2C). LC-MS/MS analysis has further shown that CerS6 knockdown prevented the increase in C 16 -, C 24 -, and C 24:1 -ceramide in response to Aldh1l1 (Fig. 2D).…”

Section: Expression Of Aldh1l1 In A549 Cellsmentioning

confidence: 99%

“…Folate also participates in the regeneration of methionine from homocysteine, a process linked to the biosynthesis of S-adenosylmethionine, a key molecule for methylation reactions in the cell (20,21). In agreement with the fundamental role of folate for cellular processes, folate deficiency causes dramatic consequences including altered protein expression (22)(23)(24), accumulation of DNA damage, increased chromosomal aberrations and fragility (25,26), reduced growth rate, and impaired cell division (27). Folate availability and efficient folate metabolism are especially crucial for rapidly proliferating cells, including cancer cells that serves as the basis for treatment of cancers with folate antimetabolites (antifolates), compounds inhibiting folate-metabolizing enzymes (28,29).…”

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confidence: 99%

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Folate Stress Induces Apoptosis via p53-dependent de Novo Ceramide Synthesis and Up-regulation of Ceramide Synthase 6

Hoeferlin¹,

Fekry²,

Öğretmen

et al. 2013

Journal of Biological Chemistry

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Background: Sphingolipid ceramide regulates cellular responses to stress stimuli. Results: Aldh1l1, the enzyme regulating folate metabolism, leads to CerS6 up-regulation and C 16 -ceramide accumulation in a p53-dependent manner as a proapoptotic signal. Conclusion: Ceramide mediates the cellular response to nongenotoxic folate stress. Significance: We have demonstrated the interaction between two major metabolic pathways, folate and sphingolipids, in regulation of cellular homeostasis.

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Section: Discussionmentioning

confidence: 65%

“…2C). LC-MS/MS analysis has further shown that CerS6 knockdown prevented the increase in C 16 -, C 24 -, and C 24:1 -ceramide in response to Aldh1l1 (Fig. 2D).…”

Section: Expression Of Aldh1l1 In A549 Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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Folate Stress Induces Apoptosis via p53-dependent de Novo Ceramide Synthesis and Up-regulation of Ceramide Synthase 6

Hoeferlin¹,

Fekry²,

Öğretmen

et al. 2013

Journal of Biological Chemistry

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“…Gene ontology analysis was performed using the Gene Ontology Tree Machine (GOTM) (Bioinformatics, Vanderbilt University), and applying differentially expressed genes as depicted in the heat maps. We chose a single gene set analysis, where GOTM compares the distribution of single gene sets in each GO category to those in an existing reference gene list from the mouse genome, identifying GO categories with statistically significant enriched gene numbers as determined by the hypergeometric test (p Ͻ 0.01) (20,21). Real time quantitative RT-PCR was used to confirm the data obtained for selected genes in DNA repair pathways as described above.…”

Section: Methodsmentioning

confidence: 99%

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Ventrella-Lucente¹,

Unnikrishnan²,

Pilling³

et al. 2010

Journal of Biological Chemistry

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Aging and DNA polymerase ␤ deficiency (␤-pol ؉/؊ ) interact to accelerate the development of malignant lymphomas and adenocarcinoma and increase tumor bearing load in mice. Folate deficiency (FD) has been shown to induce DNA damage repaired via the base excision repair (BER) pathway. We anticipated that FD and BER deficiency would interact to accelerate aberrant crypt foci (ACF) formation and tumor development in ␤-pol haploinsufficient animals. FD resulted in a significant increase in ACF formation in wild type (WT) animals exposed to 1,2-dimethylhydrazine, a known colon and liver carcinogen; however, FD reduced development of ACF in ␤-pol haploinsufficient mice. Prolonged feeding of the FD diet resulted in advanced ACF formation and liver tumors in wild type mice. However, FD attenuated onset and progression of ACF and prevented liver tumorigenesis in ␤-pol haploinsufficient mice, i.e. FD provided protection against tumorigenesis in a BER-deficient environment in all tissues where 1,2-dimethylhydrazine exerts its damage. Here we show a distinct down-regulation in DNA repair pathways, e.g. BER, nucleotide excision repair, and mismatch repair, and decline in cell proliferation, as well as an up-regulation in poly(ADP-ribose) polymerase, proapoptotic genes, and apoptosis in colons of FD ␤-pol haploinsufficient mice.Folate deficiency is an important public health concern because of the role folate plays in the development of many different health problems, including neural tube defects, cardiovascular disease, Alzheimer disease, and cancer, specifically colon cancer. It has been proposed that the carcinogenic properties of folate deficiency may be related to a decrease in DNA methylation, perhaps as a function of reduced S-adenosylmethionine levels, an increase in the uracil content of DNA, or an increase in oxidative stress by alterations in thiol switches. Folate deficiency has also been shown to increase (in cells, animal models, and humans) levels of single strand breaks (1-5), micronucleus formation (6, 7), chromosomal aberration (8, 9), and mutation frequency (10, 11), all potentially downstream effects of high levels of uracil in DNA and oxidative damage to DNA.The DNA repair pathway for removal of uracil and oxidized bases is the base excision repair (BER) 2 pathway. The BER pathway is believed to repair small, non-helix-distorting lesions in the DNA. It has been estimated to be responsible for the repair of as many as one million nucleotides per cell per day (12), stressing its importance in the maintenance of genomic stability. It has been suggested that BER has evolved in response to in vivo exposure of DNA to reactive oxygen species and endogenous alkylation, and that this pathway suppresses spontaneous mutagenesis (13). In the initial elucidation of the BER pathway the following steps were involved: (i) removal of the damaged base by a DNA glycosylase; (ii) incision of the phosphate backbone by an endonuclease; (iii) synthesis of new DNA by a polymerase; (iv) excision of the deoxyribose phosphate moie...

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“…Tissue samples of normal or diseased model organisms or humans can be analyzed with the aid of microarray techniques [1][2][3][4][5][6]. Microarray studies provide information about the activity of thousands of genes in very short times.…”

Section: Gene Profilingmentioning

confidence: 99%

Episcopic 3D Imaging Methods: Tools for Researching Gene Function

2013

Advances in Genome Science: Changing Views on Living Organisms

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This work aims at describing episcopic 3D imaging methods and at discussing how these methods can contribute to researching the genetic mechanisms driving embryogenesis and tissue remodelling, and the genesis of pathologies. Several episcopic 3D imaging methods exist. The most advanced are capable of generating high-resolution volume data (voxel sizes from 0.5x0.5x1 m upwards) of small to large embryos of model organisms and tissue samples. Beside anatomy and tissue architecture, gene expression and gene product patterns can be three dimensionally analyzed in their precise anatomical and histological context with the aid of whole mount in situ hybridization or whole mount immunohistochemical staining techniques. Episcopic 3D imaging techniques were and are employed for analyzing the precise morphological phenotype of experimentally malformed, randomly produced, or genetically engineered embryos of biomedical model organisms. It has been shown that episcopic 3D imaging also fits for describing the spatial distribution of genes and gene products during embryogenesis, and that it can be used for analyzing tissue samples of adult model animals and humans. The latter offers the possibility to use episcopic 3D imaging techniques for researching the causality and treatment of pathologies or for staging cancer. Such applications, however, are not yet routine and currently only preliminary results are available. We conclude that, although episcopic 3D imaging is in its very beginnings, it represents an upcoming methodology, which in short terms will become an indispensable tool for researching the genetic regulation of embryo development as well as the genesis of malformations and diseases.

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Differentially expressed genes in embryonic cardiac tissues of mice lacking Folr1gene activity

Cited by 28 publications

References 49 publications

Folate Stress Induces Apoptosis via p53-dependent de Novo Ceramide Synthesis and Up-regulation of Ceramide Synthase 6

Folate Stress Induces Apoptosis via p53-dependent de Novo Ceramide Synthesis and Up-regulation of Ceramide Synthase 6

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Episcopic 3D Imaging Methods: Tools for Researching Gene Function

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