scholarly journals Supra-physiological folic acid concentrations induce aberrant DNA methylation in normal human cells in vitro

Epigenetics ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. 689-694 ◽  
Author(s):  
Michelle A. Charles ◽  
Ian T. Johnson ◽  
Nigel J. Belshaw
Keyword(s):  
Dna Methylation ◽  
Folic Acid ◽  
Human Cells ◽  
Normal Human ◽  
Normal Human Cells ◽  
Aberrant Dna Methylation

Studies of X chromosome DNA methylation in normal human cells

Nature ◽  
1982 ◽  
Vol 295 (5851) ◽  
pp. 667-671 ◽  
Author(s):  
Stanley F. Wolf ◽  
Barbara R. Migeon
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Human Cells ◽  
Normal Human ◽  
Normal Human Cells

scholarly journals EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in immortalized normal human cells

2020 ◽  
Author(s):  
Akihiko Miyanaga ◽  
Masaru Matsumoto ◽  
Jessica A. Beck ◽  
Izumi Horikawa ◽  
Takahiro Oike ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Human Cells ◽  
Functional Study ◽  
Sequencing Analysis ◽  
Anchorage Independent Growth ◽  
Normal Human ◽  
Normal Human Cells

Abstract Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells.Methods: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes.Results: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with senescence-associated b-galactosidase activity, upregulation of p16INK4A and p21WAF1, and accumulated DNA damage. In contrast, when EML4-ALK was expressed in normal human fibroblasts immortalized by telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and immortalized cells, but RNA sequencing analysis suggested that the different STAT3-regulated signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice.Conclusions: Our data indicate that the immortalized state is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.

scholarly journals EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells

2020 ◽  
Author(s):  
Akihiko Miyanaga ◽  
Masaru Matsumoto ◽  
Jessica A. Beck ◽  
Izumi Horikawa ◽  
Takahiro Oike ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Human Cells ◽  
Functional Study ◽  
Sequencing Analysis ◽  
Anchorage Independent Growth ◽  
Normal Human ◽  
Normal Human Cells

Abstract Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells.Methods: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes.Results: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated b-galactosidase (SA-β-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice.Conclusions: Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.

scholarly journals EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Akihiko Miyanaga ◽  
Masaru Matsumoto ◽  
Jessica A. Beck ◽  
Izumi Horikawa ◽  
Takahiro Oike ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Human Cells ◽  
Functional Study ◽  
Sequencing Analysis ◽  
Anchorage Independent Growth ◽  
Normal Human ◽  
Normal Human Cells

Abstract Background Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. Methods Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. Results The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated β-galactosidase (SA-β-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice. Conclusions Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.

scholarly journals EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells

2020 ◽  
Author(s):  
Akihiko Miyanaga ◽  
Masaru Matsumoto ◽  
Jessica A. Beck ◽  
Izumi Horikawa ◽  
Takahiro Oike ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Human Cells ◽  
Functional Study ◽  
Sequencing Analysis ◽  
Anchorage Independent Growth ◽  
Normal Human ◽  
Normal Human Cells

Abstract Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells.Methods: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes.Results: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated b-galactosidase (SA-β-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice.Conclusions: Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.

scholarly journals Aberrant DNA methylation of imprinted loci in hepatocellular carcinoma and after in vitro exposure to common risk factors

2015 ◽  
Vol 7 (1) ◽  
pp. 15 ◽  
Author(s):  
Marie-Pierre Lambert ◽  
Pierre-Benoit Ancey ◽  
Davide Esposti ◽  
Marie-Pierre Cros ◽  
Athena Sklias ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hepatocellular Carcinoma ◽  
Dna Methylation ◽  
In Vitro Exposure ◽  
Common Risk Factors ◽  
Aberrant Dna Methylation

scholarly journals Knockdown of αII spectrin in normal human cells by siRNA leads to chromosomal instability and decreased DNA interstrand cross-link repair

2009 ◽  
Vol 381 (2) ◽  
pp. 288-293 ◽  
Author(s):  
Laura W. McMahon ◽  
Pan Zhang ◽  
Deepa M. Sridharan ◽  
Joel A. Lefferts ◽  
Muriel W. Lambert
Keyword(s):  
Chromosomal Instability ◽  
Human Cells ◽  
Cross Link ◽  
Normal Human ◽  
Normal Human Cells
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