Methyltransferase-inhibition interferes with neuronal differentiation of P19 embryonal carcinoma cells

Hong, Sukchul; Heo, Jieun; Lee, Sang-Jin; Heo, Seok; Kim, Sung-Soo; Lee, Young Don; Kwon, Moosik; Hong, Sungyoul

doi:10.1016/j.bbrc.2008.10.089

Cited by 14 publications

(12 citation statements)

References 19 publications

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“…Therefore, we used these cells in our study to examine the regulatory role of transmethylation on APP processing. Interestingly, treatment of either cell type with PIMT siRNA and AdOX, a well-known inhibitor of transmethylation [20] , remarkably induced the release of Aβ 40 peptides (Figure 1), indicating the involvement of PIMT-mediated methylation in APP cleavage. Because numerous papers have shown that the secretion of Aβ 40 is accompanied by the release of additional γ-secretase-generated Aβ peptides, such as Aβ 38 , Aβ 42 , and Aβ 43 , it is likely that the production of these peptides would also be regulated by PIMT siRNA treatment.…”

Section: Discussionmentioning

confidence: 97%

Knock-down of protein L-isoaspartyl O-methyltransferase increases β-amyloid production by decreasing ADAM10 and ADAM17 levels

et al. 2011

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Aim: To examine the role of protein l-isoaspartyl o-methyltransferase (PIMT; EC 2.1.1.77) on the secretion of Aβ peptides. Methods: HEK293 APPsw cells were treated with PIMT siRNA or adenosine dialdehyde (AdOX), a broad-spectrum methyltransferase inhibitor. Under the conditions, the level of Aβ secretion and regulatory mechanism by PIMT were examined. Results: Knock-down of PIMT and treatment with AdOX significantly increased Aβ 40 secretion. Reductions in levels of PIMT decreased the secretion of soluble amyloid precursor protein alpha (sAPPα) without altering the total expression of APP or its membrane-bound C83 fragment. However, the levels of the C99 fragment generated by β-secretase were enhanced. Moreover, the decreased secretion of sAPPα resulting from PIMT knock-down seemed to be linked with the suppression of the expression of α-secretase gene products, α-disintegrin and metalloprotease 10 (ADAM10) and ADAM17, as indicated by Western blot analysis. In contrast, ADAM10 was not down-regulated in response to treatment with the protein arginine methyltransferase (PRMT) inhibitor, AMI-1. Conclusion: This study demonstrates a novel role for PIMT, but not PRMT, as a negative regulator of Aβ peptide formation and a potential protective factor in the pathogenesis of AD.

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Section: Discussionmentioning

confidence: 97%

Knock-down of protein L-isoaspartyl O-methyltransferase increases β-amyloid production by decreasing ADAM10 and ADAM17 levels

et al. 2011

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“…Instead, a growing number of trials have been conducted to find a new anticancer effect of SAM metabolism-related analogues (28)(29)(30). Sinefungin, which is a SAM analogue can compete for SAM binding and inhibit the activity of the SAM-dependent methyltransferases.…”

Section: Discussionmentioning

confidence: 99%

S-adenosyl methionine specifically protects the anticancer effect of 5-FU via DNMTs expression in human A549 lung cancer cells

Ham

Lee

Kim

2012

Molecular and Clinical Oncology

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Abstract. Cellular methylation is associated with stabilization of the chromatin structure. S-adenosyl methionine (SAM), a metabolite of methionine metabolism, is the methyl donor of essential cellular methyltransferase reactions. Using 3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyl tetrazolium bromide (MTT) assay, we found that combination treatment of SAM and 5-fluorouracil (5-FU) specifically protected the anticancer effect of 5-FU, whereas the combination of SAM and cisplatin had no effect. This result was confirmed by FACS analysis. The combination treatment of SAM and 5-FU significantly decreased the dead cell population, while the G1 cell population was slightly increased, suggesting that protection of SAM is not associated with the cell cycle arrest of DNA-damaging drugs. We also analyzed which cellular methylation-related proteins were involved in the protective effect. Results showed the expression of DNA methyltransferases (DNMTs) was decreased with 5-FU alone but was increased with the combination treatment of SAM and 5-FU, suggesting that SAM protects the anticancer effect of 5-FU by regulating the expression of DNMTs. Taken together, the results indicated that SAM specifically modulates the anticancer effect of the DNA damage agent 5-FU and this may be modulated by aberrant DNA methylation.

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“…The expression of neuronal markers and a glial marker after the induction of differentiation in P19-con and P19-dnbis cells was examined by PCR amplification. The used primers were as follows: NeuroD forward 5´-tcaaccctcggactttcttg-3´, NeuroD reverse 5´-cattaagctgggcactcatg-3´ (Hong et al, 2008), Mash-1 forward 5´-caagttggtcaacctgggtt-3´, Mash-1 reverse 5´-gctcttgttcctctgggcta-3´, GFAP forward 5´-tttctccttgtctcgaatga-3´, GFAP reverse 5´-ggtttcatcttggagcttct-3´ (Jing et al, 2009), GAPDH forward 5´-ggtgtgaacggatttggccgtatt-3´, GAPDH reverse 5´-ggccttgactgtgccgttgaattt-3´.…”

Section: Reverse Transcription Polymerase Chain Reaction (Rt-pcr) Anamentioning

confidence: 99%

Bis Is Involved in Glial Differentiation of P19 Cells Induced by Retinoic Acid

Yoon

Lee

et al. 2009

Korean J Physiol Pharmacol

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Previous observations suggest that Bis, a Bcl-2-binding protein, may play a role the neuronal and glial differentiation in vivo. To examine this further, we investigated Bis expression during the in vitro differentiation of P19 embryonic carcinoma cells induced by retinoic acid (RA). W estern blotting and RT-PCR assays showed that Bis expression was temporarily decreased during the free floating stage and then began to increase on day 6 after the induction of differentiation. Double immunostaining indicated that Bis-expressing cells do not express several markers of differentiation, including NeuN, MAP-2 and Tuj-1. However, some of the Bis-expressing cells also were stained with GFAP-antibodies, indicating that Bis is involved glial differentiation. Using an shRNA strategy, we developed bis-knock down P19 cells and compared them with control P19 cells for the expression of NeuroD, Mash-1 and GFAP during RA-induced differentiation. Among these, only GFAP induction was significantly attenuated in P19-dnbis cells and the population showing GFAP immunoreactivity was also decreased. It is noteworthy that distribution of mature neurons and migrating neurons was disorganized, and the close association of migrating neuroblasts with astrocytes was not observed in P19-dnbis cells. These results suggest that Bis is involved in the migration-inducing activity of glial cells.

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Methyltransferase-inhibition interferes with neuronal differentiation of P19 embryonal carcinoma cells

Cited by 14 publications

References 19 publications

Knock-down of protein L-isoaspartyl O-methyltransferase increases β-amyloid production by decreasing ADAM10 and ADAM17 levels

Knock-down of protein L-isoaspartyl O-methyltransferase increases β-amyloid production by decreasing ADAM10 and ADAM17 levels

S-adenosyl methionine specifically protects the anticancer effect of 5-FU via DNMTs expression in human A549 lung cancer cells

Bis Is Involved in Glial Differentiation of P19 Cells Induced by Retinoic Acid

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