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Published in: Journal of Hematology & Oncology 1/2013

Open Access 01-12-2013 | Research

Differential responses to genotoxic agents between induced pluripotent stem cells and tumor cell lines

Authors: Yinghua Lu, Dazhong Xu, Jing Zhou, Yupo Ma, Yongping Jiang, Wenxian Zeng, Wei Dai

Published in: Journal of Hematology & Oncology | Issue 1/2013

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Abstract

Given potential values of induced pluripotent stem (iPS) cells in basic biomedical research and regenerative medicine, it is important to understand how these cells regulate their genome stability in response to environmental toxins and carcinogens. The present study characterized the effect of Cr(VI), a well-known genotoxic agent and environmental carcinogen, on major molecular components of DNA damage response pathways in human iPS cells. We compared the effect of Cr(VI) on human iPS cells with two established cell lines, Tera-1 (teratoma origin) and BEAS-2B (lung epithelial origin). We also studied the effect of hydrogen peroxide and doxorubicin on modulating DNA damage responses in these cell types. We demonstrated that ATM and p53 phosphorylation is differentially regulated in human iPS cells compared with Tera-1 and BEAS-2B cells after exposure to various genotoxic agents. Moreover, we observed that inhibition of CK2, but not p38, promotes phosphorylation of p53S392 in iPS cells. Combined, our data reveal some unique features of DNA damage responses in human iPS cells.
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Literature
1.
go back to reference Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007, 131 (5): 861-872. 10.1016/j.cell.2007.11.019.CrossRefPubMed Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007, 131 (5): 861-872. 10.1016/j.cell.2007.11.019.CrossRefPubMed
2.
3.
go back to reference Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y: Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular abeta and differential drug responsiveness. Cell Stem Cell. 2013, 12 (4): 487-496. 10.1016/j.stem.2013.01.009.CrossRefPubMed Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y: Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular abeta and differential drug responsiveness. Cell Stem Cell. 2013, 12 (4): 487-496. 10.1016/j.stem.2013.01.009.CrossRefPubMed
4.
go back to reference Xu D, TM O, Shartava A, Fowles TC, Yang J, Fink LM: Isolation, characterization, and in vitro propagation of infantile hemangioma stem cells and an in vivo mouse model. J Hematol Oncol. 2011, 4: 54-10.1186/1756-8722-4-54.PubMedCentralCrossRefPubMed Xu D, TM O, Shartava A, Fowles TC, Yang J, Fink LM: Isolation, characterization, and in vitro propagation of infantile hemangioma stem cells and an in vivo mouse model. J Hematol Oncol. 2011, 4: 54-10.1186/1756-8722-4-54.PubMedCentralCrossRefPubMed
5.
go back to reference Yang J, Aguila JR, Alipio Z, Lai R, Fink LM, Ma Y: Enhanced self-renewal of hematopoietic stem/progenitor cells mediated by the stem cell gene Sall4. J Hematol Oncol. 2011, 4: 38-10.1186/1756-8722-4-38.PubMedCentralCrossRefPubMed Yang J, Aguila JR, Alipio Z, Lai R, Fink LM, Ma Y: Enhanced self-renewal of hematopoietic stem/progenitor cells mediated by the stem cell gene Sall4. J Hematol Oncol. 2011, 4: 38-10.1186/1756-8722-4-38.PubMedCentralCrossRefPubMed
6.
go back to reference Shi X, Mao Y, Knapton AD, Ding M, Rojanasakul Y, Gannett PM: Reaction of Cr(VI) with ascorbate and hydrogen peroxide generates hydroxyl radicals and causes DNA damage: role of a Cr(IV)-mediated Fenton-like reaction. Carcinogenesis. 1994, 15 (11): 2475-2478. 10.1093/carcin/15.11.2475.CrossRefPubMed Shi X, Mao Y, Knapton AD, Ding M, Rojanasakul Y, Gannett PM: Reaction of Cr(VI) with ascorbate and hydrogen peroxide generates hydroxyl radicals and causes DNA damage: role of a Cr(IV)-mediated Fenton-like reaction. Carcinogenesis. 1994, 15 (11): 2475-2478. 10.1093/carcin/15.11.2475.CrossRefPubMed
7.
go back to reference Chiu A, Katz AJ, Beaubier J, Chiu N, Shi X: Genetic and cellular mechanisms in chromium and nickel carcinogenesis considering epidemiologic findings. Mol Cell Biochem. 2004, 255 (1–2): 181-194.CrossRefPubMed Chiu A, Katz AJ, Beaubier J, Chiu N, Shi X: Genetic and cellular mechanisms in chromium and nickel carcinogenesis considering epidemiologic findings. Mol Cell Biochem. 2004, 255 (1–2): 181-194.CrossRefPubMed
8.
go back to reference Ding M, Shi X: Molecular mechanisms of Cr(VI)-induced carcinogenesis. Mol Cell Biochem. 2002, 234-235 (1–2): 293-300.CrossRefPubMed Ding M, Shi X: Molecular mechanisms of Cr(VI)-induced carcinogenesis. Mol Cell Biochem. 2002, 234-235 (1–2): 293-300.CrossRefPubMed
9.
go back to reference Langard S: One hundred years of chromium and cancer: a review of epidemiological evidence and selected case reports. Am J Ind Med. 1990, 17 (2): 189-215. 10.1002/ajim.4700170205.CrossRefPubMed Langard S: One hundred years of chromium and cancer: a review of epidemiological evidence and selected case reports. Am J Ind Med. 1990, 17 (2): 189-215. 10.1002/ajim.4700170205.CrossRefPubMed
10.
go back to reference Chen L, Ovesen JL, Puga A, Xia Y: Distinct contributions of JNK and p38 to chromium cytotoxicity and inhibition of murine embryonic stem cell differentiation. Environ Health Perspect. 2009, 117 (7): 1124-1130.PubMedCentralCrossRefPubMed Chen L, Ovesen JL, Puga A, Xia Y: Distinct contributions of JNK and p38 to chromium cytotoxicity and inhibition of murine embryonic stem cell differentiation. Environ Health Perspect. 2009, 117 (7): 1124-1130.PubMedCentralCrossRefPubMed
11.
go back to reference Momcilovic O, Knobloch L, Fornsaglio J, Varum S, Easley C, Schatten G: DNA damage responses in human induced pluripotent stem cells and embryonic stem cells. PLoS One. 2010, 5 (10): e13410-10.1371/journal.pone.0013410.PubMedCentralCrossRefPubMed Momcilovic O, Knobloch L, Fornsaglio J, Varum S, Easley C, Schatten G: DNA damage responses in human induced pluripotent stem cells and embryonic stem cells. PLoS One. 2010, 5 (10): e13410-10.1371/journal.pone.0013410.PubMedCentralCrossRefPubMed
12.
go back to reference Su TT: Cellular responses to DNA damage: one signal, multiple choices. Annu Rev Genet. 2006, 40: 187-208. 10.1146/annurev.genet.40.110405.090428.CrossRefPubMed Su TT: Cellular responses to DNA damage: one signal, multiple choices. Annu Rev Genet. 2006, 40: 187-208. 10.1146/annurev.genet.40.110405.090428.CrossRefPubMed
13.
go back to reference Meek DW: Tumour suppression by p53: a role for the DNA damage response?. Nat Rev Cancer. 2009, 9 (10): 714-723.PubMed Meek DW: Tumour suppression by p53: a role for the DNA damage response?. Nat Rev Cancer. 2009, 9 (10): 714-723.PubMed
14.
go back to reference Sharma A, Singh K, Almasan A: Histone H2AX phosphorylation: a marker for DNA damage. Methods Mol Biol. 2012, 920: 613-626. 10.1007/978-1-61779-998-3_40.CrossRefPubMed Sharma A, Singh K, Almasan A: Histone H2AX phosphorylation: a marker for DNA damage. Methods Mol Biol. 2012, 920: 613-626. 10.1007/978-1-61779-998-3_40.CrossRefPubMed
15.
go back to reference Toledo F, Wahl GM: Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006, 6 (12): 909-923. 10.1038/nrc2012.CrossRefPubMed Toledo F, Wahl GM: Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006, 6 (12): 909-923. 10.1038/nrc2012.CrossRefPubMed
17.
go back to reference Lee JH, Paull TT: Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene. 2007, 26 (56): 7741-7748. 10.1038/sj.onc.1210872.CrossRefPubMed Lee JH, Paull TT: Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene. 2007, 26 (56): 7741-7748. 10.1038/sj.onc.1210872.CrossRefPubMed
18.
go back to reference Takayama N, Nishikii H, Usui J, Tsukui H, Sawaguchi A, Hiroyama T: Generation of functional platelets from human embryonic stem cells in vitro via ES-sacs, VEGF-promoted structures that concentrate hematopoietic progenitors. Blood. 2008, 111 (11): 5298-5306. 10.1182/blood-2007-10-117622.CrossRefPubMed Takayama N, Nishikii H, Usui J, Tsukui H, Sawaguchi A, Hiroyama T: Generation of functional platelets from human embryonic stem cells in vitro via ES-sacs, VEGF-promoted structures that concentrate hematopoietic progenitors. Blood. 2008, 111 (11): 5298-5306. 10.1182/blood-2007-10-117622.CrossRefPubMed
19.
go back to reference Momparler RL, Karon M, Siegel SE, Avila F: Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res. 1976, 36 (8): 2891-2895.PubMed Momparler RL, Karon M, Siegel SE, Avila F: Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res. 1976, 36 (8): 2891-2895.PubMed
20.
go back to reference Gewirtz DA: A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999, 57 (7): 727-741. 10.1016/S0006-2952(98)00307-4.CrossRefPubMed Gewirtz DA: A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999, 57 (7): 727-741. 10.1016/S0006-2952(98)00307-4.CrossRefPubMed
21.
go back to reference Keller DM, Lu H: p53 serine 392 phosphorylation increases after UV through induction of the assembly of the CK2.hSPT16.SSRP1 complex. J Biol Chem. 2002, 277 (51): 50206-50213. 10.1074/jbc.M209820200.CrossRefPubMed Keller DM, Lu H: p53 serine 392 phosphorylation increases after UV through induction of the assembly of the CK2.hSPT16.SSRP1 complex. J Biol Chem. 2002, 277 (51): 50206-50213. 10.1074/jbc.M209820200.CrossRefPubMed
22.
go back to reference Huang C, Ma WY, Maxiner A, Sun Y, Dong Z: p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. J Biol Chem. 1999, 274 (18): 12229-12235. 10.1074/jbc.274.18.12229.CrossRefPubMed Huang C, Ma WY, Maxiner A, Sun Y, Dong Z: p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. J Biol Chem. 1999, 274 (18): 12229-12235. 10.1074/jbc.274.18.12229.CrossRefPubMed
23.
go back to reference Cox ML, Meek DW: Phosphorylation of serine 392 in p53 is a common and integral event during p53 induction by diverse stimuli. Cell Signal. 2010, 22 (3): 564-571. 10.1016/j.cellsig.2009.11.014.CrossRefPubMed Cox ML, Meek DW: Phosphorylation of serine 392 in p53 is a common and integral event during p53 induction by diverse stimuli. Cell Signal. 2010, 22 (3): 564-571. 10.1016/j.cellsig.2009.11.014.CrossRefPubMed
24.
go back to reference Davies SP, Reddy H, Caivano M, Cohen P: Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000, 351 (Pt 1): 95-105.PubMedCentralCrossRefPubMed Davies SP, Reddy H, Caivano M, Cohen P: Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000, 351 (Pt 1): 95-105.PubMedCentralCrossRefPubMed
25.
go back to reference Sarno S, de Moliner E, Ruzzene M, Pagano MA, Battistutta R, Bain J: Biochemical and three-dimensional-structural study of the specific inhibition of protein kinase CK2 by [5-oxo-5,6-dihydroindolo-(1,2-a)quinazolin-7-yl]acetic acid (IQA). Biochem J. 2003, 374 (Pt 3): 639-646.PubMedCentralCrossRefPubMed Sarno S, de Moliner E, Ruzzene M, Pagano MA, Battistutta R, Bain J: Biochemical and three-dimensional-structural study of the specific inhibition of protein kinase CK2 by [5-oxo-5,6-dihydroindolo-(1,2-a)quinazolin-7-yl]acetic acid (IQA). Biochem J. 2003, 374 (Pt 3): 639-646.PubMedCentralCrossRefPubMed
26.
go back to reference Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L: A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007, 39 (2): 237-242. 10.1038/ng1972.PubMedCentralCrossRefPubMed Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L: A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007, 39 (2): 237-242. 10.1038/ng1972.PubMedCentralCrossRefPubMed
27.
go back to reference Marion RM, Strati K, Li H, Murga M, Blanco R, Ortega S: A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature. 2009, 460 (7259): 1149-1153. 10.1038/nature08287.PubMedCentralCrossRefPubMed Marion RM, Strati K, Li H, Murga M, Blanco R, Ortega S: A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature. 2009, 460 (7259): 1149-1153. 10.1038/nature08287.PubMedCentralCrossRefPubMed
28.
go back to reference Radhakrishnan SK, Gartel AL: CDK9 phosphorylates p53 on serine residues 33, 315 and 392. Cell Cycle. 2006, 5 (5): 519-521. 10.4161/cc.5.5.2514.CrossRefPubMed Radhakrishnan SK, Gartel AL: CDK9 phosphorylates p53 on serine residues 33, 315 and 392. Cell Cycle. 2006, 5 (5): 519-521. 10.4161/cc.5.5.2514.CrossRefPubMed
29.
go back to reference Cuddihy AR, Wong AH, Tam NW, Li S, Koromilas AE: The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. Oncogene. 1999, 18 (17): 2690-2702. 10.1038/sj.onc.1202620.CrossRefPubMed Cuddihy AR, Wong AH, Tam NW, Li S, Koromilas AE: The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. Oncogene. 1999, 18 (17): 2690-2702. 10.1038/sj.onc.1202620.CrossRefPubMed
30.
go back to reference Hupp TR, Meek DW, Midgley CA, Lane DP: Regulation of the specific DNA binding function of p53. Cell. 1992, 71 (5): 875-886. 10.1016/0092-8674(92)90562-Q.CrossRefPubMed Hupp TR, Meek DW, Midgley CA, Lane DP: Regulation of the specific DNA binding function of p53. Cell. 1992, 71 (5): 875-886. 10.1016/0092-8674(92)90562-Q.CrossRefPubMed
31.
go back to reference Meek DW, Simon S, Kikkawa U, Eckhart W: The p53 tumour suppressor protein is phosphorylated at serine 389 by casein kinase II. Embo J. 1990, 9 (10): 3253-3260.PubMedCentralPubMed Meek DW, Simon S, Kikkawa U, Eckhart W: The p53 tumour suppressor protein is phosphorylated at serine 389 by casein kinase II. Embo J. 1990, 9 (10): 3253-3260.PubMedCentralPubMed
32.
Metadata
Title
Differential responses to genotoxic agents between induced pluripotent stem cells and tumor cell lines
Authors
Yinghua Lu
Dazhong Xu
Jing Zhou
Yupo Ma
Yongping Jiang
Wenxian Zeng
Wei Dai
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2013
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/1756-8722-6-71

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