Ectopic ERK expression induces phenotypic conversion of C10 cells and alters DNA methyltransferase expression

BMC Research Notes

Thomas J Weber¹  Ryan L Sontag¹ 

[1] Systems Toxicology, Pacific Northwest National Laboratory, 790 6th Street, J4-02, Richland, WA, 99354, USA

关键词: DNMT;    ERK;    Epigenetics;   

Others  :  1166458
DOI  :  10.1186/1756-0500-5-217

 received in 2012-03-02, accepted in 2012-04-19,  发布年份 2012

【 摘 要 】

Background

Many lung carcinogens activate mitogen activated protein kinase (MAPK) pathways and DNA methyltransferases (DNMTs) are under investigation as therapeutic targets for lung cancer. Our goal is to determine whether C10 type II alveolar epithelial cells are a sensitive model to investigate ERK-dependent transformation and DNMT expression patterns in experimental lung cancer.

Findings

Ectopic expression of an extracellular signal regulated kinase (ERK)-green fluorescent protein (ERK1-GFP) induces acquisition of growth in soft agar that is selectively associated with latent effects on the expression of DNA methyl transferases (DNMT1 and 3b), xeroderma pigmentosum complementation group A (XPA), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), increased phosphatase activity and enhanced sensitivity to 5-azacytidine (5-azaC)-mediated toxicity, relative to controls.

Conclusions

Ectopic expression of ERK alone is sufficient to promote phenotypic conversion of C10 cells associated with altered DNMT expression patterns and sensitivity to DNMT inhibitor. This model may have applications for predicting sensitivity to DNMT inhibitors.

【 授权许可】

   
2012 Sontag and Weber; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Grozio A, Catassi A, Cavalieri Z, Paleari L, Cesario A, Russo P: Nicotine, lung and cancer. Anticancer Agents Med Chem 2007, 7:461-466.
• [2]Zhang J, Lodish HF: Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors. Blood 2004, 104:1679-1687.
• [3]Chung E, Hsu CL, Kondo M: Constitutive MAP kinase activation in hematopoietic stem cells induces a myeloproliferative disorder. PLoS One 2011, 6:e28350.
• [4]Scholl FA, Dumesic PA, Khavari PA: Effects of active MEK1 expression in vivo. Cancer Lett 2005, 230:1-5.
• [5]Boucher MJ, Jean D, Vezina A, Rivard N: Dual role of MEK/ERK signaling in senescence and transformation of intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2004, 286:G736-G746.
• [6]Welch DR, Sakamaki T, Pioquinto R, Leonard TO, Goldberg SF, Hon Q, Erikson RL, Rieber M, Rieber MS, Hicks DJ, et al.: Transfection of constitutively active mitogen-activated protein/extracellular signal-regulated kinase kinase confers tumorigenic and metastatic potentials to NIH3T3 cells. Cancer Res 2000, 60:1552-1556.
• [7]Alessandrini A, Greulich H, Huang W, Erikson RL: Mek1 phosphorylation site mutants activate Raf-1 in NIH 3 T3 cells. J Biol Chem 1996, 271:31612-31618.
• [8]Shukla A, Timblin C, BeruBe K, Gordon T, McKinney W, Driscoll K, Vacek P, Mossman BT: Inhaled particulate matter causes expression of nuclear factor (NF)-kappaB-related genes and oxidant-dependent NF-kappaB activation in vitro. Am J Respir Cell Mol Biol 2000, 23:182-187.
• [9]Papaiahgari S, Zhang Q, Kleeberger SR, Cho HY, Reddy SP: Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells. Antioxid Redox Signal 2006, 8:43-52.
• [10]Lounsbury KM, Stern M, Taatjes D, Jaken S, Mossman BT: Increased localization and substrate activation of protein kinase C delta in lung epithelial cells following exposure to asbestos. Am J Pathol 2002, 160:1991-2000.
• [11]Buder-Hoffmann S, Palmer C, Vacek P, Taatjes D, Mossman B: Different accumulation of activated extracellular signal-regulated kinases (ERK 1/2) and role in cell-cycle alterations by epidermal growth factor, hydrogen peroxide, or asbestos in pulmonary epithelial cells. Am J Respir Cell Mol Biol 2001, 24:405-413.
• [12]Malkinson AM, Dwyer-Nield LD, Rice PL, Dinsdale D: Mouse lung epithelial cell lines–tools for the study of differentiation and the neoplastic phenotype. Toxicology 1997, 123:53-100.
• [13]Wardlaw SA, Zhang N, Belinsky SA: Transcriptional regulation of basal cyclooxygenase-2 expression in murine lung tumor-derived cell lines by CCAAT/enhancer-binding protein and activating transcription factor/cAMP response element-binding protein. Mol Pharmacol 2002, 62:326-333.
• [14]Smith GJ, Le Mesurier SM, de Montfort ML, Lykke AW: Development and characterization of type 2 pneumocyte-related cell lines from normal adult mouse lung. Pathology 1984, 16:401-405.
• [15]Kitamura T, Onishi M, Kinoshita S, Shibuya A, Miyajima A, Nolan GP: Efficient screening of retroviral cDNA expression libraries. Proc Natl Acad Sci U S A 1995, 92:9146-9150.
• [16]Lenormand P, Sardet C, Pages G, L’Allemain G, Brunet A, Pouyssegur J: Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J Cell Biol 1993, 122:1079-1088.
• [17]Zuckerbraun BS, Shapiro RA, Billiar TR, Tzeng E: RhoA influences the nuclear localization of extracellular signal-regulated kinases to modulate p21Waf/Cip1 expression. Circulation 2003, 108:876-881.
• [18]Bates RC, Mercurio AM: The epithelial-mesenchymal transition (EMT) and colorectal cancer progression. Cancer Biol Ther 2005, 4:365-370.
• [19]Weber TJ, Markillie LM, Chrisler WB, Vielhauer GA, Regan JW: Modulation of JB6 mouse epidermal cell transformation response by the prostaglandin F2alpha receptor. Mol Carcinog 2002, 35:163-172.
• [20]Suzukawa K, Weber TJ, Colburn NH: AP-1, NF-kappa-B, and ERK activation thresholds for promotion of neoplastic transformation in the mouse epidermal JB6 model. Environ Health Perspect 2002, 110:865-870.
• [21]Deng C, Yang J, Scott J, Hanash S, Richardson BC: Role of the ras-MAPK signaling pathway in the DNA methyltransferase response to DNA hypomethylation. Biol Chem 1998, 379:1113-1120.
• [22]Scheinbart LS, Johnson MA, Gross LA, Edelstein SR, Richardson BC: Procainamide inhibits DNA methyltransferase in a human T cell line. J Rheumatol 1991, 18:530-534.
• [23]Bird A: Perceptions of epigenetics. Nature 2007, 447:396-398.
• [24]Weber TJ, Shankaran H, Wiley HS, Opresko LK, Chrisler WB, Quesenberry RD: Basic fibroblast growth factor regulates persistent ERK oscillations in premalignant but not malignant JB6 cells. J Invest Dermatol 2010, 130:1444-1456.
• [25]Lengauer C, Kinzler KW, Vogelstein B: Genetic instabilities in human cancers. Nature 1998, 396:643-649.
• [26]Morgan WF: Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects. Radiat Res 2003, 159:581-596.
• [27]Pandey D, Fulton DJ: Molecular regulation of NADPH oxidase 5 via the MAPK pathway. Am J Physiol Heart Circ Physiol 2011, 300:H1336-H1344.
• [28]Abramov AY, Jacobson J, Wientjes F, Hothersall J, Canevari L, Duchen MR: Expression and modulation of an NADPH oxidase in mammalian astrocytes. J Neurosci 2005, 25:9176-9184.
• [29]Limoli CL, Giedzinski E, Morgan WF, Swarts SG, Jones GD, Hyun W: Persistent oxidative stress in chromosomally unstable cells. Cancer Res 2003, 63:3107-3111.
• [30]Marampon F, Gravina GL, Di Rocco A, Bonfili P, Di Staso M, Fardella C, Polidoro L, Ciccarelli C, Festuccia C, Popov VM, et al.: MEK/ERK inhibitor U0126 increases the radiosensitivity of rhabdomyosarcoma cells in vitro and in vivo by downregulating growth and DNA repair signals. Mol Cancer Ther 2011, 10:159-168.
• [31]Tang M, Xu W, Wang Q, Xiao W, Xu R: Potential of DNMT and its Epigenetic Regulation for Lung Cancer Therapy. Curr Genomics 2009, 10:336-352.
• [32]Geiman TM, Sankpal UT, Robertson AK, Zhao Y, Robertson KD: DNMT3B interacts with hSNF2H chromatin remodeling enzyme, HDACs 1 and 2, and components of the histone methylation system. Biochem Biophys Res Commun 2004, 318:544-555.
• [33]Monsey MS, Ota KT, Akingbade IF, Hong ES, Schafe GE: Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala. PLoS One 2011, 6:e19958.
• [34]Weber TJ, Monks TJ, Lau SS: PGE2-mediated cytoprotection in renal epithelial cells: evidence for a pharmacologically distinct receptor. Am J Physiol 1997, 273:F507-F515.