Effects of ATF3/ATF4 on Expression of γ-GCS in Lung Tissues of Patients with Chronic Obstructive Pulmonary Disease_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LIJie ¹ ,  DAIAiguo ² , HURuicheng ¹ , LIUXiaoyan ² , KONGChunchu ¹

1. Department of Respiratory Medicine of Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410016, P.R.China;
2. Institute for Respiratory Science of Hunan Geriatric Hospital, Changsha, Hunan 410016, P.R.China;

Corresponding author：

DAIAiguo, Email: daiaiguo2003@163.com

Keywords：

Chronic obstructive pulmonary disease; Activating transcription factor 3; Activating transcription factor 4; γ-Glutamylcysteine synthetase

DOI：

10.7507/1671-6205.201606052

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Objective To investigate the expressions of activating transcription factor 3 (ATF3) and ATF4, and their effects on γ-glutamylcysteine synthetase (γ-GCS) in lung tissues of patients with chronic obstructive pulmonary disease (COPD). Methods Non-cancerous lung tissue specimens ( 5 cm or above away from tumor) were collected from 40 lung cancer patients who underwent pulmonary lobectomy between December 2008 and December 2009. The patients were divided into a COPD group and a control group according to whether they were complicated with COPD. The clinical data were collected including the history in detail, physical examination, chest X-ray or lung CT, and pulmonary function test. The mRNA and protein expressions of ATF3, ATF4, and heavy subunit of γ-GCS (γ-GCS-HS) in lung tissues were detected by in situ hybridization and immunohistochemistry. At the same time, the interaction between ATF3, ATF4 and γ-GCS-HS protein was investigated by co-immunoprecipitation method. The correlation of ATF3 and ATF4 with γ-GCS-HS was analyzed. Results The mRNA and protein expressions of ATF3, ATF4 and γ-GCS-HS in lung tissues of the COPD group were strongly positive, and significantly higher than those in the control group (P＜0.01). The co-immunoprecipitation showed that ATF3 and ATF4 antibodies could cross the clear protein bands in the immune precipitation captured by γ-GCS-HS, and the intensity in the COPD group was significantly enhanced than that in the control group (P＜0.01). Correlation analysis showed that the protein expressions of ATF3 and ATF4 were significantly positively correlated with the mRNA and protein expression of γ-GCS-HS (allP＜0.01). The protein expressions of ATF3, ATF4 and γ-GCS-HS in lung tissues were positively correlated with FEV₁%pred and FEV/FVC (P＜0.01). Conclusions Oxidative stress induces overexpression of ATF3 and ATF4 which may paly role in the pathogenesis of COPD. ATF3 and ATF4 may play antioxidative effect by affecting the mRNA and protein expression of γ-GCS.

Citation： LIJie, DAIAiguo, HURuicheng, LIUXiaoyan, KONGChunchu. Effects of ATF3/ATF4 on Expression of γ-GCS in Lung Tissues of Patients with Chronic Obstructive Pulmonary Disease. Chinese Journal of Respiratory and Critical Care Medicine, 2017, 16(1): 9-14. doi: 10.7507/1671-6205.201606052 Copy

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2.	Hibi T, Nii H, Nakatsu T, et al. Crystal structure of gamma-glutamylcysteine synthetase: insights into the mechanism of catalysis by a key enzyme for glutathione homeostasis. Proc Natl Acad Sci USA, 2004, 101(42): 15052-15057.
3.	Kumar S, Kasturia N, Sharma A, et al. Redox-dependent stability of the γ-glutamylcysteine synthetase enzyme ofEscherichia coli: a novel means of redox regulation. Biochem J, 2013, 449(3): 783-794.
4.	林书典, 戴爱国, 徐平. 慢性阻塞性肺疾病患者 γ 谷氨酰半胱氨酸合成酶活性及表达的变化. 中华结核和呼吸杂志, 2005, 28(2): 97-101.
5.	Yoshida T, Sugiura H, Mitobe M, et al. ATF3 protects against renal ischemia-reperfusion injury. J Am Soc Nephrol, 2008, 19(2): 217-224.
6.	Gilchrist M, Henderson WR JR, Clark AE, et al. Activating transcription factor 3 is a negative regulator of allergic pulmonary inflammation. J Exp Med, 2008, 205(10): 2349-2357.
7.	Miyamoto N, Izumi H, Miyamoto R, et al. Transcriptional regulation of activating transcription factor 4 under oxidative stress in retinal rigment epithelial ARPE-19/HPV-16 cells. Invest Ophthalmol Vis Sci, 2011, 52(3): 1226-1234.
8.	刘晓燕, 戴爱国, 李洁. 转录因子 ATF3 和 ATF4 在大鼠慢性阻塞性肺疾病中的表达及作用. 中国呼吸与危重监护杂志, 2011, 10(2): 121-125.
9.	Garcia-Lujan R, Conde-Gallego E, Lopez-Rios F, et al. Analysis of the molecular expression profile of non small cell lung carcinoma associated to chronic obstructive pulmonary disease. Histol Histopathol, 2009, 24(4): 417-423.
10.	Wang IM, Stepaniants S, Boie Y, et al. Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer. Am J Respir Crit Care Med, 2008, 177(4): 402-411.
11.	Li J, Dai AG, Hu RC, et al. Positive correlation between PPARγ, PGC-1α and γ-GCS in lungs of rats and patients with chronic obstructive pulmonary disease. Acta Biochim Biophys Sin, 2010, 42(9): 603-614.
12.	Ray S, Watkins DN, Misso NL, et al. Oxidant stress induces gamma-glutamylcysteine synthetase and glutathione synthesis in human bronchial epithelial NCI-H292 cells. Clin Exp Allergy, 2002, 32(4): 571-577.
13.	林书典, 周巧玲, 戴爱国. GSH 在 COPD 大鼠肺内合成机制和作用的研究. 中国热带医学杂志, 2007, 7(7): 1071-1072, 1120.
14.	Olala LO, Choudhary V, Johnson MH, et al. Angiotensin II-induced protein kinase D activates the ATF/CREB family of transcription factors and promotes StAR mRNA expression. Endocrinology, 2014, 155(7): 2524-2533.
15.	Kim KH, Jeong JY, Surh YJ, et al. Expression of stress-response ATF3 is mediated by Nrf2 in astrocytes. Nucleic Acids Res, 2010, 38 (1): 48-59.
16.	Gustems M, Woellmer A, Rothbauer U, et al. c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs. Nucleic Acids Res, 2014, 42(5): 3059-3072.
17.	Bakin AV, Stourman NV, Sekhar KR, et al. Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding Phase Ⅱ detoxifying proteins. Free Radic Biol Med, 2005, 38(3): 375-387.
18.	Wang C, Li H, Meng Q, et al. ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression. J Cell Mol Med, 2013, 18(1): 80-90.

1. 中华医学会呼吸病学分会慢性阻塞性肺疾病学组. 慢性阻塞性肺疾病诊治指南(2013 年修订版). 中华结核和呼吸杂志, 2013, 36(4): 255-264.
2. Hibi T, Nii H, Nakatsu T, et al. Crystal structure of gamma-glutamylcysteine synthetase: insights into the mechanism of catalysis by a key enzyme for glutathione homeostasis. Proc Natl Acad Sci USA, 2004, 101(42): 15052-15057.
3. Kumar S, Kasturia N, Sharma A, et al. Redox-dependent stability of the γ-glutamylcysteine synthetase enzyme ofEscherichia coli: a novel means of redox regulation. Biochem J, 2013, 449(3): 783-794.
4. 林书典, 戴爱国, 徐平. 慢性阻塞性肺疾病患者 γ 谷氨酰半胱氨酸合成酶活性及表达的变化. 中华结核和呼吸杂志, 2005, 28(2): 97-101.
5. Yoshida T, Sugiura H, Mitobe M, et al. ATF3 protects against renal ischemia-reperfusion injury. J Am Soc Nephrol, 2008, 19(2): 217-224.
6. Gilchrist M, Henderson WR JR, Clark AE, et al. Activating transcription factor 3 is a negative regulator of allergic pulmonary inflammation. J Exp Med, 2008, 205(10): 2349-2357.
7. Miyamoto N, Izumi H, Miyamoto R, et al. Transcriptional regulation of activating transcription factor 4 under oxidative stress in retinal rigment epithelial ARPE-19/HPV-16 cells. Invest Ophthalmol Vis Sci, 2011, 52(3): 1226-1234.
8. 刘晓燕, 戴爱国, 李洁. 转录因子 ATF3 和 ATF4 在大鼠慢性阻塞性肺疾病中的表达及作用. 中国呼吸与危重监护杂志, 2011, 10(2): 121-125.
9. Garcia-Lujan R, Conde-Gallego E, Lopez-Rios F, et al. Analysis of the molecular expression profile of non small cell lung carcinoma associated to chronic obstructive pulmonary disease. Histol Histopathol, 2009, 24(4): 417-423.
10. Wang IM, Stepaniants S, Boie Y, et al. Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer. Am J Respir Crit Care Med, 2008, 177(4): 402-411.
11. Li J, Dai AG, Hu RC, et al. Positive correlation between PPARγ, PGC-1α and γ-GCS in lungs of rats and patients with chronic obstructive pulmonary disease. Acta Biochim Biophys Sin, 2010, 42(9): 603-614.
12. Ray S, Watkins DN, Misso NL, et al. Oxidant stress induces gamma-glutamylcysteine synthetase and glutathione synthesis in human bronchial epithelial NCI-H292 cells. Clin Exp Allergy, 2002, 32(4): 571-577.
13. 林书典, 周巧玲, 戴爱国. GSH 在 COPD 大鼠肺内合成机制和作用的研究. 中国热带医学杂志, 2007, 7(7): 1071-1072, 1120.
14. Olala LO, Choudhary V, Johnson MH, et al. Angiotensin II-induced protein kinase D activates the ATF/CREB family of transcription factors and promotes StAR mRNA expression. Endocrinology, 2014, 155(7): 2524-2533.
15. Kim KH, Jeong JY, Surh YJ, et al. Expression of stress-response ATF3 is mediated by Nrf2 in astrocytes. Nucleic Acids Res, 2010, 38 (1): 48-59.
16. Gustems M, Woellmer A, Rothbauer U, et al. c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs. Nucleic Acids Res, 2014, 42(5): 3059-3072.
17. Bakin AV, Stourman NV, Sekhar KR, et al. Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding Phase Ⅱ detoxifying proteins. Free Radic Biol Med, 2005, 38(3): 375-387.
18. Wang C, Li H, Meng Q, et al. ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression. J Cell Mol Med, 2013, 18(1): 80-90.

Chinese Journal of Respiratory and Critical Care Medicine

Effects of ATF3/ATF4 on Expression of γ-GCS in Lung Tissues of Patients with Chronic Obstructive Pulmonary Disease

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