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Article

CREB1 and Smad3 mediate TGF‑β3‑induced Smad7 expression in rat hepatic stellate cells

  • Authors:
    • Liang Deng
    • Lu Huang
    • Qiongya Guo
    • Xiaoyu Shi
    • Keshu Xu
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Department of Immunology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China, Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
  • Pages: 8455-8462
    |
    Published online on: September 28, 2017
       https://doi.org/10.3892/mmr.2017.7654
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Abstract

Transforming growth factor (TGF)‑β3 has previously been reported to antagonize hepatic fibrosis in vivo and in vitro. The present study aimed to investigate the mechanism underlying the involvement of TGF‑β3 in hepatic fibrosis. Short hairpin (sh)RNA‑cAMP-responsive element binding protein (CREB) 1 and small interfering (si)RNA‑Smad3 were utilized to silence the expression of CREB1 and Smad3 in hepatic stellate cells (HSCs), whereas the vector pRSV‑CREB1 was used to induce CREB1 overexpression in HSCs. Cells were treated with or without exogenous TGF‑β3 or TGF‑β1, and mRNA and protein expression levels were assessed using reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Untreated cells served as the control group. Exogenous TGF‑β3 increased Smad7 mRNA and protein expression levels in rat HSCs, and CREB1 and Smad3 appeared to be implicated in the mechanism of Smad7. CREB1 knockdown inhibited the TGF‑β3‑induced upregulation of Smad7, whereas its overexpression potentiated the Smad7 upregulation in HSCs; conversely, CREB1 manipulations had no effect on Smad7 expression under basal conditions. In addition, TGF‑β3‑induced Smad7 upregulation was blocked when the activity of p38, a kinase upstream of CREB1, was inhibited. Furthermore, silencing Smad3 resulted in decreased Smad7 expression under basal conditions and in TGF‑β3‑stimulated cells. Notably, Smad7 expression appeared to also be induced by exogenous TGF‑β1, independent of CREB1. The present study demonstrated that TGF‑β3 increased Smad7 expression in HSCs, whereas CREB1 and Smad3 appeared to participate in the mechanism of induction. Smad3 is the key regulator whereas CREB‑1 acts as a co‑regulator. These results suggested that this mechanism may underlie the antagonizing effects of TGF‑β3 on hepatic fibrosis.
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View References

1 

Wallace K, Burt AD and Wright MC: Liver fibrosis. Biochem J. 411:1–18. 2008. View Article : Google Scholar : PubMed/NCBI

2 

Wells RG: Cellular sources of extracellular matrix in hepatic fibrosis. Clin Liver Dis. 12:759–768, viii. 2008. View Article : Google Scholar : PubMed/NCBI

3 

Povero D, Busletta C, Novo E, di Bonzo LV, Cannito S, Paternostro C and Parola M: Liver fibrosis: A dynamic and potentially reversible process. Histol Histopathol. 25:1075–1091. 2010.PubMed/NCBI

4 

Leask A and Abraham DJ: TGF-beta signaling and the fibrotic response. FASEB J. 18:816–827. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Li Q, Zhou X, Yu J, Qian W and Xu KS: Influence of recombinant transforming growth factor-beta3 on collagen synthesis and deposition: Experiment with rat cell model of liver fibrosis. Zhonghua Yi Xue Za Zhi. 88:1273–1278. 2008.(In Chinese). PubMed/NCBI

6 

Zhou X, Yu J, Li Q, Qian W and Xu KS: Effects of transforming growth factor-beta 3 gene transfer on type I collagen synthesis of hepatic stellate cells. Zhonghua Gan Zang Bing Za Zhi. 16:43–48. 2008.(In Chinese). PubMed/NCBI

7 

Zhang Y, Liu P, Gao X, Qian W and Xu K: rAAV2-TGF-β(3) decreases collagen synthesis and deposition in the liver of experimental hepatic fibrosis rat. Dig Dis Sci. 55:2821–2830. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Massagué J: How cells read TGF-beta signals. Nat Rev Mol Cell Biol. 1:169–178. 2000. View Article : Google Scholar : PubMed/NCBI

9 

Deng L, Li Y, Huang JM, Zhou Gy, Qian W and Xu K: Effects of p-CREB-1 on transforming growth factor-beta3 auto-regulation in hepatic stellate cells. J Cell Biochem. 112:1046–1054. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Han S, Ritzenthaler JD, Rivera HN and Roman J: Peroxisome proliferator-activated receptor-gamma ligands suppress fibronectin gene expression in human lung carcinoma cells: Involvement of both CRE and Sp1. Am J Physiol Lung Cell Mol Physiol. 289:L419–L428. 2005. View Article : Google Scholar : PubMed/NCBI

11 

Chan EC, Dusting GJ, Guo N, Peshavariya HM, Taylor CJ, Dilley R, Narumiya S and Jiang F: Prostacyclin receptor suppresses cardiac fibrosis: Role of CREB phosphorylation. J Mol Cell Cardiol. 49:176–185. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Barlow CA, Barrett TF, Shukla A, Mossman BT and Lounsbury KM: Asbestos-mediated CREB phosphorylation is regulated by protein kinase A and extracellular signal-regulated kinases 1/2. Am J Physiol Lung Cell Mol Physiol. 292:L1361–L1369. 2007. View Article : Google Scholar : PubMed/NCBI

13 

Ionescu AM, Drissi H, Schwarz EM, Kato M, Puzas JE, McCance DJ, Rosier RN, Zuscik MJ and O'Keefe RJ: CREB Cooperates with BMP-stimulated Smad signaling to enhance transcription of the Smad6 promoter. J Cell Physiol. 198:428–440. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

15 

Shaywitz AJ and Greenberg ME: CREB: A stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 68:821–861. 1999. View Article : Google Scholar : PubMed/NCBI

16 

Nishihara H, Hwang M, Kizaka-Kondoh S, Eckmann L and Insel PA: Cyclic AMP promotes cAMP-responsive element-binding protein-dependent induction of cellular inhibitor of apoptosis protein-2 and suppresses apoptosis of colon cancer cells through ERK1/2 and p38 MAPK. J Biol Chem. 279:26176–26183. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Gustin JA, Pincheira R, Mayo LD, Ozes ON, Kessler KM, Baerwald MR, Korgaonkar CK and Donner DB: Tumor necrosis factor activates CRE-binding protein through a p38 MAPK/MSK1 signaling pathway in endothelial cells. Am J Physiol Cell Physiol. 286:C547–C555. 2004. View Article : Google Scholar : PubMed/NCBI

18 

Nagarajan RP, Zhang J, Li W and Chen Y: Regulation of Smad7 promoter by direct association with Smad3 and Smad4. J Biol Chem. 274:33412–33418. 1999. View Article : Google Scholar : PubMed/NCBI

19 

Yan X, Liu Z and Chen Y: Regulation of TGF-beta signaling by Smad7. Acta Biochim Biophys Sin (Shanghai). 41:263–272. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Nakao A, Afrakhte M, Morén A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH and ten Dijke P: Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 389:631–635. 1997. View Article : Google Scholar : PubMed/NCBI

21 

Takase M, Imamura T, Sampath TK, Takeda K, Ichijo H, Miyazono K and Kawabata M: Induction of Smad6 mRNA by bone morphogenetic proteins. Biochem Biophys Res Commun. 244:26–29. 1998. View Article : Google Scholar : PubMed/NCBI

22 

Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA Jr, Wrana JL and Falb D: The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 89:1165–1173. 1997. View Article : Google Scholar : PubMed/NCBI

23 

Itoh S and ten Dijke P: Negative regulation of TGF-beta receptor/Smad signal transduction. Curr Opin Cell Biol. 19:176–184. 2007. View Article : Google Scholar : PubMed/NCBI

24 

Zhang S, Fei T, Zhang L, Zhang R, Chen F, Ning Y, Han Y, Feng XH, Meng A and Chen YG: Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation. Mol Cell Biol. 27:4488–4499. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Flanders KC: Smad3 as a mediator of the fibrotic response. Int J Exp Pathol. 85:47–64. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Wang W, Koka V and Lan HY: Transforming growth factor-beta and Smad signalling in kidney diseases. Nephrology (Carlton). 10:48–56. 2005. View Article : Google Scholar : PubMed/NCBI

27 

Lan HY: Smad7 as a therapeutic agent for chronic kidney diseases. Front Biosci. 13:4984–4992. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Liu G, Ding W, Neiman J and Mulder KM: Requirement of Smad3 and CREB-1 in mediating transforming growth factor-beta (TGF beta) induction of TGF beta 3 secretion. J Biol Chem. 281:29479–29490. 2006. View Article : Google Scholar : PubMed/NCBI

29 

Stopa M, Anhuf D, Terstegen L, Gatsios P, Gressner AM and Dooley S: Participation of Smad2, Smad3 and Smad4 in transforming growth factor beta (TGF-beta)-induced activation of Smad7. The TGF-beta response element of the promoter requires functional Smad binding element and E-box sequences for transcriptional regulation. J Biol Chem. 275:29308–29317. 2000. View Article : Google Scholar : PubMed/NCBI

30 

Brodin G, Ahgren A, ten Dijke P, Heldin CH and Heuchel R: Efficient TGF-beta induction of the Smad7 gene requires cooperation between AP-1, Sp1, and Smad proteins on the mouse Smad7 promoter. J Biol Chem. 275:29023–29030. 2000. View Article : Google Scholar : PubMed/NCBI

31 

Hua X, Miller ZA, Benchabane H, Wrana JL and Lodish HF: Synergism between transcription factors TFE3 and Smad3 in transforming growth factor-beta-induced transcription of the Smad7 gene. J Biol Chem. 275:33205–33208. 2000. View Article : Google Scholar : PubMed/NCBI

32 

Uchida K, Suzuki H, Ohashi T, Nitta K, Yumura W and Nihei H: Involvement of MAP kinase cascades in Smad7 transcriptional regulation. Biochem Biophys Res Commun. 289:376–381. 2001. View Article : Google Scholar : PubMed/NCBI

33 

Gohla G, Krieglstein K and Spittau B: Tieg3/Klf11 induces apoptosis in OLI-neu cells and enhances the TGF-beta signaling pathway by transcriptional repression of Smad7. J Cell Biochem. 104:850–861. 2008. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Deng L, Huang L, Guo Q, Shi X and Xu K: CREB1 and Smad3 mediate TGF‑β3‑induced Smad7 expression in rat hepatic stellate cells. Mol Med Rep 16: 8455-8462, 2017.
APA
Deng, L., Huang, L., Guo, Q., Shi, X., & Xu, K. (2017). CREB1 and Smad3 mediate TGF‑β3‑induced Smad7 expression in rat hepatic stellate cells. Molecular Medicine Reports, 16, 8455-8462. https://doi.org/10.3892/mmr.2017.7654
MLA
Deng, L., Huang, L., Guo, Q., Shi, X., Xu, K."CREB1 and Smad3 mediate TGF‑β3‑induced Smad7 expression in rat hepatic stellate cells". Molecular Medicine Reports 16.6 (2017): 8455-8462.
Chicago
Deng, L., Huang, L., Guo, Q., Shi, X., Xu, K."CREB1 and Smad3 mediate TGF‑β3‑induced Smad7 expression in rat hepatic stellate cells". Molecular Medicine Reports 16, no. 6 (2017): 8455-8462. https://doi.org/10.3892/mmr.2017.7654
Copy and paste a formatted citation
x
Spandidos Publications style
Deng L, Huang L, Guo Q, Shi X and Xu K: CREB1 and Smad3 mediate TGF‑β3‑induced Smad7 expression in rat hepatic stellate cells. Mol Med Rep 16: 8455-8462, 2017.
APA
Deng, L., Huang, L., Guo, Q., Shi, X., & Xu, K. (2017). CREB1 and Smad3 mediate TGF‑β3‑induced Smad7 expression in rat hepatic stellate cells. Molecular Medicine Reports, 16, 8455-8462. https://doi.org/10.3892/mmr.2017.7654
MLA
Deng, L., Huang, L., Guo, Q., Shi, X., Xu, K."CREB1 and Smad3 mediate TGF‑β3‑induced Smad7 expression in rat hepatic stellate cells". Molecular Medicine Reports 16.6 (2017): 8455-8462.
Chicago
Deng, L., Huang, L., Guo, Q., Shi, X., Xu, K."CREB1 and Smad3 mediate TGF‑β3‑induced Smad7 expression in rat hepatic stellate cells". Molecular Medicine Reports 16, no. 6 (2017): 8455-8462. https://doi.org/10.3892/mmr.2017.7654
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