SENP1 has an important role in lung development and influences the differentiation of alveolar type 2 cells

Wan,Xue‑Qing; Cai,Jia‑Yu; Zhu,Yue; Wang,Qiu‑Xia; Zhu,Hai‑Tao; Ju,Hui‑Min; Lu,Hong‑Yan

doi:10.3892/ijmm.2018.3964

SENP1 has an important role in lung development and influences the differentiation of alveolar type 2 cells

Authors:
- Xue‑Qing Wan
- Jia‑Yu Cai
- Yue Zhu
- Qiu‑Xia Wang
- Hai‑Tao Zhu
- Hui‑Min Ju
- Hong‑Yan Lu
View Affiliations

Affiliations: Department of Pediatrics, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212000, P.R. China
Published online on: October 29, 2018 https://doi.org/10.3892/ijmm.2018.3964
Pages: 371-381
Copyright: © Wan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Post‑translational modification via small ubiquitin‑like modifier (SUMO) is involved in the regulation of various important cellular processes. SUMO modification can be regulated at the level of conjugation, and can also be reversed by the SUMO‑specific proteases (SENPs). However, current studies of the regulation and function of SENP in lung development remain limited. In this study, the expression levels of SENP1 and SUMO1 were assessed during lung development in rats. SUMO1 modification occurred during lung development and changes in SENP1 expression were consistent with the changes in the presence of free SUMO1. In order to investigate the function of SENP1, alveolar type (AT) 2 cells were transfected with SENP1‑targeting small interfering RNA, and the proliferation, apoptosis and differentiation function of AT2 cells was subsequently evaluated. Marked upregulation of conjugated SUMO1 was observed following SENP1 inhibition. Furthermore, depletion of SENP1 resulted in increased apoptosis, decreased proliferation and impaired differentiation status of AT2 cells. Thus, the results support that SENP1 is an essential regulator of the balance between SUMOylation and deSUMOylation during lung development, specifically affecting the proliferation and differentiation status of AT2 cells.

View Figures

View References

1	Warburton D and Bellusci S: The molecular genetics of lung morphogenesis and injury repair. Paediatr Respir Rev. 5(Suppl A): S283–S287. 2004. View Article : Google Scholar : PubMed/NCBI
2	Claudio N and Morty RE: MicroRNA in late lung development and bronchopulmonary dysplasia: The need to demonstrate causality. Mol Cell Pediatr. 3:192016. View Article : Google Scholar
3	Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, Randell SH, Noble PW and Hogan LM: Type 2 alveolar cells are stem cells in adult lung. J Clin Invest. 123:3025–3036. 2013. View Article : Google Scholar : PubMed/NCBI
4	Adamson IY and Bowden DH: The type 2 cell as progenitor of alveolar epithelial regeneration: A cytodynamic study in mice after exposure to oxygen. Lab Invest. 30:35–42. 1974.PubMed/NCBI
5	Adamson IY and Bowden DH: Derivation of type 1 epithelium from type 2 cells in the developing rat lung. Lab Invest. 32:736–745. 1975.PubMed/NCBI
6	Siegel R, Naishadham D and Jemal A: Cancer statistics. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
7	Lomelí H and Vázquez M: Emerging roles of the SUMO pathway in development. Cell Mol Life Sci. 68:4045–4064. 2011. View Article : Google Scholar : PubMed/NCBI
8	Garciadominguez M and Reyes JC: SUMO association with repressor complexes, emerging routes for transcriptional control. Biochim Biophys Acta. 1789:451–459. 2009. View Article : Google Scholar
9	Tempé D, Piechaczyk M and Bossis G: SUMO under stress. Biochem Soc Trans. 36:874–878. 2008. View Article : Google Scholar : PubMed/NCBI
10	Kim JH and Baek SH: Emerging roles of desumoylating enzymes. Biochim Biophys Acta. 1792:155–162. 2009. View Article : Google Scholar : PubMed/NCBI
11	Saho E, Takuya A, Hiroshi A, Shunsuke K, Barnabas S, Yusuke Y, Akira M, Shunichi T and Dana B: The SUMO protease SENP1 is required for cohesion maintenance and mitotic arrest following spindle poison treatment. Biochem Biophys Res Commun. 42:310–316. 2012.
12	Chen CH, Chang CC, Lee TH, Luo M, Huang P, Liao P, Wei S, Li F, Chen R, Zhou XZ, et al: SENP1 deSUMOylates and regulates Pin1 protein activity and cellular function. Cancer Res. 73:3951–3962. 2013. View Article : Google Scholar : PubMed/NCBI
13	Flotho A and Melchior F: Sumoylation: A regulatory protein modification in health and disease. Annu Rev Biochem. 82:357–385. 2013. View Article : Google Scholar : PubMed/NCBI
14	Bawa-Khalfe T and Yeh ET: SUMO losing balance: SUMO proteases disrupt SUMO homeostasis to facilitate cancer development and progression. Genes Cancer. 1:748–752. 2010. View Article : Google Scholar : PubMed/NCBI
15	Nacerddine K, Lehembre F, Bhaumik M, Artus J, Cohen- Tannoudji M, Babinet C, Pandolfi PP and Dejean A: The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev Cell. 9:769–779. 2005. View Article : Google Scholar : PubMed/NCBI
16	Yamaguchi T, Sharma P, Athanasiou M, Kumar A, Yamada S and Kuehn MR: Mutation of SENP1/SuPr-2 reveals an essential role for desumoylation in mouse development. Mol Cell Biol. 25:5171–5182. 2005. View Article : Google Scholar : PubMed/NCBI
17	Chen YD, Liu JY, Lu YM, Zhu HT, Tang W, Wang QX and Lu HY: Functional roles of C/EBPα and SUMO-modification in lung development. Int J Mol Med. 40:1037–1046. 2017. View Article : Google Scholar : PubMed/NCBI
18	Zhou F, Dai A, Fu D, Jiang Y, Tan X and Zhang X: SENP-1 enhances hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells by regulating hypoxia-inducible factor-1α. Mol Med Rep. 13:3482–3490. 2016. View Article : Google Scholar : PubMed/NCBI
19	Jiang Y, Wang J, Tian H, Li G, Zhu H, Liu L, Hu R and Dai A: Increased SUMO-1 expression in response to hypoxia: Interaction with HIF-1α in hypoxic pulmonary hypertension. Int J Mol Med. 36:271–281. 2015. View Article : Google Scholar : PubMed/NCBI
20	Pandey D, Nomura Y, Rossberg MC, Hori D, Bhatta A, Keceli G, Leucker T, Santhanam L, Shimoda LA, Berkowitz D and Romer L: Hypoxia triggers SENP1 (sentrin-specific protease 1) modulation of KLF15 (Kruppel-like factor 15) and transcriptional regulation of Arg2 (Arginase 2) in pulmonary endothelium. Arterioscler Thromb Vasc Biol. 38:913–926. 2018. View Article : Google Scholar : PubMed/NCBI
21	Wang RT, Zhi XY, Zhang Y and Zhang J: Inhibition of SENP1 induces radiosensitization in lung cancer cells. Exp Ther Med. 6:1054–1058. 2013. View Article : Google Scholar : PubMed/NCBI
22	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
23	Gao RW, Kong XY, Zhu XX, Zhu GQ, Ma JS and Liu XX: Retinoic acid promotes primary fetal alveolar epithelial type II cell proliferation and differentiation to alveolar epithelial type I cells. In Vitro Cell Dev Biol Anim. 51:479–487. 2015. View Article : Google Scholar
24	Sharma P, Yamada S, Lualdi M, Dasso M and Kuehn MR: SENP1 is essential for desumoylating SUMO1-modified proteins but dispensable for SUMO2 and SUMO3 deconjugation in the mouse embryo. Cell Rep. 3:1640–1650. 2013. View Article : Google Scholar : PubMed/NCBI
25	Juarez-Vicente F, Luna-Pelaez N and Garcia-Dominguez M: The SUMO protease SENP7 is required for proper neuronal differentiation. Biochim Biophys Acta. 1863:1490–1498. 2016. View Article : Google Scholar : PubMed/NCBI
26	Besnard V, Nabeyrat E, Henrion-Caude A, Chadelat K, Perin L, Le Boucn Y and Clement A: Protective role of retinoic acid from antiproliferative action of TNF-alpha on lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 282:L863–L871. 2002. View Article : Google Scholar : PubMed/NCBI
27	Londhe VA, Maisonet TM, Lopez B, Shin BC, Huynh J and Devaskar SU: Retinoic acid rescues alveolar hypoplasia in the calorierestricted developing rat lung. Am J Respir Cell Mol Biol. 48:179–187. 2013. View Article : Google Scholar :
28	Evans MJ, Cabral LJ, Stephens RJ and Freeman G: Renewal of alveolar epithelium in the rat following exposure to NO₂. Am J Pathol. 70:175–198. 1973.PubMed/NCBI
29	Lu H, Chang L, Li W, Jiang N, Peng Q, Cai C and Liu J: Effects of hyperoxia on the dynamic expression of Aquaporin5 in premature rats lung development. J Huazhong Univ Sci Technolog Med Sci. 27:318–312. 2007. View Article : Google Scholar : PubMed/NCBI
30	George UM, Ashna U, Kumar SS and Nandkumar AM: Effect of tobacco extract on surfactant synthesis and its reversal by retinoic acid-role of cell-cell interactions in vitro. In Vitro Cell Dev Biol Anim. 49:260–269. 2013. View Article : Google Scholar : PubMed/NCBI
31	Nomura J, Horie I, Seto M, Nagai K, Hisatsune A, Miyata T and Isohama Y: All-trans retinoic acid increases expression of aquaporin-5 and plasma membrane water permeability via transactivation of Sp1 in mouse lung epithelial cells. Biochem Biophys Res Commun. 351:1048–1053. 2006. View Article : Google Scholar : PubMed/NCBI
32	Schittny JC: Development of the lung. Cell Tissue Res. 367:427–444. 2017. View Article : Google Scholar : PubMed/NCBI
33	Yuasa E and Saitoh H: In situ SUMOylation and DeSUMOylation assays: fluorescent methods to visualize SUMOylation and DeSUMOylation in permeabilized cells. Methods Mol Biol. 1475:151–159. 2016. View Article : Google Scholar : PubMed/NCBI
34	Desai TJ, Brownfield DG and Krasnow MA: Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature. 507:190–194. 2014. View Article : Google Scholar : PubMed/NCBI
35	Tan F, Dong W, Lei X, Li Q, Kang L, Zhao S and Zhang C: Attenuated SUMOylation of sirtuin 1 in premature neonates with bronchopulmonary dysplasia. Mol Med Rep. 17:1283–1288. 2018.