PIAS1 Mediates TGFbeta-induced SM Alpha-actin Gene Expression Through Inhibition of KLF4 Function-expression by Protein Sumoylation

Overview

Journal Arterioscler Thromb Vasc Biol

Date 2008 Oct 18

PMID 18927467

Citations 27

Authors

Keiko Kawai-Kowase

Takayuki Ohshima

Hiroki Matsui

Toru Tanaka

Takehisa Shimizu

Tatsuya Iso

Masashi Arai

Gary K Owens

Masahiko Kurabayashi

Affiliations

Soon will be listed here.

Abstract

Objective: TGFbeta and proliferation/phenotypic switching of smooth muscle cells (SMCs) play a pivotal role in pathogenesis of atherosclerotic and restenotic lesions after angioplasty. We have previously shown that the protein inhibitor of activated STAT (PIAS)1 activates expression of SMC differentiation marker genes including smooth muscle (SM) alpha-actin by interacting with serum response factor (SRF) and class I bHLH proteins. Here, we tested the hypothesis that TGFbeta activates SM alpha-actin through PIAS1.

Methods And Results: An siRNA specific for PIAS1 and ubc9, an E2-ligase for sumoylation, inhibited TGFbeta-induced expression of SM alpha-actin in cultured SMCs as determined by real-time RT-PCR. Overexpression of PIAS1 increased SM alpha-actin promoter activity in a TGFbeta control element (TCE)-dependent manner. Because the TCE within the SM alpha-actin promoter could mediate repression through interaction with KLF4, we tested whether PIAS1 regulates the function of KLF4 for SMC gene expression. PIAS1 interacted with KLF4 in mammalian two-hybrid and coimmunoprecipitation assays, and overexpression of PIAS1 inhibited KLF4-repression of SM alpha-actin promoter activity. Moreover, PIAS1 promoted degradation of KLF4 through sumoylation.

Conclusions: These results provide evidence that PIAS1 promotes TGFbeta-induced activation of SM alpha-actin gene expression at least in part by promoting sumoylation and degradation of the TCE repressor protein, KLF4.

Citing Articles

Epsins oversee smooth muscle cell reprograming by influencing master regulators KLF4 and OCT4.

Wang B, Cui K, Zhu B, Dong Y, Wang D, Singh B bioRxiv. 2024; .

PMID: 39131381 PMC: 11312448. DOI: 10.1101/2024.01.08.574714.

MBNL2 promotes aging-related cardiac fibrosis via inhibited SUMOylation of Krüppel-like factor4.

Lu J, Zhao Q, Wang L, Li J, Wang H, Lv L iScience. 2024; 27(7):110163.

PMID: 38974966 PMC: 11226984. DOI: 10.1016/j.isci.2024.110163.

New insights into KLFs and SOXs in cancer pathogenesis, stemness, and therapy.

Zeng L, Zhu Y, Moreno C, Wan Y Semin Cancer Biol. 2023; 90:29-44.

PMID: 36806560 PMC: 10023514. DOI: 10.1016/j.semcancer.2023.02.003.

Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts.

Sanchez-Ovando S, Pavlidis S, Kermani N, Baines K, Barker D, Gibson P Respirology. 2022; 27(9):730-738.

PMID: 35673765 PMC: 9540453. DOI: 10.1111/resp.14302.

Fibrotic Signaling in Cardiac Fibroblasts and Vascular Smooth Muscle Cells: The Dual Roles of Fibrosis in HFpEF and CAD.

Bachmann J, Baumgart S, Uryga A, Bosteen M, Borghetti G, Nyberg M Cells. 2022; 11(10).

PMID: 35626694 PMC: 9139546. DOI: 10.3390/cells11101657.

References

King K, Iyemere V, Weissberg P, Shanahan C . Krüppel-like factor 4 (KLF4/GKLF) is a target of bone morphogenetic proteins and transforming growth factor beta 1 in the regulation of vascular smooth muscle cell phenotype. J Biol Chem. 2003; 278(13):11661-9. DOI: 10.1074/jbc.M211337200. View

Yoshida T, Sinha S, Dandre F, Wamhoff B, Hoofnagle M, Kremer B . Myocardin is a key regulator of CArG-dependent transcription of multiple smooth muscle marker genes. Circ Res. 2003; 92(8):856-64. DOI: 10.1161/01.RES.0000068405.49081.09. View

Kumar M, Hendrix J, Johnson A, Owens G . Smooth muscle alpha-actin gene requires two E-boxes for proper expression in vivo and is a target of class I basic helix-loop-helix proteins. Circ Res. 2003; 92(8):840-7. DOI: 10.1161/01.RES.0000069031.55281.7C. View

Matsuzaki K, Minami T, Tojo M, Honda Y, Uchimura Y, Saitoh H . Serum response factor is modulated by the SUMO-1 conjugation system. Biochem Biophys Res Commun. 2003; 306(1):32-8. DOI: 10.1016/s0006-291x(03)00910-0. View

Lin X, Liang M, Liang Y, Brunicardi F, Feng X . SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4. J Biol Chem. 2003; 278(33):31043-8. DOI: 10.1074/jbc.C300112200. View

Liu Y, Sinha S, Owens G . A transforming growth factor-beta control element required for SM alpha-actin expression in vivo also partially mediates GKLF-dependent transcriptional repression. J Biol Chem. 2003; 278(48):48004-11. DOI: 10.1074/jbc.M301902200. View

Qiu P, Feng X, Li L . Interaction of Smad3 and SRF-associated complex mediates TGF-beta1 signals to regulate SM22 transcription during myofibroblast differentiation. J Mol Cell Cardiol. 2003; 35(12):1407-20. DOI: 10.1016/j.yjmcc.2003.09.002. View

Ohshima T, Shimotohno K . Transforming growth factor-beta-mediated signaling via the p38 MAP kinase pathway activates Smad-dependent transcription through SUMO-1 modification of Smad4. J Biol Chem. 2003; 278(51):50833-42. DOI: 10.1074/jbc.M307533200. View

Chen S, Lechleider R . Transforming growth factor-beta-induced differentiation of smooth muscle from a neural crest stem cell line. Circ Res. 2004; 94(9):1195-202. DOI: 10.1161/01.RES.0000126897.41658.81. View

10.

Liang M, Melchior F, Feng X, Lin X . Regulation of Smad4 sumoylation and transforming growth factor-beta signaling by protein inhibitor of activated STAT1. J Biol Chem. 2004; 279(22):22857-65. DOI: 10.1074/jbc.M401554200. View

11.

Owens G, Kumar M, Wamhoff B . Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004; 84(3):767-801. DOI: 10.1152/physrev.00041.2003. View

12.

Kawai-Kowase K, Sato H, Oyama Y, Kanai H, Sato M, Doi H . Basic fibroblast growth factor antagonizes transforming growth factor-beta1-induced smooth muscle gene expression through extracellular signal-regulated kinase 1/2 signaling pathway activation. Arterioscler Thromb Vasc Biol. 2004; 24(8):1384-90. DOI: 10.1161/01.ATV.0000136548.17816.07. View

13.

Gill G . SUMO and ubiquitin in the nucleus: different functions, similar mechanisms?. Genes Dev. 2004; 18(17):2046-59. DOI: 10.1101/gad.1214604. View

14.

Molkentin J, Black B, Martin J, Olson E . Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. Cell. 1995; 83(7):1125-36. DOI: 10.1016/0092-8674(95)90139-6. View

15.

Hautmann M, Madsen C, Owens G . A transforming growth factor beta (TGFbeta) control element drives TGFbeta-induced stimulation of smooth muscle alpha-actin gene expression in concert with two CArG elements. J Biol Chem. 1997; 272(16):10948-56. DOI: 10.1074/jbc.272.16.10948. View

16.

Li L, Liu Z, Mercer B, Overbeek P, Olson E . Evidence for serum response factor-mediated regulatory networks governing SM22alpha transcription in smooth, skeletal, and cardiac muscle cells. Dev Biol. 1997; 187(2):311-21. DOI: 10.1006/dbio.1997.8621. View

17.

Hirschi K, Rohovsky S, DAmore P . PDGF, TGF-beta, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J Cell Biol. 1998; 141(3):805-14. PMC: 2132737. DOI: 10.1083/jcb.141.3.805. View

18.

Mack C, Owens G . Regulation of smooth muscle alpha-actin expression in vivo is dependent on CArG elements within the 5' and first intron promoter regions. Circ Res. 1999; 84(7):852-61. DOI: 10.1161/01.res.84.7.852. View

19.

Sinha S, Hoofnagle M, Kingston P, McCanna M, Owens G . Transforming growth factor-beta1 signaling contributes to development of smooth muscle cells from embryonic stem cells. Am J Physiol Cell Physiol. 2004; 287(6):C1560-8. DOI: 10.1152/ajpcell.00221.2004. View

20.

Liu Y, Sinha S, McDonald O, Shang Y, Hoofnagle M, Owens G . Kruppel-like factor 4 abrogates myocardin-induced activation of smooth muscle gene expression. J Biol Chem. 2004; 280(10):9719-27. DOI: 10.1074/jbc.M412862200. View