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Peptide Regulation of Gene Expression and Protein Synthesis in Bronchial Epithelium

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Abstract

Introduction

Some studies have shown that peptides have high treatment potential due to their biological activity, harmlessness, and tissue-specific action. Tetrapeptide Ala-Asp-Glu-Leu (ADEL) was effective on models of acute bacterial lung inflammation, fibrosis, and toxic lung damage in several studies.

Methods

We measured Ki67, Mcl-1, p53, CD79, and NOS-3 protein levels in the 1st, 7th, and 14th passages of bronchoepithelial human embryonic cell cultures. Gene expression of NKX2-1, SCGB1A1, SCGB3A2, FOXA1, FOXA2, MUC4, MUC5AC, and SFTPA1 was measured by real-time polymerase chain reaction. Using the methods of spectrophotometry, viscometry, and circular dichroism, we studied the ADEL–DNA interaction in vitro.

Results

Peptide ADEL regulates the levels of Ki67, Mcl-1, p53, CD79, and NOS-3 proteins in cell cultures of human bronchial epithelium in various passages. The strongest activating effect of peptide ADEL on bronchial epithelial cell proliferation through Ki67 and Mcl-1 was observed in “old” cell cultures. ADEL regulates the expression of genes involved in bronchial epithelium differentiation: NKX2-1, SCGB1A1, SCGB3A2, FOXA1, and FOXA2. ADEL also activates several genes, which reduced expression correlated with pathological lung development: MUC4, MUC5AC, and SFTPA1. Spectrophotometry, viscometry, and circular dichroism showed ADEL–DNA interaction, with a binding region in the major groove (N7 guanine).

Conclusions

ADEL can bind to specific DNA regions and regulate gene expression and synthesis of proteins involved in the differentiation and maintenance of functional activity of the bronchial epithelium. Through activation of some specific gene expression, peptide ADEL may protect the bronchial epithelium from pulmonary pathology. ADEL also may have a geroprotective effect on bronchial tissue.

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Abbreviations

AEDG:

Ala-Glu-Asp-Gly-peptide

BAL fluid:

Bronchoalveolar fluid

CD:

Circular dichroism

CD79:

Cluster of differentiation 79, CD79a and CD79b types are members of immunoglobulin superfamily and both activate B cells

CD79A:

CD79a molecule, immunoglobulin-associated alpha (gene)

cDNA:

Complementary DNA

COPD:

Chronic obstructive pulmonary disease

GAPD:

Glyceraldehyde-3-phosphate dehydrogenase

Hoxa3:

Homeobox protein

FoxA2:

Forkhead box protein A2

FOXA1:

Forkhead box A1 gene

FOXA2:

Forkhead box A2 gene

KEDW:

KEDW-NH2, Lys-Glu-Asp-Trp-NH2–peptide

KI-67:

Antigen KI-67 protein

Mcl-1:

Induced myeloid leukemia cell differentiation protein, inhibits apoptosis and enhances cell survival

MCL1:

Myeloid cell leukemia sequence 1 (BCL2-related) gene

miRNA 365:

Small noncoding RNAs, regulates NKX2-1

MKI67:

Marker of proliferation Ki-67 gene

MUC4:

Mucin 4, cell surface associated (gene)

MUC5AC:

Mucin 5AC, oligomeric mucus/gel-forming (gene)

NOS-3:

Nitric oxide synthase 3

NOS3:

Nitric oxide synthase 3 gene

Nkx2.1:

NK2 homeobox 1 protein also known as thyroid transcription factor 1

NKX2-1:

Homeobox protein Nkx-2.1, isoform 2 (gene)

Notch1:

Transmembrane protein of the Notch family, member 1, promotes differentiation

Scgb3A2:

Secretoglobin, family 3A, member 2

SCGB1A1:

Secretoglobin, family 1A, member 1 (uteroglobin) (gene)

SCGB3A2:

Secretoglobin, family 3A, member 2 (gene)

SFTPA1:

Surfactant protein (gene)

SP-A1:

Pulmonary surfactant-associated protein A1

p53:

Cellular tumor antigen p53, phosphoprotein p53 or tumor suppressor p53

TP53:

Tumor protein p53 gene

TNF-a:

Tumor necrosis factor alpha

References

  1. Boland MRS, Tsiachristas A, Kruis AL et al (2013) The health economic impact of disease management programs for COPD: a systematic literature review and meta-analysis. BMC Pulm Med. doi:10.1186/1471-2466-13-40

    Google Scholar 

  2. Khavinson VK, Malinin VV (2005) Gerontological aspects of genome peptide regulation. Karger AG, Basel

    Book  Google Scholar 

  3. Huang H, Kozekov ID, Kozekova A et al (2010) Minor groove orientation of the KWKK peptide tethered via the N-terminal amine to the acrolein-derived 1, N2-gamma-hydroxypropanodeoxyguanosine lesion with a trimethylene linkage. Biochemistry 49:6155–6164

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Ryan KK, Seeley RJ (2013) Physiology. Food as a hormone. Science 339:918–919. doi:10.1126/science.1234062

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Anisimov VN, Khavinson VK (2010) Peptide bioregulation of aging: results and prospects. Biogerontology 11:139–149. doi:10.1007/s10522-009-9249-8

    Article  CAS  PubMed  Google Scholar 

  6. Fedoreyeva LI, Vanyushin BF (2011) CNG site-specific and methyl-sensitive endonuclease WEN1 from wheat seedlings. Biochemistry (Mosc) 76:651–657. doi:10.1134/S0006297911060058

    Article  CAS  Google Scholar 

  7. Fedoreyeva LI, Kireev II, Khavinson VK, Vanyushin BF (2011) Penetration of short fluorescence-labeled peptides into the nucleus in HeLa cells and in vitro specific interaction of the peptides with deoxyribooligonucleotides and DNA. Biochem (Mosc) 76:1210–1219

    Article  CAS  Google Scholar 

  8. Khavinson VK, Tarnovskaya SI, Linkova NS et al (2013) Short cell-penetrating peptides: a model of interactions with gene promoter sites. Bull Exp Biol Med 154:403–410

    Article  CAS  PubMed  Google Scholar 

  9. Khavinson VK, Ryzhak GA, Grigoriev EI, Ryadnova IY (2009) Peptide substance restoring respiratory organs function. US Patent US 7,625,870

  10. Khavinson VK, Linkova NS, Polyakova VO et al (2012) Peptides tissue-specifically stimulate cell differentiation during their aging. Bull Exp Biol Med 153:148–151

    Article  CAS  PubMed  Google Scholar 

  11. Chiappara G, Gjomarkaj M, Virzì A et al (2013) The role of p21 Waf1/Cip1 in large airway epithelium in smokers with and without COPD. Biochim Biophys Acta 1832:1473–1481. doi:10.1016/j.bbadis.2013.04.022

    Article  CAS  PubMed  Google Scholar 

  12. Liu XH, Tang CS (2006) Protection against ischemia-reperfusion injury: from bench to bedside. Zhonghua Xin Xue Guan Bing Za Zhi 34:677–679

    PubMed  Google Scholar 

  13. Porebska 1., Wyrodek E, Kosacka M, et al. (2006) Apoptotic markers p53, Bcl-2 and Bax in primary lung cancer. In Vivo 20:599–604

  14. Kamdar O, Le W, Zhang J et al (2008) Air pollution induces enhanced mitochondrial oxidative stress in cystic fibrosis airway epithelium. FEBS Lett 582:3601–3606. doi:10.1016/j.febslet.2008.09.030

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. O’Neill SK, Getahun A, Gauld SB et al (2011) Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy. Immunity 35:746–756. doi:10.1016/j.immuni.2011.10.011

    Article  PubMed Central  PubMed  Google Scholar 

  16. Nakken B, Munthe LA, Konttinen YT et al (2011) B-cells and their targeting in rheumatoid arthritis–current concepts and future perspectives. Autoimmun Rev 11:28–34. doi:10.1016/j.autrev.2011.06.010

    Article  CAS  PubMed  Google Scholar 

  17. Nawa A, Fujita-Hamabe W, Nakamoto K, Tokuyama S (2011) Nitric oxide synthase-mediated alteration of intestinal P-glycoprotein under hyperglycemic stress. Yakugaku Zasshi 131:487–492

    Article  CAS  PubMed  Google Scholar 

  18. Yang Z, Hikosaka K, Sharkar MTK et al (2010) The mouse forkhead gene Foxp2 modulates expression of the lung genes. Life Sci 87:17–25. doi:10.1016/j.lfs.2010.05.009

    Article  CAS  PubMed  Google Scholar 

  19. Qi J, Rice SJ, Salzberg AC et al (2012) MiR-365 regulates lung cancer and developmental gene thyroid transcription factor 1. Cell Cycle 11:177–186

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Kang S-M, Lee H-J, Cho J-Y (2013) MicroRNA-365 regulates NKX2-1, a key mediator of lung cancer. Cancer Lett 335:487–494. doi:10.1016/j.canlet.2013.03.006

    Article  CAS  PubMed  Google Scholar 

  21. Kurotani R, Tomita T, Yang Q et al (2008) Role of secretoglobin 3A2 in lung development. Am J Respir Crit Care Med 178:389–398. doi:10.1164/rccm.200707-1104OC

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Kurotani R, Okumura S, Matsubara T et al (2011) Secretoglobin 3A2 suppresses bleomycin-induced pulmonary fibrosis by transforming growth factor beta signaling down-regulation. J Biol Chem 286:19682–19692. doi:10.1074/jbc.M111.239046

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Kido T, Tomita T, Okamoto M et al (2011) FOXA1 plays a role in regulating secretoglobin 1a1 expression in the absence of CCAAT/enhancer binding protein activities in lung in vivo. Am J Physiol Lung Cell Mol Physiol 300:441–452

    Article  Google Scholar 

  24. Li Z, Gadue P, Chen K et al (2012) Foxa2 and H2A.Z mediate nucleosome depletion during embryonic stem cell differentiation. Cell 151:1608–1616. doi:10.1016/j.cell.2012.11.018

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Madeddu P (2013) FoxA2 hunting research identifies the early trail of mesenchymal differentiation. Stem Cell Res Ther 4:40

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Kwon KY, Ro JY, Singhal N et al (2007) MUC4 expression in non-small cell lung carcinomas: relationship to tumor histology and patient survival. Arch Pathol Lab Med 131:593–598

    CAS  PubMed  Google Scholar 

  27. Van Diemen CC, Postma DS, Aulchenko YS et al (2010) Novel strategy to identify genetic risk factors for COPD severity: a genetic isolate. Eur Respir J 35:768–775. doi:10.1183/09031936.00054408

    Article  PubMed  Google Scholar 

  28. Khavinson VK, Gapparov MM-G, Sharanova NE et al (2010) Study of biological activity of Lys-Glu-Asp-Trp-NH2 endogenous tetrapeptide. Bull Exp Biol Med 149:351–353

    Article  CAS  PubMed  Google Scholar 

  29. Frisman EV, Shchagina LV, Vorobev VI (1965) A glass rotating viscometer. Biorheology 2:189–194

    CAS  PubMed  Google Scholar 

  30. Kasyanenko N, Prokhorova S, Haya EF et al (1999) Interaction of protonated DNA with trans-diclorodiammineplatinum (II). Colloids Surf 148:121–128

    Article  CAS  Google Scholar 

  31. Johnson NP, Lindstrom J, Baase WA, von Hippel PH (1994) Double-stranded DNA templates can induce alpha-helical conformation in peptides containing lysine and alanine: functional implications for leucine zipper and helix-loop-helix transcription factors. Proc Natl Acad Sci USA 91:4840–4844

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Chisaka O, Kameda Y (2005) Hoxa3 regulates the proliferation and differentiation of the third pharyngeal arch mesenchyme in mice. Cell Tissue Res 320:77–89. doi:10.1007/s00441-004-1042-z

    Article  CAS  PubMed  Google Scholar 

  33. Lawless C, Wang C, Jurk D et al (2010) Quantitative assessment of markers for cell senescence. Exp Gerontol 45:772–778. doi:10.1016/j.exger.2010.01.018

    Article  CAS  PubMed  Google Scholar 

  34. Yuan B, Li C, Kimura S et al (2000) Inhibition of distal lung morphogenesis in. Dev Dyn 217:180–190

    Article  CAS  PubMed  Google Scholar 

  35. Khavinson VK, Fedoreeva LI, Vanyushin BF (2011) Short peptides modulate the effect of endonucleases of wheat seedling. Biochem Biophys reports 437:64–67

    CAS  Google Scholar 

  36. Kubo T, Yokoyama K, Ueki R et al (2000) Structure and affinity of DNA binding peptides. Nucleic Acids Symp Ser 44:49–50

    Article  PubMed  Google Scholar 

  37. Khavinson VK, Soloviev AY, Tarnovskaya SI, Linkova NS (2013) Mechanism of biological activity of short peptides: Cell penetration and epigenetic regulation of gene expression. Biol Bull Rev 3:451–455

    Article  Google Scholar 

  38. Frankel AD, Pabo CO (1988) Cellular uptake of the tat protein from human immunodeficiency virus. Cell 8:33–34

    Google Scholar 

  39. Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132

    Article  CAS  PubMed  Google Scholar 

  40. Futaki S, Goto S, Sugiura Y (2003) Membrane permeability commonly shared among arginine-rich peptides. J Mol Recognit 16:260–264. doi:10.1002/jmr.635

    Article  CAS  PubMed  Google Scholar 

  41. Duchardt F, Fotin-Mleczek M, Schwarz H et al (2007) A comprehensive model for the cellular uptake of cationic cell-penetrating peptides. Traffic 8:848–866. doi:10.1111/j.1600-0854.2007.00572.x

    Article  CAS  PubMed  Google Scholar 

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Conflict of interest

None of the authors has any conflict of interest related to this manuscript.

Author information

Authors and Affiliations

  1. Karolinska University Hospital, Solna, Stockholm, Sweden

    S. M. Tendler

  2. Pavlov Institute of Physiology of RAS, St-Petersburg, Russia

    V. Kh. Khavinson

  3. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia

    B. F. Vanyushin & V. V. Ashapkin

  4. Saint-Petersburg State University, St-Petersburg, Russia

    N. A. Kasyanenko

  5. Saint-Petersburg Institute of Bioregulation and Gerontology, St-Petersburg, Russia

    V. Kh. Khavinson, S. M. Tendler, I. M. Kvetnoy, N. S. Linkova, V. O. Polyakova, V. S. Basharina & A. Bernadotte

  6. D.O. Ott Research Institute of Obstetrics and Gynecology, St-Petersburg, Russia

    I. M. Kvetnoy & V. O. Polyakova

  7. Department of Neurobiology, Care Sciences and Society, Division for Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden

    A. Bernadotte

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  1. V. Kh. Khavinson
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  2. S. M. Tendler
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  3. B. F. Vanyushin
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  4. N. A. Kasyanenko
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  7. V. V. Ashapkin
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  8. V. O. Polyakova
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  9. V. S. Basharina
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  10. A. Bernadotte
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Correspondence to A. Bernadotte.

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Khavinson, V.K., Tendler, S.M., Vanyushin, B.F. et al. Peptide Regulation of Gene Expression and Protein Synthesis in Bronchial Epithelium. Lung 192, 781–791 (2014). https://doi.org/10.1007/s00408-014-9620-7

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  • DOI: https://doi.org/10.1007/s00408-014-9620-7

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