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Peptide Regulation of Gene Expression and Protein Synthesis in Bronchial Epithelium

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

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

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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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Keywords

  • Tetrapeptide
  • Bronchial epithelium
  • Signal molecule
  • Gene expression
  • Peptide–DNA interaction
  • Cell culture
  • Geroprotection
  • Geroprotector
  • Anti-aging
  • Peptide
  • COPD
  • ADEL