Abstract

Opioid growth factor (OGF) is an endogenous opioid peptide ([Met 5]enkephalin) that interacts with the OGF receptor (OGFr) and serves as a tonically active negative growth factor in cell proliferation of normal cells. To clarify the mechanism by which OGF inhibits cell replication in normal cells, we investigated the effect of the OGF-OGFr axis on cell cycle activity in human umbilical vein endothelial cells (HUVECs) and human epidermal keratinocytes (NHEKs). OGF markedly depressed cell proliferation of both cell lines by up to 40% of sterile water controls. Peptide treatment induced cyclin-dependent kinase inhibitor (CKI) p16 INK4a protein expression and p21 WAF1/CIP1 protein expression in HUVECs and NHEKs, but had no effect on p15, p18, p19, or p27 protein expression in either cell type. Inhibition of either p16 INK4a or p21 WAF1/CIP1 activation by specific siRNAs blocked OGF inhibitory action. Human dermal fibroblasts and mesenchymal stem cells also showed a similar dependence of OGF action on p16 INK4a and p21 WAF1/CIP1. Collectively, these results indicate that both p16 INK4a and p21 WAF1/CIP1 are required for the OGF-OGFr axis to inhibit cell proliferation in normal cells.

Original languageEnglish (US)
Pages (from-to)319-327
Number of pages9
JournalMolecular biology of the cell
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2009

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Opioid Analgesics
Intercellular Signaling Peptides and Proteins
Cell Proliferation
Human Umbilical Vein Endothelial Cells
Cyclin-Dependent Kinase Inhibitor p16
Methionine Enkephalin
Proteins
Opioid Peptides
Mesenchymal Stromal Cells
Keratinocytes
Cell Cycle
Fibroblasts
methionine-enkephalin receptor
Cell Line
Skin
Peptides
Water

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

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title = "The OGF-OGFr axis utilizes the p16 INK4a and p21 WAF1/CIP1 pathways to restrict normal cell proliferation",
abstract = "Opioid growth factor (OGF) is an endogenous opioid peptide ([Met 5]enkephalin) that interacts with the OGF receptor (OGFr) and serves as a tonically active negative growth factor in cell proliferation of normal cells. To clarify the mechanism by which OGF inhibits cell replication in normal cells, we investigated the effect of the OGF-OGFr axis on cell cycle activity in human umbilical vein endothelial cells (HUVECs) and human epidermal keratinocytes (NHEKs). OGF markedly depressed cell proliferation of both cell lines by up to 40{\%} of sterile water controls. Peptide treatment induced cyclin-dependent kinase inhibitor (CKI) p16 INK4a protein expression and p21 WAF1/CIP1 protein expression in HUVECs and NHEKs, but had no effect on p15, p18, p19, or p27 protein expression in either cell type. Inhibition of either p16 INK4a or p21 WAF1/CIP1 activation by specific siRNAs blocked OGF inhibitory action. Human dermal fibroblasts and mesenchymal stem cells also showed a similar dependence of OGF action on p16 INK4a and p21 WAF1/CIP1. Collectively, these results indicate that both p16 INK4a and p21 WAF1/CIP1 are required for the OGF-OGFr axis to inhibit cell proliferation in normal cells.",
author = "Fan Cheng and McLaughlin, {Patricia J.} and Verderame, {Michael F.} and Zagon, {Ian S.}",
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T1 - The OGF-OGFr axis utilizes the p16 INK4a and p21 WAF1/CIP1 pathways to restrict normal cell proliferation

AU - Cheng, Fan

AU - McLaughlin, Patricia J.

AU - Verderame, Michael F.

AU - Zagon, Ian S.

PY - 2009/1/1

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N2 - Opioid growth factor (OGF) is an endogenous opioid peptide ([Met 5]enkephalin) that interacts with the OGF receptor (OGFr) and serves as a tonically active negative growth factor in cell proliferation of normal cells. To clarify the mechanism by which OGF inhibits cell replication in normal cells, we investigated the effect of the OGF-OGFr axis on cell cycle activity in human umbilical vein endothelial cells (HUVECs) and human epidermal keratinocytes (NHEKs). OGF markedly depressed cell proliferation of both cell lines by up to 40% of sterile water controls. Peptide treatment induced cyclin-dependent kinase inhibitor (CKI) p16 INK4a protein expression and p21 WAF1/CIP1 protein expression in HUVECs and NHEKs, but had no effect on p15, p18, p19, or p27 protein expression in either cell type. Inhibition of either p16 INK4a or p21 WAF1/CIP1 activation by specific siRNAs blocked OGF inhibitory action. Human dermal fibroblasts and mesenchymal stem cells also showed a similar dependence of OGF action on p16 INK4a and p21 WAF1/CIP1. Collectively, these results indicate that both p16 INK4a and p21 WAF1/CIP1 are required for the OGF-OGFr axis to inhibit cell proliferation in normal cells.

AB - Opioid growth factor (OGF) is an endogenous opioid peptide ([Met 5]enkephalin) that interacts with the OGF receptor (OGFr) and serves as a tonically active negative growth factor in cell proliferation of normal cells. To clarify the mechanism by which OGF inhibits cell replication in normal cells, we investigated the effect of the OGF-OGFr axis on cell cycle activity in human umbilical vein endothelial cells (HUVECs) and human epidermal keratinocytes (NHEKs). OGF markedly depressed cell proliferation of both cell lines by up to 40% of sterile water controls. Peptide treatment induced cyclin-dependent kinase inhibitor (CKI) p16 INK4a protein expression and p21 WAF1/CIP1 protein expression in HUVECs and NHEKs, but had no effect on p15, p18, p19, or p27 protein expression in either cell type. Inhibition of either p16 INK4a or p21 WAF1/CIP1 activation by specific siRNAs blocked OGF inhibitory action. Human dermal fibroblasts and mesenchymal stem cells also showed a similar dependence of OGF action on p16 INK4a and p21 WAF1/CIP1. Collectively, these results indicate that both p16 INK4a and p21 WAF1/CIP1 are required for the OGF-OGFr axis to inhibit cell proliferation in normal cells.

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