Differentiation of human melanoma cells through p38 MAP kinase is associated with decreased retinoblastoma protein phosphorylation and cell cycle arrest

Melanoma Res. 2002 Jun;12(3):187-92. doi: 10.1097/00008390-200206000-00001.


The retinoblastoma protein (pRB), the product of the retinoblastoma gene, is a key regulator of the cell cycle, affecting apoptosis, proliferation and differentiation. Dysregulation of pRB is implicated in the pathogenesis of many cancers, including malignant melanoma. Recently we demonstrated that alpha-melanocyte-stimulating hormone (alpha-MSH)-induced activation of p38 mitogen-activated protein (MAP) kinase leads to differentiation of B16 murine melanoma cells. The current study assesses the ability of alpha-MSH to activate p38 MAP kinase in COLO 853 human melanoma cells and determines whether this is linked to modulation of pRB activity. Treatment of COLO 853 cells with alpha-MSH induced time- and concentration-dependent increases in the phosphorylation of p38 MAP kinase, which corresponded with its ability to induce melanogenesis and inhibit cell growth. SB 203580, a selective inhibitor of p38 MAP kinase, blocked both the alpha-MSH-induced melanogenic response and inhibition of cell growth. Cell cycle analysis using flow cytometry revealed that treatment of COLO 853 cells with alpha-MSH for 72 h led to an increase in the proportion of cells in the G(1) phase and a marked reduction in the amount of phosphorylated pRB. Both of these effects were reversed by pre-treatment of cells with SB 203580. In summary, we have demonstrated for the first time that the alpha-MSH-induced differentiation of COLO 853 human melanoma cells proceeds via a p38 MAP kinase-mediated pathway and is associated with decreased pRB phosphorylation and accumulation of cells in the G(1) phase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / drug effects
  • Colforsin / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • G1 Phase
  • Humans
  • Imidazoles / pharmacology
  • Kinetics
  • MAP Kinase Signaling System* / drug effects
  • Melanins / biosynthesis
  • Melanins / metabolism
  • Melanoma / enzymology
  • Melanoma / pathology*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / physiology*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology*
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • Pyridines / pharmacology
  • Retinoblastoma Protein / metabolism*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / enzymology
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology
  • alpha-MSH / pharmacology*


  • Enzyme Inhibitors
  • Imidazoles
  • Melanins
  • Neoplasm Proteins
  • Pyridines
  • Retinoblastoma Protein
  • Colforsin
  • alpha-MSH
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • SB 203580