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Phosphatidylinositol 3-kinase/Akt-dependent and -independent protection against apoptosis in normal human melanocytes.

Abstract
Normal human melanocytes require the synergistic action of several growth-promoting agents for their growth in serum-free medium. The ability of four representative growth promoting agents including insulin, 12-O-tetradecanoylphorbol-13-acetate (TPA), basic fibroblast growth factor (bFGF), and 3-isobutyl-1-methylxanthine (IBMX), (iTbI) to protect melanocytes against apoptosis was examined. Also, the involvement of phosphatidylinositol (PI) 3-kinase and Akt, one of the downstream targets of PI 3-kinase, in the survival signaling pathway was examined. The percentage of apoptotic cells was negligible when the cells were grown in the presence of iTbI. Deprivation of iTbI from the culture medium for 72 h caused approximately 30% of melanocytes to undergo apoptosis and this was suppressed to variable extents by the addition of one of the iTbI to the medium. Insulin and TPA protected against apoptosis almost completely, whereas bFGF and IBMX rescued melanocytes from apoptosis to a lesser extent. Wortmannin, an inhibitor of PI 3-kinase, potently inhibited the protective effect of insulin on melanocytes, whereas it did not block the ability of TPA, bFGF, or IBMX to rescue the cells from apoptosis. Furthermore, apoptosis of melanocytes induced by deprivation of iTbI was prevented almost completely by infection with an adenovirus vector encoding a constitutively active mutant of either PI 3-kinase or Akt. These results indicate that melanocytes can operate both PI 3-kinase/Akt-dependent and -independent mechanisms for protection against apoptosis and that activation of the PI 3-kinase/Akt pathway is sufficient for protection against apoptosis induced by deprivation of growth-promoting agents.
AuthorsMasahiro Oka, Akiko Kageyama, Mizuho Fukunaga, Toshinori Bito, Hiroshi Nagai, Chikako Nishigori
JournalThe Journal of investigative dermatology (J Invest Dermatol) Vol. 123 Issue 5 Pg. 930-6 (Nov 2004) ISSN: 0022-202X [Print] United States
PMID15482482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carcinogens
  • Hypoglycemic Agents
  • Insulin
  • Phosphodiesterase Inhibitors
  • Proto-Oncogene Proteins
  • Fibroblast Growth Factor 2
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Tetradecanoylphorbol Acetate
  • 1-Methyl-3-isobutylxanthine
Topics
  • 1-Methyl-3-isobutylxanthine (pharmacology)
  • Adenoviridae (genetics)
  • Apoptosis (drug effects, physiology)
  • Carcinogens (pharmacology)
  • Fibroblast Growth Factor 2 (pharmacology)
  • Humans
  • Hypoglycemic Agents (pharmacology)
  • Insulin (pharmacology)
  • Melanocytes (cytology, enzymology)
  • Mutation
  • Phosphatidylinositol 3-Kinases (genetics, metabolism)
  • Phosphodiesterase Inhibitors (pharmacology)
  • Protein Serine-Threonine Kinases (genetics, metabolism)
  • Proto-Oncogene Proteins (genetics, metabolism)
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction (drug effects, physiology)
  • Tetradecanoylphorbol Acetate (pharmacology)

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