Fas-induced apoptosis in human malignant melanoma cell lines is associated with the activation of the p34(cdc2)-related PITSLRE protein kinases

Maria E. Ariza, Marianne Broome-Powell, Jill M. Lahti, Vincent J. Kidd, Mark A. Nelson

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

The Cdc2L locus encoding the PITSLRE protein kinases maps to chromosome band 1p36 and consists of two duplicated and tandemly linked genes. The purpose of the present study was to determine whether diminution of PITSLRE kinases leads to deregulation of apoptosis. The human melanoma cell lines A375 (Cdc2L wild-type alleles) and UACC 1227 (mutant Cdc2L alleles) were tested with agonist anti-Fas monoclonal antibody. We found that exposure of these cells to anti-Fas for 24, 48, or 72 h resulted in differential sensitivity to Fas-induced apoptosis. In A375, cell death started at 24-48 h post-treatment, and it was maximal by 72 h. Conversely, UACC 1227 cells were resistant to Fas-mediated apoptosis. Induction of PITSLRE histone H1 kinase activity was observed in A375 anti-Fas treated but not in UACC 1227 cells. Also, the PITSLRE protein kinase activity in A375 anti-Fas-treated cells preceded maximal levels of apoptosis. Finally, fluorescence confocal microscopy revealed a nuclear localization of PITSLRE proteins in normal melanocytes and A375 cells but a cytoplasmic localization in UACC 1227 cells. The differences in PITSLRE protein and cellular localization between A375 and UACC 1227 cells appear to account for the differences in sensitivity of the two cells lines to anti-Fas and staurosporine. These observations suggest that alterations in PITSLRE gene expression and protein localization may result in the loss of apoptotic signaling.

Original languageEnglish (US)
Pages (from-to)28505-28513
Number of pages9
JournalJournal of Biological Chemistry
Volume274
Issue number40
DOIs
StatePublished - Oct 1 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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