Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines

Cancer Res. 2000 Apr 1;60(7):1800-4.

Abstract

Both inactivation of the tumor suppressor gene, PTEN/MMAC1, and oncogenic activation of RAS have been described in human cutaneous melanoma. In mice, activation of a RAS-containing pathway is a necessary step in the pathogenesis of murine melanomas. Because PTEN negatively regulates on the downstream effects of phosphatidylinositol-3-kinase (PI3-K), we hypothesized that the loss of PTEN/MMAC1 and the activation of RAS may be largely equivalent because RAS is a known positive upstream regulator of PI3-K. We expanded our previous survey of PTEN/MMAC1 mutations and analyzed the RAS status of 53 cutaneous melanoma cell lines, 18 glioma cell lines, and 17 uncultured cutaneous melanoma metastasis. Overall, 51% of the cell lines had alterations in either PTEN/MMAC1 or RAS. We found 16 cell lines (30%) with alterations in PTEN/MMAC1 and 11 cell lines (21%) with activating NRAS mutations; only 1 cell line had concurrent alterations in both genes. Moreover, glioma cell lines with a high frequency of PTEN/MMAC1 inactivation had no identifiable RAS alterations. Ectopic expression of PTEN in several cutaneous melanoma cell lines suppressed colony formation irrespective of PTEN/MMAC1 status; furthermore, PTEN expression in cell lines carrying activated RAS also suppressed colony formation. The relative reciprocity of PTEN/MMAC1 abrogation and NRAS activation suggests that the two genetic changes, in a subset of cutaneous melanomas, are functionally overlapping.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Brain Neoplasms / genetics
  • Exons
  • Frameshift Mutation
  • Gene Deletion
  • Genes, Tumor Suppressor*
  • Genes, ras*
  • Glioma / genetics
  • Humans
  • Melanoma / genetics*
  • Melanoma, Experimental / genetics
  • Mice
  • Mutation*
  • PTEN Phosphohydrolase
  • Phosphoric Monoester Hydrolases / genetics*
  • Point Mutation
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Sequence Deletion
  • Skin Neoplasms / genetics*
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*

Substances

  • Tumor Suppressor Proteins
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)