The product of the cph oncogene is a truncated, nucleotide-binding protein that enhances cellular survival to stress

Oncogene. 1999 Jan 21;18(3):689-701. doi: 10.1038/sj.onc.1202324.

Abstract

Cph was isolated from neoplastic Syrian hamster embryo fibroblasts initiated by 3-methylcholanthrene (MCA), and was shown to be a single copy gene in the hamster genome, conserved from yeast to human cells, expressed in fetal cells and most adult tissues, and acting synergistically with H-ras in the transformation of murine NIH3T3 fibroblasts. We have now isolated Syrian hamster full-length cDNAs for the cph oncogene and proto-oncogene. Nucleotide sequence analysis revealed that cph was activated in MCA-treated cells by a point-mutational deletion at codon 214, which caused a shift in the normal open reading frame (ORF) and brought a translation termination codon 33 amino acids downstream. While proto-cph encodes a protein (pcph) of 469 amino acids, cph encodes a truncated protein (cph) of 246 amino acids with a new, hydrophobic C-terminus. Similar mechanisms activated cph in other MCA-treated Syrian hamster cells. The cph and proto-cph proteins have partial sequence homology with two protein families: GDP/GTP exchange factors and nucleotide phosphohydrolases. In vitro translated, gel-purified cph proteins did not catalyze nucleotide exchange for H-ras, but were able to bind nucleotide phosphates, in particular ribonucleotide diphosphates such as UDP and GDP. Steady-state levels of cph mRNA increased 6.7-fold in hamster neoplastic cells, relative to a 2.2-fold increase in normal cells, when they were subjected to a nutritional stress such as serum deprivation. Moreover, cph-transformed NIH3T3 cells showed increased survival to various forms of stress (serum starvation, hyperthermia, ionizing radiation), strongly suggesting that cph participates in cellular mechanisms of response to stress.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Catalysis
  • Cell Line
  • Cell Survival
  • Cell Transformation, Neoplastic
  • Cloning, Molecular
  • Cricetinae
  • DNA, Complementary
  • Gene Expression Regulation, Neoplastic
  • Guanine Nucleotide Exchange Factors
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • Mesocricetus
  • Mice
  • Molecular Sequence Data
  • Nucleotides / metabolism
  • Oncogene Protein p21(ras) / metabolism
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Oncogenes
  • Point Mutation
  • Proteins / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogenes
  • Sequence Homology, Amino Acid
  • ras Guanine Nucleotide Exchange Factors

Substances

  • DNA, Complementary
  • Guanine Nucleotide Exchange Factors
  • Nucleotides
  • Oncogene Proteins
  • Pcph protein, mouse
  • Proteins
  • Proto-Oncogene Proteins
  • ras Guanine Nucleotide Exchange Factors
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • Oncogene Protein p21(ras)

Associated data

  • GENBANK/AF084568
  • GENBANK/AF084569