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

Cph was isolated from neoplastic Syrian hamster embryo fibroblasts initiate d 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 h amster full-length cDNAs for the cph oncogene and proto-oncogene, Nucleotid e 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 norm al open reading frame (ORF) and brought a translation termination codon 33 amino acids downstream. While proto-cph encodes a protein (pcph) of 469 ami no acids, cpk encodes a truncated protein (cph) of 246 amino acids with a n ew, hydrophobic C-terminus, Similar mechanisms activated cph in other MCA-t reated Syrian hamster cells. The cph and proto-cph proteins have partial se quence homology with two protein families: GDP/GTP exchange factors and nuc leotide phosphohydrolases. In vitro translated, gel-purified cph proteins d id not catalyze nucleotide exchange for H-ras, but were able to bind nucleo tide phosphates, in particular ribonucleotide diphosphates such as UDP and GDP, Steady-state levels of cph mRNA increased 6.7-fold in hamster neoplast ic cells, relative to a 2.2-fold increase in normal cells, when they were s ubjected to a nutritional stress such as serum deprivation, Moreover, cph-t ransformed NIH3T3 cells showed increased survival to various forms of stres s (serum starvation, hyperthermia, ionizing radiation), strongly suggesting that cph participates in cellular mechanisms of response to stress.