ABERRANT EXPRESSION OF BASIC FIBROBLAST GROWTH-FACTOR IN NIH-3T3 CELLS ALTERS DRUG-RESISTANCE AND GENE AMPLIFICATION POTENTIAL

We have investigated the genetic stability of NIH-3 T3 cells transfect ed with sequences coding for basic fibroblast growth factor (bFGF) by determining drug resistance and gene amplification potential. Colony-f orming experiments and fluctuation analyses showed that the frequency and rate of resistance to N-(phosphonacetyl)-L-aspartate (PALA) was dr amatically elevated in cells transfected with either the normal bFGF c oding sequence that lacks a known signal for secretion or a chimeric b FGF sequence that targets the growth factor to the secretory pathway. Basic FGF-transfected cells that grew in the presence of PALA were fou nd to possess an amplification of the CAD gene, which codes for a mult ifunctional protein involved in pyrimidine biosynthesis and is the sit e of action for PALA. The observation that these alterations occur in cells transfected with a bFGF sequence, without a conventional signal sequence for secretion, suggests an intracrine as opposed to autocrine mechanism of action. The results describe a new function for this gro wth factor and suggest a novel role for aberrant expression of bFGF in mechanisms of tumor progression. (C) 1994 Academic Press, Inc.