Induction of the Tat-binding protein 1 gene accompanies the disabling of oncogenic erbB receptor tyrosine kinases

Conversion of a malignant phenotype into a more normal one can be accomplis hed either by downregulation of erbB family surface receptors or by creatin g inactive erbB heterodimers on the cell surface. In this report, we report the identification and cloning of differentially expressed genes from anti body-treated vs. untreated fibroblasts transformed by oncogenic p185(neu). We repeatedly isolated a 325-bp cDNA fragment that, as determined by Northe rn analysis, was expressed at higher levels in anti-p185(neu)-treated tumor cells but not in cells expressing internalization defective p185(neu) rece ptors. This cDNA fragment was identical in amino acid sequence to the recen tly cloned mouse Tat binding protein-1 (mTBP1), which has 98.4% homology to the HIV tat-binding protein-1 (TBP1). TBP1 mRNA levels were found to be el evated on inhibition of the oncogenic phenotype of transformed cells expres sing erbB family receptors. TBP1 overexpression diminished cell proliferati on, reduced the ability of the parental cells to form colonies in vitro, an d almost completely inhibited transforming efficiency in athymic mice when stably expressed in human tumor cells containing erbB family receptors. Col lectively, these results suggest that the attenuation of erbB receptor sign aling seems to be associated with activation/induction or recovery of a fun ctional tumor suppressor-like gene, TBP1. Disabling erbB tyrosine kinases b y antibodies or by trans-inhibition represents an initial step in triggerin g a TBP1 pathway.