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 accomplished either by down-regulation of erbB family surface receptors or by creating inactive erbB heterodimers on the cell surface. In this report, we report the identification and cloning of differentially expressed genes from antibody-treated vs. untreated fibroblasts transformed by oncogenic p185(neu). We repeatedly isolated a 325-bp cDNA fragment that, as determined by Northern analysis, was expressed at higher levels in anti-p185(neu)-treated tumor cells but not in cells expressing internalization defective p185(neu) receptors. This cDNA fragment was identical in amino acid sequence to the recently 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 elevated on inhibition of the oncogenic phenotype of transformed cells expressing erbB family receptors. TBP1 overexpression diminished cell proliferation, reduced the ability of the parental cells to form colonies in vitro, and almost completely inhibited transforming efficiency in athymic mice when stably expressed in human tumor cells containing erbB family receptors. Collectively, these results suggest that the attenuation of erbB receptor signaling seems to be associated with activation/induction or recovery of a functional tumor suppressor-like gene, TBP1. Disabling erbB tyrosine kinases by antibodies or by trans-inhibition represents an initial step in triggering a TBP1 pathway.
Park
B W
BW
Department of Pathology and Laboratory Medicine, Center for Receptor Biology and Cell Growth, University of Pennsylvania School of Medicine, 36th and Hamilton Walk, Philadelphia, PA 19104, USA.
O'Rourke
D M
DM
Wang
Q
Q
Davis
J G
JG
Post
A
A
Qian
X
X
Greene
M I
MI
D016475:3T3 Cells; D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms; D002455:Cell Division; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016147:Genes, Tumor Suppressor; D018734:Genes, erbB-2; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000074183:ATPases Associated with Diverse Cellular Activities; D004268:DNA-Binding Proteins; D046988:Proteasome Endopeptidase Complex; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C064757:PSMC3 protein, human