Increased expression of TATA-binding protein, the central transcription factor, can contribute to oncogenesis.
Despite the central role of TATA-binding protein (TBP) in transcription, changes in cellular TBP concentration produce selective effects on gene expression. Moreover, TBP is up-regulated by oncogenic signaling pathways. These findings suggest that TBP could be a nexus in pathways that regulate cell proliferation and that genetic lesions that result in cellular transformation may produce their effects at least in part through TBP. We provide evidence consistent with this hypothesis, demonstrating that increases in TBP expression contribute to cellular transformation. A Ras-mediated increase in TBP expression is required for full Ras transforming activity. TBP overexpression induces cells to grow in an anchorage-independent manner and to form tumors in athymic mice. These effects on cellular transformation require changes in RNA polymerase II-dependent transcription and on the selective recruitment of TBP to promoters via its DNA binding activity. TBP expression is elevated in human colon carcinomas relative to normal colon epithelium. Both Ras-dependent and Ras-independent mechanisms mediate increases in TBP expression in colon carcinoma cell lines. We conclude that TBP may be a critical component in dysregulated signaling that occurs downstream of genetic lesions that cause tumors.
Johnson
Sandra A S
SA
Department of Biochemistry and Molecular Biology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033, USA.
Dubeau
Louis
L
Kawalek
Michael
M
Dervan
Andrew
A
Schönthal
Axel H
AH
Dang
Chi V
CV
Johnson
Deborah L
DL
D016475:3T3 Cells / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015197:Carcinogenicity Tests; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D035181:TATA-Box Binding Protein / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D035181:TATA-Box Binding Protein; D012319:RNA Polymerase II; D018631:ras Proteins