TATA binding protein (
TBP) is a central
transcription factor used by all three cellular
RNA polymerases. Changes in the levels of
TBP have been shown to have selective effects on gene activity. Overexpression of
TBP has been recently shown to contribute to cellular transformation, and elevated levels of
TBP occur in a clinically significant proportion of human colon
tumors relative to matched normal tissue. To understand the mechanisms by which
TBP is regulated, we have analyzed whether activation of the
epidermal growth factor receptor (EGFR), a membrane-bound
tyrosine receptor kinase that is activated in a large number of human
cancers, can serve to regulate cellular
TBP. We show that treatment of mouse epidermal cells with
EGF produces an increase in
TBP levels, which can be blocked with an EGFR-specific inhibitor. In contrast,
TBP levels remain unchanged after
EGF treatment of EGFR null cells.
EGF-mediated increases in
TBP are regulated at the transcriptional level, as transient expression of the human
TBP promoter is induced with
EGF. This regulatory event is dependent upon the downstream activation of Ras and requires the activation of p38, JNK, and ERK
mitogen-activated protein kinases. The consequence of elevated
TBP on gene expression was further determined. Transcription by
RNA polymerase (Pol) I and III was induced by
EGF. Directly overexpressing
TBP also stimulated transcription from these promoters. Thus, we have identified a new and important target of EGFR signaling,
TBP, that contributes to
EGF-mediated stimulation of
RNA Pol I- and III-dependent gene activity. Since the cellular levels of the products of these genes, tRNAs and rRNAs, determine the translational capacity of cells, this event may be an important contributor to the transforming function of
EGF.