Increased Expression of TATA-Binding Protein, the Central Transcription Factor, Can Contribute to Oncogenesis

Abstract

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 Rasdependent 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.The TATA-binding protein (TBP) is a central eucaryotic transcription factor used by all three cellular RNA polymerases. TBP associates with additional polypeptides to form at least three unique complexes, SL1, TFIID, and TFIIIB, which specify its role in the transcription of RNA polymerase I, II, and III genes, respectively. Two general mechanisms are used in the recruitment of TBP to these promoters. For those promoters that contain a TATA element, TBP binds directly to this sequence via its DNA binding domain. For promoters that lack this element, TBP is recruited solely through its interactions with other proteins that are bound to the promoter. The intracellular levels of TBP have been shown to be limiting for the transcription of both RNA polymerase I-dependent rRNA promoters (19) and RNA polymerase III-dependent tRNA, 5S RNA, and U6 RNA promoters (16). RNA polymerase II-dependent promoters are affected by increases in cellular TBP levels differently, depending on their architecture (3, 12). Generally, promoters containing TATA elements can be stimulated by TBP overexpression (3,8). In contrast, TATAlacking promoters are either unaffected or repressed by TBP overexpression (3,8). Increased cellular TBP amounts also potentiate the effects of certain activators, such as VP16, while inhibiting the effect of others, such as Sp1 or NF-1 (12). Thus, increasing the cellular amounts of TBP can have profound effects on cellular gene activity. Decreases in the amount of TBP have also been shown to produce specific changes in gene expression. Expression of a cell cycle regulatory protein, cdc25B phosphatase, was found to be reduced in a chicken B-cell line when one copy of the TBP gene was disrupted (17). Furthermore, heterozygous disruption ...

Enhanced RNA Polymerase III-dependent Transcription Is Required for Oncogenic Transformation*

“…Expression Plasmids-The human TBP expression plasmid pLTR-E2TBP and construction of the TBP mutants L185E and K249E were as described previously (15). The human Brf1 expression plasmids pcDNA3-HA-Brf1 and HA-Brf1-T145D were provided by R. J.…”

“…Heterozygous disruption of TBP in chicken DT cells results in slower growth rates and delayed mitosis (14). In Rat1a fibroblasts, increased cellular TBP expression does not alter proliferation rates but promotes anchorage-independent growth and tumor formation in athymic mice (15). Although it is clear that oncogenic proteins can stimulate RNA pol III transcription, the role of enhanced RNA pol III transcription in their transforming function remains unclear.…”

Covalent Small Ubiquitin-like Modifier (SUMO) Modification of Maf1 Protein Controls RNA Polymerase III-dependent Transcription Repression

“…Maf1-mediated decreases in TBP may also indirectly repress RNA pol I-dependent rDNA genes, as well as other genes, that can be limiting for TBP. Increased cellular concentrations of TBP have been shown to induce cell proliferation (7) and oncogenic transformation (8). The fact that Maf1 represses genes involved in oncogenesis and that it suppresses anchorage-independent growth (6) suggests that Maf1 may function as a tumor suppressor.…”

TBP, un facteur de transcription universel ?

“…L'inactivation d'un des allèles de TBP dans les cellules DT40 provoque un ralentissement du cycle cellulaire et une augmentation de l'apoptose [34] dus à une baisse de l'expression de la phosphatase Cdc25B entraînant une augmentation de la forme phosphorylée et inactive de Cdc2. Un rôle direct pour TBP dans la régulation du cycle cellulaire est également suggéré par l'observation selon laquelle le niveau de TBP est augmenté dans les cellules transformées par l'oncogène Ras [35]. De plus, la surexpression de TBP provoque la transformation oncogé-nique.…”