Review
Transcriptional regulation through Mediator-like coactivators in yeast and metazoan cells

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Abstract

A novel multiprotein complex has recently been identified as a coactivator for transcriptional control of protein-encoding genes by RNA polymerase II in higher eukaryotic cells. This complex is evolutionarily related to the Mediator complex from yeast and, on the basis of its structural and functional characteristics, promises to be a key target of diverse regulatory circuits.

Section snippets

The Yeast Mediator/RNA polymerase II holoenzyme

The identification of a novel entity, called the Pol II holoenzyme, as the ultimate target of transcriptional activators was initially the outcome of biochemical and genetic studies in yeast. Such studies were spurred, in part, by the observation that metazoan activators also function in yeast, thus indicating a high degree of functional conservation of the transcription apparatus over eukaryotic evolution.

Biochemical analysis first pointed to the existence of a coactivator activity, termed

Metazoan Mediator complexes

Given the impetus from the findings in yeast, several Pol II holoenzymes were subsequently described in metazoans (reviewed in Ref. 17). These holoenzyme preparations contained, in some cases, homologs of SRB7, SRB10 or SRB11, in addition to a wide range of GTFs, putative coactivators [including CREB-binding protein (CBP)] and factors implicated in nuclear processes other than transcription (e.g. DNA repair). However, the exact relevance of these preparations to transcriptional activation has

Structural and functional modularity of the Mediator

The modular organization of the yeast Mediator first became apparent from combined genetic and biochemical studies of components that had originally been identified as dedicated transcription factors. For example, GAL11 and SIN4 were originally identified in screens examining galactose utilization and mating-type switching, respectively10. Like the SRB8, SRB9, SRB10 and SRB11 proteins, which form one subcomplex (cited in Ref. 33), GAL11, SIN4 and another genetically defined polypeptide,

Potential mechanisms for Mediator function as a coactivator

The available evidence seems to be compatible with TRAP/SMCC and the related metazoan complexes acting as adaptors. The original, and so far the most compelling, evidence for the physiological relevance of interactions of activators with TRAP/SMCC came from the finding that TRAPs could be isolated from extracts of ligand-treated (but not untreated) cells in association with TR (Ref. 20). Direct physical interactions of TRAP220 with TR (Ref. 42) and of TRAP80 with the activators p53 and VP16 (

Gene-specific activation mechanisms and coactivator redundancy

The structural modularity of TRAP/SMCC has implications for tissue- and gene-specific activation mechanisms, and also lends itself to models both for differential activation by certain activators and for synergistic activation of a given gene by multiple activators. Indeed, for the latter situation, the demonstration that TRAP80 (p53, VP16) and TRAP220 (TR, VDR) are targets for diverse activators suggests how multiple enhancer-bound activators could channel their combined activation potential

Concluding remarks

The discovery of TRAP/SMCC and related coactivator complexes has uncovered another layer of control in the expression of metazoan genes and has led to a pleasing convergence of disparate coactivator studies. These complexes, like the yeast Mediator to which they are evolutionarily related, display a modular organization and a consequent potential for integrating diverse regulatory signals. However, because many of the subunits in the metazoan complexes are divergent, they could reflect

Acknowledgements

We apologize to colleagues whose work could not be cited directly owing to space limitations. We thank M. Ito and C-X. Yuan for permission to cite unpublished results. Our work was supported, in part, by NIH grants to R.G.R.

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