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Mammalian transcription factors in yeast: strangers in a familiar land

Nature Reviews Molecular Cell Biology volume 3, pages 41–49 (2002)Cite this article

Key Points

  • Yeast has proven a valuable model system to understand eukaryotic transcription mechanisms. Extending the vale of the system even further, several investigators have attempted to express mammalian transcriptional activators or repressors directly in yeast.

  • Mammalian transcriptional activators have been tested in yeast either directly or as fusion proteins targeted to reporters by fusion to a yeast DNA-binding domain. Most mammalian activators retain function in yeast.

  • Yeast is an ideal system to carry out structure–function analysis. In many cases, activation domains of mammalian activators have been defined in yeast. Fine-structure analysis has also been carried out, particularly with p53. Several screens have identified point mutations in p53 that alter its activation potential.

  • When a mammalian activator is expressed in yeast and studied at a reporter where its endogenous DNA-binding sites have been inserted, structure–function analysis has been carried out both to map DNA-binding regions within the activator and to identify the ideal DNA-binding sequence.

  • Genetic approaches have been used in yeast to identify potential co-activators for mammalian transcription factors. This has been particularly useful in the case of nuclear hormone receptors, in which both the yeast SAGA–ADA and the SWI–SNF complex among other proteins have been identified as important for activator function.

  • Nuclear hormone receptors require binding to hormone for full activation potential. This hormone-dependent stimulation can be recapitulated in yeast, which has led investigators to map hormone-binding domains and study the efficacy of different ligands. Furthermore, regulation of activator function in yeast by phosphorylation and binding to other mammalian regulatory proteins has been studied.

  • Transcriptional repression by mammalian proteins has also been shown in yeast, although to a lesser extent than with activators. Both Mad–Max and pRB recruit histone deacetylase activity in yeast much as they do in mammalian cells.

Abstract

Many transcription factors in human cells have functional orthologues in yeast, and a common experimental theme has been to define the function of the yeast protein and then test whether the mammalian version behaves similarly. Although, at first glance, this approach does not seem feasible for factors that do not have yeast counterparts, mammalian transcriptional activators or repressors can be expressed directly in yeast. Often, the mammalian factor retains function in yeast, and this allows investigators to exploit the experimental tractability of yeast to ask a diverse set of questions.

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Figure 1: Identifying transcriptional activators.
Figure 2: Structure–function analysis of activators.
Figure 3: Studying protein–DNA interactions.
Figure 4: Mechanisms of activation.
Figure 5: Regulation of transcriptional activators.
Figure 6: Transcriptional repressors.

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Acknowledgements

The author would like to thank A. Weiner for comments on the manuscript, and would also like to apologize for any reports that were not cited in the manuscript.

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Authors and Affiliations

  1. Department of Biochemistry, University of Washington, Seattle, 98195, Washington, USA

    Brian K. Kennedy

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  1. Brian K. Kennedy
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DATABASES

LocusLink:

FXR

 Saccharomyces Genome Database:

ADE2

ERG6

Gal4

Gcn4

His3

LEM1/PDR5

LEM3

PDR1

RPD3

SIN3

SNF12

Swi3

SWP73

 Swiss-Prot:

AP-1

c-Fos

c-Myb

c-Myc

glucocorticoid receptor

GRIP1

LacZ

MAD1

MAX

Oct1

p53

Pgc-1

PIG3

PPAR-γ

Sp1

v-Jun

v-Myb

Glossary

BASAL TRANSCRIPTION FACTORS

The minimal complement of proteins that is necessary to generate transcription from a minimal promoter.

HATs

Enzymes that have histone acetyltransferase activity. They are generally thought to stimulate transcription.

HDACs

Enzymes that deacetylate histones. They are generally thought to promote repressive chromatin states.

HISTONE METHYLASE

Enzyme that transfers methyl groups to histone tails.

HISTONE KINASE

Enzyme that phosphorylates histones.

TATA BOX

A DNA-binding site for the formation of transcription pre-initiation complexes that contain RNA polymerase.

ORTHOLOGUE

A pair of genes, one in each species, that are descended from a single gene. If these two genes encode proteins with functional similarity, they are referred to as functional orthologues.

ENHANCER ELEMENT

(Also known as upstream activating sequence (UAS) elements in yeast.) Upstream DNA-binding sequences for transcriptional activators.

HETEROLOGOUS

For this review, heterologous refers to mammalian proteins that are expressed in yeast, but do not have functional orthologues in yeast.

SECOND-SITE INTRAGENIC SUPPRESSOR

A second mutation in a gene that reverses the effect of the original mutation.

PHENOCOPY

An environmental or non-hereditary change that resembles the phenotype of a genetic mutation.

SWI/SNF

An ATP-dependent chromatin- modifying protein complex that is required for expression of many genes. This complex has also been implicated in transcriptional repression of other genes.

SAGA/ADA

A protein complex that includes Ada proteins, the TATA-binding protein (TBP) set of Spt gene products, and some TATA-box-associated factors (TAFs). This complex promotes transcriptional activation, at least in part, through histone acetyltransferase activity.

ATP-BINDING CASSETTE PROTEIN

From a large class of transport proteins that move molecules across membranes in an ATP-dependent manner.

DEXAMETHASONE

A potent glucocorticoid with immunosuppressant effects that potently stimulates the activity of some nuclear hormone receptors, including the glucocorticoid receptor.

NF-κB/IκB

NF-κB is a transcription factor that activates genes that are involved in cell growth, as well as immune and inflammatory responses. IκB is thought to interfere with NF-κB activity at least in part by sequestering it in the cytoplasm.

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Kennedy, B. Mammalian transcription factors in yeast: strangers in a familiar land. Nat Rev Mol Cell Biol 3, 41–49 (2002). https://doi.org/10.1038/nrm704

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