Science (pages 813-818)
February 1, 2002

Signal Transduction and the Control of Gene Expression

by Ali H. Brivanlou1 and James E. Darnell Jr.2*

Abstract- More than 2000 transcription factors are encoded in the human genome. Such proteins have often been classified according to common structural elements. But because transcription factors evolved in the service of biologic function, we propose an alternative grouping of eukaryotic transcription factors on the basis of characteristics that describe their roles within cellular regulatory circuits.

1 Laboratory of Molecular Vertebrate Embryology,
2 Laboratory of Molecular Cell Biology, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

[Introductory paragraphs]

All cellular life can recognize and properly respond to molecules in the extracellular environment. Indeed, an increased repertoire of recognized extracellular signaling molecules matched with increasingly sophisticated intracellular responses was the central requirement for the evolution of metazoan life. Two very broad fields of research, which are often described as "signal transduction" and "control of gene expression," have merged
recently to become a pivotal arena for developmental genetics as well as cellular biochemistry. In this review we present a classification of transcription factors that is intended to organize thinking about the connection of extracellular signaling to the regulation of transcription in eukaryotic cells.

A host of proteins crucial to transcription initiation are assembled into the RNA polymerase, the general transcription factors, coactivators, corepressors, chromatin remodelers, histone acetylases, deacetylases,
kinases, and methylases, to list the main participants (1-5). These crucial proteins are present in all eukaryotic cells and contribute to the initiation of every RNA polymerase II primary transcript that eventually becomes messenger RNA.

As important as the ~200 to 300 proteins that constitute the coactivators and the transcriptional machinery may be to the survival of cells and organisms, the regulation of the choice of specific initiation sites for transcription is not vested in these proteins. Rather, transcriptional regulation depends on members of an even larger number of proteins, in mammals perhaps 2000 to 3000 (6, 7), with two characteristic domains: a DNA binding domain that binds gene-specific regulatory sites directly, and a second domain that exhibits transcriptional activation potential. In some cases this dual requirement is shared between partner proteins, so that the site-specific binding domain and transcription activation domain occur on separate proteins. These site-specific transcription factors recruit
coactivators and the transcription machinery to initiate gene-specific transcription (1-5). As development and cell specialization occurs, selection among these 2000+ transcription factors for the regulation of cell-specific gene expression involves (i) a cascade of transcriptional control of transcription factor genes, and (ii) signals from outside the cell that activate, posttranscriptionally, already formed transcription factors. In the regulatory regions in the DNA of a few well-studied vertebrate genes (8, 9), as many as six to eight different protein chains, acting on one enhancer (together forming an "enhanceosome"), are required for gene-specific regulation, and this is likely true for many other genes. The combinatorial use of subsets of the 2000+ proteins could easily mean that the complete set of regulators for each gene is unique, ensuring the right amount of the right protein at the right time as development proceeds.

[ 08 February 2002: Message edited by: Moderator ]