Transcriptional Regulation by Extracellular signals: Mechanisms and Specificity

This review shall concentrate on transcriptional responses to cell surface receptor-activated signaling pathways; however, much of the discussion is also applicable to signals induced by environmental stresses or to extracellular signals that act directly on transcription factors, such as steroid hormones.

Abstract

Changes in cell behavior induced by extracellular signaling molecules such as growth factors and cytokines require execution of a complex program of transcriptional events. While the route followed by the intracellular signal from the cell membrane to its transcription factor targets can be traced in an increasing number of cases, how the specificity of the transcriptional response of the cell to different stimuli is determined is much less clear. However, it is possible to understand at least in principle how different stimuli can activate the same signal pathway yet activate different genes and how small differences in signal strength can generate qualitative differences in gene expression. In this review we shall concentrate on transcriptional responses to cell surface receptor-activated signaling pathways; however, much of our discussion is also applicable to signals induced by environmental stresses or to extracellular signals that act directly on transcription factors, such as steroid hormones. Rather than describe in detail each of the many separate pathways from receptor to transcription factor, we have attempted to compare and contrast regulation of a representative set of transcription factors. These factors are introduced in Figure 1, and their properties are summarized in Table 1. To set the stage, we briefly discuss the different properties of transcription factors that can be modified to regulate their behavior in response to signals. We then use relatively well-characterized signaling pathways to illustrate different strategies by which an extracellular stimu lus is converted to an active transcription factor in the nucleus. Finally, we use these examples to illustrate two aspects of specificity in the transcriptional response to signals: first, the means by which a given stimulus specifically targets particular transcription factors and DNA targets; and second, the means by which differential responses to qualitatively and quantitatively different signals can be generated.