Linking Signal Transduction and Gene Regulation

Abstract

A central characteristic of life is the response to molecules of the extra-cellular environment. These responses are mediated by signal transduction cascades that mostly start with an extra-cellular signaling molecule and end with an activated transcription factor. Latent transcription factors, such as SMADs, STATs, NF-κB and others, are central to these pathways, as they are activated through different mechanisms of their translocation from the cytoplasm to the nucleus.

The activation cascade of a transcription factor can be considered as a module in a biological network. Delineating the topology and dynamics of such a transcription factor network helps to understand, how they originate and how these networks enable the cell to respond to environmental signals, such as dietary molecules, growth signals or stress derived from infections and inflammation.

A central transcription factor network is that of cellular differentiation from omnipotent ES cells to terminally differentiated cells. Insight into this network is the basis for reprogramming of cells and the creation of iPS cells. Another example of a transcription factor network is that of NF-κB and its regulation by IKK proteins having central impact in apoptosis and inflammation. In addition, the NF-κB pathway interferes with a number of other signal transduction pathways, i.e. NF-κB signaling is integrated with many other networks, such as the signaling of nuclear receptors. Acute inflammation is the response of cells to stress derived from microbial infection. The inflammatory gene expression program is critically controlled by three classes of transcription factors, including NF-κB, ATF3 and CEBPδ. In contrast, other forms of cellular stress, such as DNA damage, are sensed via the activation of p53. This transcription factor is encoded by a tumor suppressor gene and regulates cell-cycle arrest, senescence and apoptosis.

In this chapter, we present a number of examples of signal transduction pathways that critically involve the action of some of the most intensively studied transcription factors, such as NF-κB and p53. We will formalize the action of these transcription factors in respective biological networks. Moreover, we will discuss these transcription factor networks at examples of (i) the cascade cell fate determining transcription factors in cellular differentiation, (ii) the gene expression program in response to acute inflammation and (iii) the sensing of DNA damage and activation of the p53 pathway.