MAP Kinase Regulates the Activity of Many Transcription Factors Controlling Early Response Genes
Addition of a growth factor (e.g., EGF or PDGF) to quiescent (non-growing) cultured mammalian cells causes a rapid increase in the expression of as many as a hundred different genes. These genes are called early response genes because they are induced well before cells enter the S phase and replicate their DNA (see Chapter 19). One important early response gene encodes the transcription factor c-Fos. Together with other transcription factors, such as c-Jun, c-Fos induces the expression of many genes that encode proteins necessary for cells to progress through the cell cycle. Most RTKs that bind growth factors use the MAP kinase pathway to activate genes encoding proteins such as c-Fos, which in turn propel the cell through the cell cycle.
The enhancer that regulates the c-fos gene contains a serum response element (SRE), so named because it is activated by many growth factors in serum. This complex enhancer contains DNA sequences that bind multiple transcription factors. As depicted in Figure 16-26, activated (phosphorylated) dimeric MAP kinase induces transcription of the c-fos gene by directly activating one transcription factor, ternary complex factor (TCF), and indirectly activating another, serum response factor (SRF). In the cytosol, MAP kinase phosphorylates and activates a kinase called p90RSK, which translocates to the nucleus, where it phosphorylates a specific serine in SRF. After translocating to the nucleus, MAP kinase directly phosphorylates specific serines in TCF. Association of phosphorylated TCF with two molecules of phosphorylated SRF forms an active trimeric factor that activates c-fos gene transcription.
FIGURE 16-26 Induction of gene transcription by MAP kinase. Steps 1–3: In the cytosol, MAP kinase phosphorylates and activates the kinase p90RSK, which then moves into the nucleus and phosphorylates the SRF transcription factor. Steps 4 and 5: After translocating into the nucleus, MAP kinase directly phosphorylates the transcription factor TCF, which is already bound to the promoter of the c-fos gene. Step 6: Phosphorylated TCF and SRF act together to stimulate transcription of c-fos and other genes that contain an SRE sequence in their promoter. See the text for details. See R. Marais et al., 1993, Cell 73:381, and V. M. Rivera et al., 1993, Mol. Cell Biol. 13:6260.
Unlike the Raf and MEK kinases, which phosphorylate only a few target kinases in the MAP kinase cascade, MAP kinases are known to phosphorylate more than 175 proteins in the nucleus and cytosol. Many MAP kinase targets are regulators of gene expression, and different MAP kinase targets are expressed in different mammalian cell types. As with Stats, Smads, and other transcription factors activated directly or indirectly by cell-surface receptors, the precise proteins induced by MAP kinase depend on the particular target proteins expressed in the cell, on epigenetic markers on DNA and chromatin proteins, and on the presence of other transcription factors (see Figure 16-2).