The Variety of Transcriptional Responses

Multicomponent Hormonal Systems Facilitate a Great Variety of Responses The Guanylate Cyclase Pathway Calcium and the Inositol Trisphosphate Pathway Steroid Receptors Modulate the Rate of Transcription... 

Estrogen (i.e. 17p-estradiol, 5) is an important hormone that mediates a wide variety of cellular responses through its binding to a specific nuclear estrogen receptor (ER).6 The hormone-bound ER forms an active dimer, which functions as a transcription factor that mediates biological response by binding to specific promoter elements of DNA to... 

Once Ras is in its active form, it binds to another oncogene product called Raf, which localizes Raf to the membrane and activates its serine/threonine specific kinase activity. Among the many phosphorylation targets of Raf is another kinase called MAP kinase kinase (also called MEK), which is activated by Raf and in turn phosphorylates cytosolic MAP kinases on threonine and tyrosine residues. Activated MAP kinases (also called ERK1 and ERK2) are serine/threonine kinases that, once activated, can localize to the nucleus where they phosphorylate transcription factors such as Fos and Jun. MAP kinases also phosphorylate and activate other kinases (such as Rsk) which then pass the signal on to additional transcription factors (e.g., SRF, serum response factor). Therefore, downstream of Ras, a series of phosphorylation reactions culminate in the activation or inactivation of a variety of transcription... 

The transcription factor nuclear factor kappa B (NF-kB) is a member of the Rel family of proteins that plays an important role in a variety of cellular response mechanisms including immunity, inflammation, cell growth, and apoptosis. Recent evidence suggests that this transcription factor is induced following exposure of cancer cells to apoptotic... 

Many inflammatory cytokines including IL-8 are regulated at transcriptional levels, and a variety of transcription factors such as nuclear factor-K B (NFkB) and activator protein-1 (AP-1) play important roles in such processes. Abe and coworkers [71] demonstrated that CAM repressed TNF-a-induced AP-1 activation in human bronchial epithelial cells. We studied the effect of EM and CAM on the phorbol myristate acetate (PMA)-induced activation of NFkB and AP-1. Pretreatment of EM and CAM before the PMA treatment showed an inhibitory effect on both of the transcription factors as assessed by electrophoretic mobility shift assay (EMSA) (Fig. 14) [20]. In contrast, the macrolides showed no effect on the activation of cyclic AMP-responsive element binding protein (CREB), suggesting that the suppressive effect on some transcription factors is specific. We further evaluated the effect of EM on the phosphorylation of inhibitor of NFkB (IkB), which is a crucial step for transactivation of NFkB. EM did not influence the phosphorylation processes in vitro (Okazaki et at, unpublished data, January 2001). These data suggest that EM acts at the process of nuclear translocation of... 

Changes in the phosphorylation state of proteins that bind to cAMP response elements (CREs) in the promoter region of genes contribute to the regulation of gene transcription by a number of cAMP-coupled hormones (see Chapter 16). For instance, cAMP response element binding protein (CREB) is directly phosphory-lated by protein kinase A, a step essential for the initiation of transcription. Phosphorylation at other sites on CREB, by a variety of kinases, also may play a role in regnlating transcription. 

---