Signal Transduction Cell Surface to the Nucleus: MAP Kinases and AP-1

Z-G. Liu and M. Karin
Department of Pharmacology
School of Medicine
University of California, San Diego

AP-1 is a sequence specific transcriptional activator composed of Jun and Fos subunits. AP-1 activity is present in most cell types prior to their stimulation, but it is further induced in response to external stimuli, resulting in induction of AP-1 target genes. Both physiological and pathological stimuli induce AP-1 activity, which is involved in mitogenesis, differentiation, transformation and inflammation. Both transcriptional and posttranscriptional mechanisms contribute to induction of AP-1 activity. Many of the genes encoding AP-1 components are immediate early genes. The activity of both newly synthesized and preexisting AP-1 components is modulated through their post-translational modification. A key row in stimulation of AP-1 activity is played by various mitogen activation protein kinases (MAPKS). The activity of these enzymes are rapidly stimulated in response to various extracellular signals through activation of MAPK modules consisting of a MAPK, a MAPS kinase (MAPKK), and a MAPK kinase kinase (MAPKKK).

Upon activation in response to growth factors or phorbol esters, members of the ERK subgroup of MAPKs translocate to the nucleus where they phosphorylate transcription factors, such as TCF/Elk1, which is bound to the c-fos promoter. Phosphorylation of TCF/Elk-1 stimulates its transcriptional activity leading to c-fos induction. Increased c-Fos synthesis results in elevated AP-1 activity. Other MAPKs, the JNKs, are activated by growth factors, cytokines and stressors. So far the JNKs have two known nuclear targets, c-Jun and ATF2. These proteins form a heterodimer that binds to a variant AP-1 site within the c-jun promoter. Phosphorylation of both c-jun and ATF2 stimulates their transcriptional activity leading to c-jun induction. In addition to induction of c-Jun synthesis, the JNKs contribute to AP-1 activity for phosphorylating of both newly synthesized and pre-existing c-Jun.

The regulation of c-Jun and JNK activity in response to UV and various genotoxic agents will be discussed. The induction of the activity of tyrosine kinase, c-ABL and tumor suppressor, p53, in response to these treatment in murine fibroblasts will also be discussed.