Cell signaling transduction modulate the activity of many different types of transcription factors. One important group of signal-regulated transcription factors are the BZip proteins. The most studied members of this superfamily are the AP-1 (Jun/Fos) and CREB/ATF proteins that control gene expression by binding to the TPA (12-O tetradecanoylphorbol-13-acetate) response element (TRE) and cyclic AMP (cAMP) response element (CRE), respectively. In addition to TPA, AP-1 activity is induced by a variety of polypeptide hormones, growth factors, cytokines and neurotransmitters. These agents activate signalling pathways that are initiated with either stimulation of membrane-associated tyrosine kinases or phospholipid turnover, the latter giving rise to increased PKC activity. In addition, AP-1 activity is elevated in cells that express a variety of transforming oncogenes, whose products act as constitutively activated intermediates in the signal transduction pathway that transmits information from cell-surface tyrosine kinases to the nucleus. Such oncogene products include v-Src, Ha-Ras, and v-Raf. Another class of agents that induce AP-1 activity share the common ability to induce oxidative stress. These agents also seem to activate a signalling pathway that is initiated with the stimulation of membrane-associated tyrosine kinases. In all of these pathways, tyrosine-specific protein kinases act at the top, being either an integral part of cell-surface receptors or directly activated by interaction with occupied cell-surface receptors. The activation of tyrosine kinases results in a series of rather nebulous events that lead to increased Ras activity, which appears to play a pivotal role in the activation of downstream serine/threonine-specific protein kinases, such as Raf-1 and the ERKs.
These signalling pathways mainly affect AP-1 activity at two levels: transcriptional and post-translational. First, transcription of the fos genes, which is very low in most non-stimulated cells, is induced in response to a variety of extracellular stimuli. The most rapid induction is exhibited by c-fos, the expression of which is also highly transient while induction of other fos genes, such as fra-I is somewhat slower and longer lasting. Most of the signals stimulate c-fos transcription through the serum response element (SRE) which is recognized by several different factors of which the major ones are p67 SRF and p62TCF. It is still not clear how the activities of these constitutively expressed proteins are stimulated by extracellular signals.
The promoters of other fos genes have not been analysed as thoroughly as the c-fos promoter. Induction of fos transcription results in increased synthesis of Fos proteins, which combine with pre-existing Jun proteins to form more stable heterodimers and thereby increase the level of AP-1 binding activity. Although most cells contain substantial levels of pre-existing Jun proteins that are responsible for their basal AP-1 activity, expression of some of the jun genes is also inducible. Most of the signals that stimulate AP-1 activity induce c-jun transcription, which usually is longer lasting than c-fos induction. The persistent induction of c-jun is presumbly due to the ability of c-Jun to autoregulate its expression by binding to a TRE in the c-jun promoter. Expression of junB is also stimulated by extracellular stimuli but appears to respond to different signals than those which affect c-jun. For example, in 3T3 cells, c-jun transcription is stimulated by TPA and partially inhibited by cAMP, while jun B (and c-fos) transcription is stimulated by cAMP. In most cells, expression of junD is constitutive, but in Hela cells its expression is induced only by the simultaneous activation of both PKC and PKA. The differential responsiveness and induction kinetics of the various jun and fos genes results in the formation of different AP-1 complexes at different times after cell stimulation. The exact role of these dynamic changes in the composition and activity of AP-I is not fully understood, but at least part of them could be involved in termination of the induction response, as was shown for JunB, which can repress the activation of c-jun.
The major level of control affecting these proteins is post-translational. As mentioned above, the only CREB/ATF protein with well-understood regulation is CREB itself. All of the signals known to stimulate CREB activity in vivo are those which activate the PKA pathway. The regulation of this pathway is much less complicated than that of signalling pathways centered around the Ras proteins. PKA activity is directly stimulated by elevation of cAMP levels; cAMP binds to the regulatory subunit of this tetrameric enzyme, leading to its dissociation and liberation of the catalytic subunit. This results in the activation of the catalytic subunit and its translocation to the nucleus where it can phosphorylate CREB. The activation of CREB activity is rapid, generally peaking within 30 minutes and declining gradually over 24 hours. This 'burst attenuation' kinetics closely parallels the phosphorylation state of CREB, which will be discussed in the following section. Also, ATF-1, which has a regulatory domain similiar to the one of CREB, but lacks the glutamine activation domain present in CREB, is activated by the catalytic subunit of PKA. The ATF-2 protein, which has a different regulatory domain, responds to a different type of signal: the Ela protein of adenovirus TM. Ela, which probably mimicks the activity of a (yet to be identified) physiological signal, binds to the activation domain of ATF-2 resulting in a large increase in its trans-activation potential.
Karin M, Smeal T. Control of transcription factors by signal transduction pathways: the beginning of the end[J]. Trends in biochemical sciences, 1992, 17(10): 418-422.