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First published online November 24, 2004
doi: 10.1242/10.1242/jcs.01589

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AP-1 subunits: quarrel and harmony among siblings

Deutsches Krebsforschungszentrum, Division of Signal Transduction and Growth Control, 69120 Heidelberg, Germany

View larger version (45K): [in a new window]   Fig. 1. The Jun-Fos heterodimer. The bZIP domains of Jun and Fos form an X-shaped -helical structure, which binds to the palindromic AP-1 site (TGAGTCA) (Glover and Harrison, 1995). The bZIP domain of Jun is shown in blue and the bZIP domain of Fos in red. The DNA backbone is shown in yellow. The Jun and Fos proteins exhibit several domains, including the bZIP domain (leucine zipper plus basic domain), transactivation domains and docking sites for several kinases, such as JNK or ERK. These kinases phosphorylate two serine and threonine residues and thereby modulate the activity of both proteins. JNK specifically phosphorylates serine residues within the transactivation domain of Jun at position 63 and 73 and thereby regulates its transactivation activity. Mutation of serine to alanine generates a Jun mutant (Jun-AA) that cannot be activated by JNKs. Jun is also phosphorylated by casein kinase II, GSK-3ß and ERK, which is not depicted in this scheme (for details, see Eferl and Wagner, 2003). ERK phosphorylates threonine residues at positions 325 and 331 and a serine residue at position 374 of Fos. Additionally, a Fos-related kinase phosphorylates a threonine residue at position 232 of Fos.

View larger version (31K): [in a new window]   Fig. 2. Pro- and anti-proliferative activities of AP-1 subunits during cell-cycle progression. AP-1 modulates cell proliferation through its ability to regulate the expression and function of cell-cycle regulators such as cyclin D1, cyclin A, p53, p21Cip1, p16Ink4a and p19ARF. The capacity of AP-1 both to promote and inhibit cell-cycle progression is most likely due to the abundance of distinct members within a given cell, as well as the cell type and its microenvironment. JunB and ATF-2 regulate expression of cyclin A in chondrocytes and osteoblasts, whereas Fos-dependent expression of cyclin A and cyclin E has been described for chondrocytes. Additionally, ATF-2 regulates expression of cyclin D1 in chondrocytes and osteoblasts.

View larger version (24K): [in a new window]   Fig. 3. Functions of AP-1 subunits in various cellular processes and disease. Antagonistic (indicated by the double-headed arrow) or common tasks for AP-1 members are observed in various cell types. Positive, negative or even dual functions of individual subunits influence pivotal cellular processes, such as differentiation, cell-cycle regulation or apoptosis. Deregulation of these processes by alterations in either single or multiple AP-1 subunits, thereby modulating AP-1 net activity, can be fatal for the cell and organism.

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