AP-1 transcription factor

Activator protein 1 (AP-1) is a

C-JUN homodimer (PDB: 1JUN​) Left: The helical wheel projection of c-jun homodimer. When viewed down the axis, the alpha helices have a ~7 amino acid repeating leucine at position a. Two helices may be aligned so that repeating hydrophobic side chains (gray) form an interacting surface which facilitates dimerization. Dashed lines indicate potential electrostatic bridges. Right: Side view of c-jun homodimer. Residues on position a and d in helical wheel diagram are shown. Leucines are colored in blue, and other hydrophobic residues are colored in yellow.

AP-1 transcription factor is assembled through the dimerization of a characteristic

The basic region of the bZIP domain is just upstream to the leucine zipper, and contains positively charged residues. This region interacts with DNA target sites.^[9] Apart from the “leucine zipper” and the “basic region” which are important for dimerization and DNA-binding, the c-jun protein contains three short regions, which consist of clusters of negatively charged amino acids in its N-terminal half that are important for transcriptional activation in vivo.^[10]

Dimerization happens between the products of the c-jun and c-fos protooncogenes, and is required for DNA-binding. Jun proteins can form both homo and heterodimers and therefore are capable of binding to DNA by themselves. However, Fos proteins do not dimerize with each other and therefore can only bind to DNA when bound with Jun.^[11][12] The Jun-Fos heterodimer is more stable and has higher DNA-binding activity than Jun homodimers.

Function

AP-1 transcription factor has been shown to have a hand in a wide range of cellular processes, including

Cellular senescence has been identified as "a dynamic and reversible process regulated by (in)activation of a predetermined enhancer landscape controlled by the pioneer transcription factor AP-1", which "defines the organizational principles of the transcription factor network that drives the transcriptional programme of senescent cells".^[15][16]

Cellular differentiation

AP-1 transcription is deeply involved in the modulation of

AP-1 transcription factor is associated with a broad range of apoptosis related interactions. AP-1 activity is induced by numerous extracellular matrix and genotoxic agents, suggesting involvement in programmed cell death.^[2] Many of these stimuli activate the c-Jun N-terminal kinases (JNKs) leading to the phosphorylation of Jun proteins and enhanced transcriptional activity of AP-1 dependent genes.^[2] Increases in the levels of Jun and Fos proteins and JNK activity have been reported in scenarios in which cells undergo apoptosis. For example, inactivated c-Jun-ER cells show a normal morphology, while c-Jun-ER activated cells have been shown to be apoptotic.^[19]

Regulation of AP-1

Increased AP-1 levels lead to increased transactivation of target gene expression. Regulation of AP-1 activity is therefore critical for cell function and occurs through specific interactions controlled by dimer-composition, transcriptional and post-translational events, and interaction with accessory proteins.^[20]

AP-1 functions are heavily dependent on the specific Fos and Jun subunits contributing to AP-1 dimers.^[10] The outcome of AP-1 activation is dependent on the complex combinatorial patterns of AP-1 component dimers.^[2] The AP-1 complex binds to a palindromic DNA motif (5’-TGA G/C TCA-3’) to regulate gene expression, but specificity is dependent on the dimer composition of the bZIP subunit.^[2]

Physiological relevance

AP-1 transcription factor has been shown to be involved in skin physiology, specifically in tissue regeneration. The process of skin metabolism is initiated by signals that trigger undifferentiated proliferative cells to undergo cell differentiation. Therefore, activity of AP-1 subunits in response to extracellular signals may be modified under conditions where the balance of keratinocyte proliferation and differentiation has to be rapidly and temporally altered.^[21] The AP-1 transcription factor also has been shown to be involved in breast cancer cell growth through multiple mechanisms, including regulation of cyclin D1, E2F factors and their target genes. c-Jun, which is one of the AP-1 subunits, regulates the growth of breast cancer cells. Activated c-Jun is predominantly expressed at the invasive front in breast cancer and is associated with proliferation of breast cells.^[22] Due to the AP-1 regulatory functions in cancer cells, AP-1 modulation is studied as a potential strategy for cancer prevention and therapy.^[23][24][25]

Regulome

See also

• Activator protein
• Transcription factor

References