Encyclopedia of Cancer

Living Edition
| Editors: Manfred Schwab


  • Peter Angel
  • Jochen Hess
Living reference work entry
DOI: https://doi.org/10.1007/978-3-642-27841-9_341-2


Primary Liver Cell Culture Tumor Suppressor Gene MEN1 
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Activating protein-1 (AP-1) is a transcription factor usually consisting of a member of the Jun family and a member of the Fos or ATF family of proto-oncogenes. AP-1 is activated in response to cytokines, growth factors, and stress factors during cell differentiation, tumor formation, or mitogenic response.


Much of our present knowledge about transcription factors comes from the discovery and study of the activating protein-1 (AP-1) family. AP-1 (and the transcription factor NFκB) has served to detect one of the decisive DNA-binding motifs required for gene regulation by a variety of extracellular signals including growth factors, cytokines, tumor promoters, such as the phorbol ester TPA (12-O-tetradecanoyl-phorbol-13-acetate), and carcinogens, for example, UV irradiation and other DNA-damaging agents. One of its members, the heterodimer Fos-Jun, was found in the mid-1980s, as a protein complex containing the viral oncogene product Fos without a clue of its function. The term AP-1 was coined for an activity that supports both basal and inducible transcription of several genes containing AP-1 binding sites (5′-TGAG/CTCA-3′), also known as TPA-responsive elements (TRE), in their promoter region. AP-1 was purified from cell extracts by TRE-based affinity chromatography and despite multiple rounds of purification, the AP-1 preparations contained several distinct polypeptides. Within a year, it became evident that these polypeptides correspond to members of jun and fos gene families and that the first member of the Jun family, c-Jun, represents the cellular homologue of the transforming oncogene (v-Jun) of the chicken retrovirus ASV-17. At present, the Jun protein family consists of c-Jun, JunB, and JunD; and the Fos protein family consists of c-Fos, FosB, Fra-1, and Fra-2. During the past decade, additional proteins, such as members of the ATF family, have been identified (mostly by yeast-two-hybrid screening), which share structural homologies and form heterodimeric complexes predominantly with Jun proteins (see below) to bind to TRE-like sequences.

General Structure of the AP-1 Subunits

According to its function in controlling gene expression, the prototype of a transcription factor has to comprise at least two properties: a region of the protein that is responsible for binding to a specific DNA recognition sequence (DNA-binding domain) and a second region that is required for transcriptional activation (transactivation domain) following DNA binding.

DNA-Binding Domain

The DNA-binding domain is evolutionarily conserved between the Jun, Fos, and CREB/ATF proteins, thus defining the protein family called “bZip” proteins. bZip stands for the amino acid sequences of the two independently acting subregions of the DNA-binding domain: the “basic domain,” which is rich in basic amino acids and responsible for contacting the DNA, and the “leucine-zipper” region, which is characterized by heptad repeats of leucine being part of the well-known “4–3 repeats” forming a coiled-coil structure. The latter domain is responsible for dimerization, which is a prerequisite for DNA binding (Fig. 1). In addition to the leucines, other hydrophobic and charged amino acid residues within the leucine zipper region are responsible for specificity and stability of homo- or heterodimer formation between the various Jun, Fos, or CREB/ATF proteins. The Fos proteins do not form stable homodimers but heterodimerize efficiently with the Jun proteins. The Jun proteins can form homodimers, although with reduced stability compared to Jun/Fos or Jun/ATF. Jun–Jun and Jun–Fos dimers preferentially bind to the 7-bp motif 5′-TGAG/CTCA-3′ whereas Jun-ATF dimers or ATF homodimers prefer to bind to a related 8-bp consensus sequence 5′-TTACCTCA-3′. Therefore, individual AP-1 dimers are expected to regulate specific subsets of AP-1 target genes depending on the characteristics of the AP-1 site in their promoter.
Fig. 1

Structural organization of the Fos and Jun proteins

In addition to the “classical” AP-1 members (Jun, Fos, ATF), on the basis of DNA sequence specificity and heterodimer formation with Jun and Fos proteins, several new bZip proteins have recently been defined. These include Maf and Maf-related proteins and Smads and Jun-dimerizing partners (JDPs). The exact function of these proteins in AP-1-regulated process is still largely ill-defined. Binding of AP-1 to DNA also supports binding of other transcription factors to adjacent or overlapping binding sites (composite elements) to allow the formation of larger complexes. The interaction of NFAT and Ets proteins with DNA on the IL-2 and collagenase promoters, respectively, serves as paradigms for this type of protein–protein interaction.

Transactivation Domain

In contrast to the well-defined DNA-binding domain, the structural properties of the domains in the AP-1 proteins mediating transcriptional activation of target genes (transactivation domain, TAD) are still poorly understood. The activity of the TAD can be transferred to heterologous DNA-binding domains, such as the yeast transcription factor GAL4. By employing such chimeric proteins, which in contrast to the wild-type proteins do not depend on a dimerization partner, critical amino acids in the TADs could be identified. Moreover, it is clear that the various Jun, Fos, and ATF proteins greatly differ in their transactivation potential. Usually, c-Jun, c-Fos, and FosB are strong transactivators, whereas JunB, JunD, Fra-1, and Fra-2 exhibit only weak transactivation potential. Under specific circumstances, they may even act as repressors of AP-1 activity by competitive binding to AP-1 sites or by forming inactive heterodimers with c-Fos, FosB, or c-Jun. Most importantly, transactivation studies using fusion proteins led to the identification of protein kinases, which bind to and phosphorylate AP-1 proteins in the TAD in response to extracellular signals thereby controlling expression of AP-1 target genes.

Transcriptional and Posttranslational Control of AP-1 Activity

Regulation of AP-1 net activity in a given cell can be achieved through changes in transcription of genes encoding AP-1 subunits, control of the stability of their mRNA, posttranslational processing and turnover of preexisting or newly synthesized AP-1 subunits, and specific interactions between AP-1 proteins and other transcription factors or cofactors.

The jun and fos genes are members of a class of cellular genes, termed early response or “immediate-early” genes. They are characterized by a rapid and transient activation of transcription in response to changes of environmental conditions, such as growth factors, cytokines, tumor promoters, carcinogens, and expression of certain oncogenes. Since this type of regulation of promoter activity is also observed in the absence of ongoing protein synthesis, it is generally accepted that preexisting factors, whose activity gets altered by changes in posttranslational modification (described in detail in the subsequent section), are responsible for the regulation of promoter activity.

Transcriptional Activation

Most of our current knowledge on transcriptional activation of immediate early genes is derived from studies on deletion and point mutations within the c-fos and c-jun promoters, combined with in vitro and in vivo footprinting analyses. The serum response element (SRE) is required for induced transcription in response to the majority of extracellular stimuli including growth factors and phorbol esters. The ternary complex containing the transcription factor p67-SRF and p62-TCF, which stands for a class of related proteins described as Elk/SAP, specifically bounds to this element. Changes in the phosphorylation pattern of SRF and, predominantly, TCF regulates c-fos promoter activity by these stimuli. Other elements include the cAMP response element (CRE) and the Sis-inducible enhancer (SIE), which is recognized by the STAT group of transcription factors. These factors are at the receiving end of the Jak/Stat signaling pathway initiated by specific classes of cytokines. The element responsible for negative autoregulation of the c-fos promoter has not yet been identified conclusively.

Analysis of deletion mutants within the c-jun promoter identified two AP-1-like binding sites (Jun1, Jun2), which are recognized by Jun/ATF heterodimers or ATF homodimers and are involved in transcriptional regulation in response to the majority of extracellular stimuli affecting c-jun transcription. In response to G-protein coupled receptor activation (e.g., the muscarinic acetylcholine receptor), or treatment, EGF and other growth factors with the AP-1 sites and an additional element in the c-jun promoter recognized by MEF2 proteins cooperate in transcriptional control of the c-jun gene. Similar to the factors binding to the c-fos promoter, the activity of factors binding to the c-jun promoter is regulated by their phosphorylation status.

Regulation of AP-1 Activity

The most critical members of the class of protein kinases regulating the activity of AP-1 in response to extracellular stimuli are mitogen-activated protein kinases (MAPKs). Depending on the type of stimuli, these proline-directed kinases can be dissected into three subgroups. The extracellular signal-regulated kinases (ERK-1, -2) are robustly activated by growth factors and phorbol esters but are less efficiently activated by cytokines and cellular stress-inducing stimuli (UV irradiation, chemical carcinogens). In contrast, Jun-N-terminal kinases (JNK-1, -2, -3), also known as stress-activated kinases (SAPK), and a structurally related class, p38 MAP kinases (p38α, -β, -γ), are strongly activated by cytokines and environmental stress but are poorly activated by growth factors and phorbol esters. These kinases themselves are under strict control of upstream kinases and phosphatases, which are part of individual signaling pathways initiated by specific classes of extra- and intracellular stimuli (e.g., growth factors, DNA-damaging agents, oncoproteins). This network, which exhibits a high degree of evolutionary conservation between yeast, drosophila, and mammals, is, however, far too complex to be discussed in greater detail in this review (for in-depth information on this subject see Eferl and Wagner (2003)).

ERK1 and ERK2 carry out mitogen-stimulated phosphorylation of JunD, and phosphorylation of distinct serine residues at the C-terminus of c-Jun and Fos family members has also been postulated to depend on the ERK pathway. The JNK/SAPKs were originally identified by their ability to specifically phosphorylate c-Jun at two positive regulatory sites (Ser-63, Ser-73) residing within the TAD (Fig. 2). Hyperphosphorylation of both sites, which was originally identified by 2D-phospho-amino acid-peptide mapping (peptides x, y in Fig. 2), is observed in response to stress stimuli as well as oncoprotein expression and is required for transcriptional activation of numerous c-Jun target genes. The JNKs can also phosphorylate and potentiate the activity of JunD and ATF-2. Notably, the nuclear protein Menin that is encoded by the tumor suppressor gene MEN1 specifically interacts with JunD and inhibits ERK- and JNK-dependent phosphorylation of JunD, but also of c-Jun. The amino acids that are phosphorylated on ATF2 by JNKs also serve as phospho-acceptor sites for p38, while Ser-63 and -73 of c-Jun are not affected by p38. Most likely, hyperphosphorylation of Jun and ATF proteins results in a conformational change of the TAD allowing more efficient interaction with cofactors, such as CBP, which facilitate and stabilize the connection with the RNA polymerase II/initiation complex to enhance transcription of target genes. In addition to enhanced transactivation, phosphorylation-dependent changes in the half-life of Jun and Fos proteins have been observed. In nonstimulated cells, the DNA-binding domain of c-Jun becomes phosphorylated at multiple sites (peptide a, b2, and c in Fig. 2) by GSK-3 and/or casein kinase II (CK-II) resulting in reduced DNA binding. In response to extracellular stimuli, such as UV, phosphorylation is reduced leading to enhanced DNA binding. The mechanism (reduced activity of the kinase or enhanced activity of a phosphatase) has not yet been defined conclusively. Recently, GSK3-mediated phosphorylation of c-Jun was also detected at the C-terminus creating a high affinity binding site for the E3 ligase Fbw7, which targets c-Jun for poly-ubiquitination and proteosomal degradation.
Fig. 2

Top: schematic diagram of the human c-Jun protein. Amino acids are numbered. The numbers on top refer to the trypsin cleavage sites that lead to the appearance of phosphopeptides after in vivo labeling of cells with 32P-orthophosphate. The locations of the tryptic peptides “ac” in the DNA-binding domain and peptides “x” and “y” in the transactivation domain are indicated. Bottom: Autoradiogram of in vivo labeled c-Jun protein isolated by immunoprecipitation from untreated and UV-treated cells, digested with trypsin, and separated by gel electrophoresis into two dimensions. On the right, the positions of the tryptic peptides are schematically illustrated. Peptide “z” most likely represents a peptide-containing residual phosphorylation at threonine-89 and/or threonine-91 of c-Jun

In addition to phosphorylation, other mechanisms of posttranslational processing have been identified, which regulate AP-1 activity including redox-dependent DNA binding and regulation of nuclear localization.

The mutual interference between AP-1 and steroid hormone receptors, particularly the glucocorticoid receptor (GR), represents another extensively analyzed example of protein–protein interaction-based crosstalk. In this context, there is experimental evidence that the anti-inflammatory and immunosuppressive activities of glucocorticoids are mediated, at least in part, by GR-mediated repression of AP-1 activity. In addition to GR, numerous transcription factors (e.g., C/EBP, Ets, Gata, MyoD, NFAT, NFκB, Runx, Smad, SP-1, Stat, TCF, and the Lim-only protein YY1), transcriptional cofactors (e.g., alphaNAC, Jab1, p300/CBP, TAF1, TAF4b, TAF 7, Trip6, and WWOX), subunit of the chromatin-remodeling complex (e.g., SWI/SNF and HDAC3), as well as other types of cellular proteins (e.g., DexD/H-box RNA helicase RHII/Gu and BAF60a) have been found to physically interact and modulate AP-1 activity. In most cases, the exact mechanism of interaction between AP-1 and these proteins remains to be determined.

AP-1 in Physiology and Pathology

The generation of genetically modified mice harboring genetic disruption and/or transgenic overexpression as well as the availability of genetically defined mutant cells isolated from these animals represent a major breakthrough in our understanding of the regulatory functions of AP-1 subunits (Tables 1 and 2). Distinct and overlapping phenotypes of the individual knockout mice induced by defects in cells or tissues in which the subunit was particularly important, or where its absence became rate-limiting, support the notion that AP-1 subunits exhibit unique but also common functions in vivo. As a general rule derived from all studies, the AP-1 family members must be present in a complementary and coordinated manner in order to ensure proper development or physiology of the organism.
Table 1

Knockout and knockin mouse models



Affected tissues


Embryonic lethality at E12.5

Liver, heart

c-JunAA/AA for c-Jun

Rescue of embryonic lethality and resistance to epileptic seizures and neuronal apoptosis induced by excitatory amino acid kainate

Liver, heart, CNS

JunB for c-Jun

Rescue of embryonic lethality until birth

Liver, heart

JunD for c-Jun

Rescue of embryonic lethality until birth

Liver, heart

c-JunΔ/Δ Alfp-Cre

Impaired postnatal hepatocyte proliferation and liver regeneration


c-JunΔ/Δ Bal1-Cre

Malformation of axial skeleton


c-JunΔ/Δ Col2a1-Cre

Increased apoptosis of notochordal cells, fusion of ventral bodies, and scoliosis of axial skeleton


c-JunΔ/Δ K5-Cre

Eyelid closure defect


c-JunΔ/Δ Nestin-Cre

Impaired axonal regeneration



Embryonic lethality at day E8.0 to E10

Extraembryonic tissue, placenta


Pronounced epidermal hyperplasia, disturbed differentiation, and prolonged inflammation

Skin, immune system




JunBΔ/Δ More-Cre

Osteopenia and myeloproliferative disease

Immune system, Skeleton

JunB−/− Ubi-JunB

Myeloproliferative disease, altered T-helper 2-cell differentiation, impaired allergen-induced airway inflammation, and osteoporosis-like phenotype

Immune system, Skeleton

c-JunΔ/ΔJunBΔ/Δ K5-Cre-ER

Psoriasis-like phenotype



Male sterility, growth retardation, cardiomyocyte hypertrophy, and impaired T-helper-cell differentiation

Testis, heart, immune system


Osteopetrosis and accelerated light-induced apoptosis of photoreceptor cells

Skeleton, CNS

c-Fos−/− H2Kb-Fra1

Rescue of osteopetrosis and photoreceptor cell apoptosis

Skeleton, CNS

c-FosΔΔ Nestin-Cre

Impaired long-term memory and synaptic plasticity



Nurturing defect

CNS, hypothalamus


Embryonic lethality at E9.5

Extraembryonic tissue, placenta

Fra1Δ/Δ More-Cre




Postnatal lethality and defective chondrocyte differentiation


Fra2Δ/Δ Coll2a1-Cre

Defective chondrocyte differentiation and kyphosis-like phenotype


−/− conventional knockout, Δ/Δ Cre-induced conditional knockout

Table 2

Transgenic mouse models



Affected tissues





Increased bone mass



Altered T helper cell differentiation

Immune system


Reduced peripheral T- and B-cells and impaired T-cell activation

Immune system








Impaired T-cell differentiation

Immune system


Osteosclerosis and impaired adipogenesis

Bone, fat tissue





Ocular malformation

Anterior eye structure


Increased bone mass


Conventional knockout approaches demonstrate that expression of JunD, c-Fos, and FosB is dispensable for normal embryogenesis (Table 1). However, junD null mice develop age-dependent defects in reproduction, hormone imbalance, and impaired spermatogenesis in male and cardiomyocyte hypertrophy that is enhanced by chronic moderate pressure overload. Additionally, junD deficiency impacts T helper cell differentiation. An important regulatory role for JunD in lymphocyte maturation and activation is supported by reduced peripheral T- and B-cell populations in transgenic mice with ectopic JunD overexpression. Whereas, adult fosB −/− females nurture insufficiently, tissue-specific overexpression of ΔFosB, a naturally occurring truncated form of FosB that arises from alternative splicing of the fosB transcript, causes impaired T-cell differentiation or osteosclerosis, respectively. Lack of c-Fos expression in adult animals causes an accelerated light-induced apoptosis of photoreceptor cells as well as osteopetrosis and further experimental evidence support that c-Fos is a master regulator of osteoclastogenesis. Noteworthy, both phenotypes could be rescued by transgenic Fra-1 overexpression in c-fos −/− animals in a dose-dependent manner implicating that Fra-1 is an important c-Fos target gene in vivo.

In contrast to the AP-1 subunits discussed so far, c-Jun, JunB, Fra1, and Fra2 expression is indispensable for embryonic development or postnatal survival (Table 1). While c-jun null embryos die at midgestation (E12.5) due to failure in heart and liver development, lethality of junB (E8.0 to E10) and fra1 (E9.5) deficient embryos is caused by placentation failure due to multiple defects in the extraembryonic tissue. These data suggest that JunB and Fra1, possibly as heterodimers, address common target genes responsible for the generation of a functional placental labyrinth. Knockin approaches revealed complete restoration of c-Jun dependent defects during embryogenesis by JunB and JunD indicating that spatial and temporal regulation of Jun protein expression may be more important than the coding sequence of the individual family member (Table 1). Finally, Fra-2-deficient mice die shortly after birth, are growth retarded, and show defective chondrocyte differentiation.

Embryonic or postnatal lethality largely prevented functional studies in vivo, and therefore conditional tissue- and cell-type specific ablations have become an important tool to study the regulation and function of AP-1 subunits in physiological and pathological processes (Table 1). These approaches confirmed initially seen phenotypes during embryogenesis, but also revealed novel nonoverlapping and common functions of distinct AP-1 family members in adult animals, specifically in skeletal and bone morphogenesis, the immune system, skin homeostasis, and the central nervous system. In adult mice, c-jun deficiency results in axial skeleton malformation accompanied by accelerated apoptosis of notochordal cells, fusion of ventral bodies, and scoliosis, while compromised JunB or Fra-2 expression is associated with defective endochondral ossification partially due to impaired chondrocyte differentiation. Postnatal and cell-type specific loss of junB also causes osteopenia or osteopetrosis, respectively, due to failure in osteoblasts and osteoclast differentiation and physiology. Again, junB or fra-1 deficiency in osteoblasts (osteopenia) or overexpression in transgenic mice (osteosclerosis and increased bone mass) results in comparable phenotypes. Furthermore and similar to JunD, JunB is required for a proper regulation of T-helper-cell-specific cytokine expression and differentiation that is also confirmed by T-cell specific JunB overexpression in transgenic mice (Table 2).

Animal studies further unraveled an important role of c-Jun in skin development and homeostasis as an important regulator of keratinocyte proliferation as well as differentiation through transcriptional regulation of the epidermal growth factor receptor (EGFR). In contrast, JunB can antagonize keratinocyte proliferation, and an inducible downregulation of both, c-Jun and JunB, in epidermal keratinocytes causes a psoriatic-like phenotype with epidermal hyperplasia as well as deregulated cytokine expression. Finally, specific ablation of AP-1 subunits in cells of the central nervous system revealed crucial functions for c-Jun in axonal regeneration upon transection of the facial nerve and for c-Fos in long-term memory and synaptic plasticity.

Importantly, primary and immortalized cells could be isolated from almost all mice lacking individual AP-1 members. Analysis of fibroblasts revealed that c-Jun acts as positive regulator of the cell cycle by suppressing p53 and indirectly the p53 target gene p21. Moreover, loss of c-Jun results in reduced cyclin D1 activity, while its overexpression was found to upregulate cyclin D levels. On the other hand, JunB contributes to both positive and negative regulation of cell-cycle progression by induction of the cyclin-CDK inhibitor p16, downregulation of c-Jun and cyclin D expression, or transcriptional activation of cyclin A. JunD-deficient fibroblasts exhibit specific alterations in cell proliferation depending on p53 and p19-ARF expression. Moreover, data from fibroblasts lacking both c-Fos and FosB established a critical role of these AP-1 subunits in cyclin D expression, whereas fibroblasts lacking either c-Jun or c-Fos cannot be transformed by oncogenes, such as Ras and Src, providing additional evidence for a critical role of AP-1 members in the control of cell proliferation and transformation. In addition to these cell-autonomous effects, critical and antagonistic functions of c-Jun and JunB on cell proliferation in trans were observed using knockout fibroblasts in an in vitro skin equivalent model system with primary human keratinocytes.

As described before, AP-1 activity is also greatly enhanced upon treatment of cells with genotoxic agents, implying that AP-1 target genes are involved in the cellular stress response, such as DNA repair, induction of survival, or initiation of the apoptotic program. Detailed studies demonstrate that AP-1 subunits, depending on the cell type and quality of the stimuli, are involved in both anti- and pro-apoptotic responses. As an example, fibroblasts lacking the c-Fos protein are hypersensitive to UV irradiation compared to wild-type cells, which is caused by a higher rate of apoptosis rather than the inability to repair damaged DNA. However, c-fos −/− deficiency results in the loss of light-induced apoptosis of photoreceptor cells in retinal degeneration. In contrast to c-fos −/− fibroblasts, the ability of c-jun-deficient fibroblasts to undergo apoptosis is greatly reduced due to the absence of CD95 (Fas/APO)-ligand induction. Vice versa, c-Jun overexpression induced apoptosis in fibroblasts. Reduced CD95-L induction was also observed in cells from mice expressing a c-Jun mutant protein, which lacks the critical JNK/SAPK phosphorylation sites in its transactivation domain (JunAA). Reduced apoptosis in response to genotoxic agents was also observed in mice lacking members of the JNK/SAPK family of protein kinases, suggesting that c-Jun and ATF proteins are the major substrates of JNK/SAPKs to mediate the cellular stress response. However, primary liver cell cultures and erythroblasts derived from c-jun −/− embryos exhibit increased apoptotic rates. Finally, while JunD participates in anti-apoptotic regulation, JunB appears to be part of a pro-apoptotic pathway through negative regulation of anti-apoptotic genes, at least in myeloid cells.

AP-1 Subunits in Cancer

As described previously, AP-1 activity is enhanced in cells that are stimulated by agents promoting cell proliferation. Moreover, oncogenic versions of c-Jun and c-Fos have been isolated from retroviruses, and various membrane-associated or cytoplasmic oncogenes (e.g., Ras, Src, Raf) permanently upregulate AP-1 abundance as part of their transforming capacity, suggesting that AP-1 members play an important role in cell proliferation and transformation. Initial evidence for this assumption has been obtained by blocking AP-1 activity either through expression of a transdominant-negative c-Jun mutant, by expression of antisense sequences, or by microinjection of Jun- and Fos-specific antibodies. Under these conditions cell-cycle progression was disturbed in cultured cells and the efficiency of oncoprotein-mediated cell transformation was reduced. However, different lines of evidence suggested that members of the Jun and Fos families play specific roles during these processes or may even antagonize each other.

Genetic analysis of AP-1 function in transgenic mice revealed that overexpression of c-Fos induces osteosarcoma formation. More recently, expression of transdominant-negative or phosphorylation-defective mutants and studies using knockout mice confirmed an essential contribution of distinct AP-1 subunits not only in osteosarcoma formation, but also in skin carcinogenesis, intestinal tumors, liver tumors, lymphomas, and rhabdomyosarcomas.

These studies demonstrate that JNK-dependent phosphorylation of c-Jun as well as RSK-2 dependent phosphorylation of c-Fos on Ser-362 are essential for osteosarcoma formation in mice and may also be important for human osteosarcomas. Additionally, expression and phosphorylation of c-Jun is critically implicated in skin tumor formation, whereas c-Fos function is absolutely required for malignant progression in mouse models of skin carcinogenesis. Tissue-specific ablation of c-Jun also reduces tumorigenesis in the APC (Min) mouse model of intestinal cancer and chemically induced hepatocellular carcinoma, respectively. During chemically induced liver tumorigenesis, c-Jun prevents apoptosis by antagonizing p53 activity and thereby contributes to early-stage hepatocellular cancer development. In contrast to c-Jun, JunB was identified as a potential tumor suppressor gene, at least in hematopoietic cells, since inactivation of JunB in postnatal mice results in a transplantable myeloproliferative disorder eventually progressing to blast crisis and resembling early human chronic myelogenous leukemia (CML). More recently, JunB has also been shown to inhibit proliferation and transformation of B-lymphoid cells and to function as a gatekeeper for B-lymphoid leukemia. Surprisingly, p53/c-fos double knockout mice develop highly proliferative and invasive rhabdomyosarcomas suggesting tumor suppression also by the c-Fos oncogene under specific conditions.

Despite a broad knowledge concerning genes, which harbor AP-1 binding sites in their regulatory elements, only a few directly regulated AP-1 target genes have been identified, which are affected in AP-1 null mice or cells derived thereof and may critically contribute to cellular transformation and tumor formation in vivo. In addition to AP-1 target genes involved in cell proliferation, differentiation, and apoptosis, the most well-characterized AP-1-responsive genes in cancer are those implicated in signal transduction (e.g., EGFR), chromatin remodeling (e.g., DMNT1, HDAC3), invasion (e.g., MMPs, uPA), metastasis (e.g., CD44, osteopontin), and angiogenesis (e.g., VEGF). Some of these target genes support the notion that AP-1 critically contributes to the aggressive spread of malignant tumor cells and metastasis that is a major cause of death in cancer patients (for in-depth information on this subject see Eferl and Wagner (2003)).

Despite the fact that AP-1 has been identified two decades ago, it still maintains a lot of its mystery. Further research on tissue-specific inactivation of AP-1 members and the identification of subunit-specific target genes may yield an even more complex picture of function and regulation of AP-1.



  1. Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3:859–868CrossRefPubMedGoogle Scholar
  2. Hess J, Angel P, Schorpp-Kistner M (2004) AP-1 subunits: quarrel and harmony among siblings. J Cell Sci 117:5965–5973CrossRefPubMedGoogle Scholar
  3. Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4:E131–E136CrossRefPubMedGoogle Scholar
  4. Wagner EF (2001) AP-1 reviews. Oncogene 20:2333–2497CrossRefGoogle Scholar
  5. Weston CR, Davis RJ (2002) The JNK signal transduction pathway. Curr Opin Genet Dev 12:14–21CrossRefPubMedGoogle Scholar

See Also

  1. (2012) Cellular Transformation Assay. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 743. doi: 10.1007/978-3-642-16483-5_1020Google Scholar
  2. (2012) G-protein Couple Receptor. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 1587. doi: 10.1007/978-3-642-16483-5_2294Google Scholar
  3. (2012) MAPK. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 2167. doi: 10.1007/978-3-642-16483-5_3532Google Scholar
  4. (2012) P53. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 2747. doi: 10.1007/978-3-642-16483-5_4331Google Scholar
  5. (2012) Polyubiquitination. In: Schwab M (ed) Encyclopedia of Cancer, 3rd edn. Springer Berlin Heidelberg, p 2957. doi: 10.1007/978-3-642-16483-5_4678Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Division of Signal Transduction and Growth ControlDeutsches KrebsforschungszentrumHeidelbergGermany