<<

Oncogene (2001) 20, 2413 ± 2423 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc

Function and regulation of AP-1 subunits in and pathology

Peter Angel*,1, Axel Szabowski1 and Marina Schorpp-Kistner1

1Deutsches Krebsforschungszentrum, Division of Signal Transduction and Growth Control, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

The mouse skin has become the model of choice to study functions of Fos, Jun and ATF (see Jochum the regulation and function of AP-1 subunits in many et al. this issue). physiological and pathological processes in vivo and in The skin represents a very elegant, easily accessible vitro. Genetically modi®ed mice, in vitro reconstituted and highly informative system to study the regulation skin equivalents and epidermal lines were established, and function of AP-1 and AP-1-regulated genes in in which AP-1-regulated genetic programs of cell multiple biological processes such as cell proliferation proliferation, di€erentiation and tumorigenesis can be and di€erentiation. It allows elucidating cell-autono- analysed. Since the , as our interface with the mous functions of AP-1 proteins as well as AP-1- environment, is subjected to radiation and , signal dependent genetic programs regulated by cell-cell and transduction pathways and critical AP-1 members cell-matrix interactions, or by soluble factors acting in regulating the mammalian response could be an autocrine or paracrine fashion. Moreover, both identi®ed. Regulated expression of important components culture and animal models have been established of the network, cell surface receptors and to determine the role of AP-1 subunits in tumour proteases, which orchestrate the process of formation and progression. Since the skin functions as healing has been found to rely on AP-1 activity. Here the outer protective barrier of a body exposed to a we review our current knowledge on the function of AP-1 variety of environmental stress factors (e.g. radiation subunits and AP-1 target genes in these fascinating ®elds and chemical xenobiotics, injury by mechanical stress) of skin physiology and pathology. Oncogene (2001) 20, genetic programs controlling the cellular stress re- 2413 ± 2423. sponse and tissue remodelling and regeneration during wound healing can be determined. This review Keywords: epidermis; Fos; Jun; proliferation; di€eren- summarises our current knowledge on the function of tiation; target genes AP-1 members in these aspects of skin biology.

Introduction Expression of AP-1 subunits in the skin

The transcription factor AP-1 mediates gene regulation The skin can be dissected into two major compart- in response to a variety of extracellular stimuli ments, the epidermis representing the outermost skin including growth factors, , oncogenes, tumour layer, and the , both of which are separated by promoters and chemical (Angel and Karin, the basal lamina. of the epidermis relies 1991; Karin et al., 1997). AP-1 represents a hetero- on a tightly regulated balance between proliferation genous set of dimeric proteins consisting of members of and di€erentiation. Continuous proliferation of epi- the Jun, Fos and ATF families. Small di€erences in dermal stem cells in the and a shift in sequence speci®city for individual AP-1 dimers have the balance between proliferation and di€erentiation in been observed. Moreover, once bound to DNA, the cells of the adjacent layers are a prerequisite to replace transactivation function of subunits of a given dimeric the shed material of the (Figure 1). complex may vary which can be explained by The di€erent cell layers can be classi®ed by histological di€erences in phosphorylation by upstream means, or e.g. by abundant as cells kinases (see Rincon et al. this issue) as well as by belonging to the spinous layer and by the presence of protein/protein interaction with other cellular factors. hyaline granula in the . Impor- In consequence, distinct sets of genes are targeted, tantly, typical marker genes indicative for a speci®c suggesting that individual members of the AP-1 family phase of the di€erentiation process have been have speci®c functions in AP-1-regulated cellular identi®ed. Certain members of the cytokeratin protein processes. Loss of function approaches in mice and family, K5 and K14, are indicative for the basal layer, analysis of cells derived from such mutants already led whereas K1 and K10 are representative of the spinous to the identi®cation of speci®c, non-overlapping layer. Filaggrin, type I as well as the envelope precursor proteins involucrin and loricrin are other markers speci®cally expressed in the suprabasal *Correspondence: P Angel layers of the skin (for review Eckert and Welter, 1996). AP-1 in skin biology P Angel et al 2414

Figure 1 Expression pattern of AP-1 subunits in skin. A schematic illustration of the skin, which can be divided in the two major compartments epidermis and dermis, is shown on the left. The multi-layered structure of the epidermis forming de®ned strata re¯ects speci®c di€erentiation states of epidermal . The pattern of expression and abundance of and mouse c- Jun, JunB, JunD, c-Fos, FosB, Fra-1 and Fra-2 proteins in these layers are shown on the right. Low but signi®cant expression of most of these proteins is found in ®broblasts, which are located in the dermal compartment

While the expression pattern of AP-1 subunits in the showing highest levels in the stratum basale and dermis, in particular in dermal ®broblasts, has not been . In contrast, c-Jun was found to be analysed in great detail, expression of a few family restricted to the granular layer (Figure 1). A somewhat members was studied in human and mouse epidermis broader pattern was observed for c-Fos which was by both in situ hybridization and immunohistochemical present in both the spinous and granular layers but analysis (Welter and Eckert, 1995; Rutberg et al., 1996; seemed to be completely absent in the basal layer and Schorpp-Kistner and Angel, unpublished). During the lower zone of the stratum spinosum. mouse embryonic development expression of c-Jun Interestingly, there was only a very low degree of and JunB in skin becomes ®rst visible at E17.5 showing overlap in the expression of c-Fos and the other an ill-de®ned pattern of expression of c-jun in the members of the Fos protein family, particularly FosB, epidermis. JunB expression was found in the super®cial suggesting subunit-speci®c regulation of target genes. stratum corneum, but not in basal layers of proliferat- FosB, Fra-1 and Fra-2 proteins were co-ordinately ing epidermal cells (Wilkinson et al., 1989). In contrast, expressed in the spinous layer and expression of Fra-1 Fra-2-expressing cells were detected at E16.5 in the and Fra-2, but not FosB, was even further increased in basal layer and the upper granular layer, but not in the cells of the lower zone of the stratum granulosum. stratum corneum (Carrasco and Bravo, 1995). These (Figure 1; for review, Eckert and Welter, 1996). A data suggest that during the process of skin develop- detailed analysis of expression of ATF proteins in the ment (e.g. the stratum corneum ®rst arises at E16) skin has yet to be performed. neither c-Jun, nor JunB play a decisive role. In the epidermis of newborn mice a distinct expression pattern of Fos and Jun proteins has been described Regulation and function of Fos and Jun proteins in (Rutberg et al., 1996). Expression of c-jun, junD and proliferation and di€erentiation Fra-1 are co-ordinately expressed in the basal and spinous layers of the epidermis. Basal cells also express Signalling pathways and AP-1 target genes in skin c-fos, junBandFra-1, but not fosB. JunB and Fra-2 are the only AP-1 members, which are also found in the The distinct expression pattern of the Jun and Fos granular layer (Carrasco and Bravo, 1995; Rutberg et proteins in the epidermis suggests a general role for al., 1996; Figure 1), suggesting the existence of individual AP-1 subunits in cell proliferation and subgroups of AP-1 target genes involved in keratino- di€erentiation. Protein interference experiments in cyte proliferation and di€erentiation, whose expression tissue culture cells, such as expression of antisense is modulated by distinct AP-1 subunits. Interestingly, RNA or injection of neutralizing antibodies, and di€erences in the expression pattern of Fos and Jun generation of subunit-speci®c knock out mice and cells proteins in mouse (newborn) and human (neonatal) derived thereof have established a critical role for Fos epidermis (Eckert and Welter, 1996) have been and Jun members in these processes. This includes the detected. In human, JunB was, similar to JunD, negative regulatory function of c-Jun on p53, its ubiquitously expressed in all layers of the epidermis positive e€ect on cyclin D1 regulation and the positive

Oncogene AP-1 in skin biology P Angel et al 2415 transcriptional regulation of p16 by JunB as reported proline-rich protein (SPRR)-1A (Sark et al., 1998) for ®broblasts (see Jochum et al.; Shaulian and Karin, and SPRR3 (Fischer et al., 1999). In contrast, this issue). Moreover, binding of c-Jun to Rb has been expression of another member of the SPRR family described in human keratinocyte cell lines (Nead et al., sprr2, is negatively regulated by c-Jun. Interestingly, 1998) suggesting protein/protein interactions between this e€ect is likely to be indirect, since repression is AP-1 members and regulators as an mediated by a region, which di€ers from the AP-1 site additional level of cell cycle control by AP-1 subunits. in the sprr promoter (Lohman et al., 1997). Transient However, it is important to note that the general co-transfection experiments suggested that c-Fos/JunB concept of c-Jun being a positive regulator of cell heterodimers are critically involved in the di€erentia- proliferation and of JunB (and possibly JunD) acting tion-speci®c expression of loricrin. However, analysis as an attenuator of cell cycle progression to favour of the loricrin promoter in transgenic mice showed that di€erentiation may not account for cells of the an additional negatively acting element is needed to epidermis, at least in human. As described above, the restrict loricrin expression to the granular layer (Di proliferating cells of the basal layer do neither express Sepio et al., 1999). Similarly, AP-1, ETS and members c-Jun nor c-Fos, but exhibit signi®cant amounts of of the AP-2 transcription factor families, binding to JunB and JunD. Surprisingly, c-Jun (and c-Fos) two distinct promoter regions, are required to orches- expression is restricted to proliferation incompetent, trate keratinocyte-speci®c activity of the K14 promoter terminally di€erentiated cells of the stratum granulo- in transgenic mice (Sinha et al., 2000). sum, which express only low amounts of JunB and In addition to this impressive and still increasing JunD. These ®ndings suggest that in human AP-1 number of AP-1-regulated genes in epidermal cells, subunits expressed in keratinocytes are predominantly di€erences in the expression pattern of AP-1 subunits involved in the regulation of the di€erentiation during in vitro di€erentiation of keratinocytes have program rather than in the proliferation control. On pointed to a regulatory function of AP-1 in the the other , the expression pattern of Fos and Jun formation and maintenance of the epidermis. In vitro proteins in mice may point to a critical role of c-Jun, multiple phenotypes of keratinocyte di€erentiation can JunD and Fra-1 in keratinocyte proliferation or in the be recapitulated e.g. by raising the calcium concentra- early stages of di€erentiation. tion or treatment of cells with phorbol esters (for Additional lines of evidence for a critical role of references see Rutberg et al., 1997). Under such AP-1 subunits in keratinocyte proliferation and/or conditions speci®c alterations in the expression of Fos, di€erentiation come from the increasing number of Jun and AP-1 target genes (sprr1, pro®laggrin) can be genes, which have been found to harbour AP-1 binding detected suggesting speci®c and partially opposing sites in their promoters, and which are expressed in functions of AP-1 subunits in keratinocyte di€erentia- distinct layers of the epidermis. In most cases, tion (Gandarillas and Watt, 1995; Rutberg et al., 1997). functional relevance of these sites for di€erentiation- Moreover, there is strong evidence that signal transduc- speci®c basal expression or for induced expression tion pathways modulating AP-1 activity (see Rincor et upon critical extracellular signals, e.g. levels of calcium, al. this issue) are main regulators of keratinocyte was con®rmed in established keratinocyte cell lines. proliferation and di€erentiation. For example, cal- The list of AP-1 target genes in the epidermis, which cium-induced terminal di€erentiation depends on spe- are considered to encode critical players of skin ci®c isoforms of PKC, and PKC activation is required homeostasis includes transglutaminase and di€erent for calcium-induced expression of Fra-2, JunB and members of the cytokeratin gene family such as K1, JunD expression and enhanced AP-1 binding activity K5, K6, K8, K14, K18 and K19 (for references, see (Rutberg et al., 1996; Takahashi et al., 1998). On the Eckert and Welter, 1996; Navarro et al., 1995; Hu and other hand, transdominant negative versions of Gudas, 1994). The requirement of the AP-1 site in the MEKK1, MEK1, MEK3, MEK7, p38 and c-jun, but human K14 and K18 promoters was con®rmed in not mutants of the Raf/Erk or MEK4/JNK signalling transgenic mice (Rhodes and Oshima, 1998; Sinha et pathway, interfere with TPA-dependent induction of al., 2000). High basal level expression of the pro®lag- involucrin expression (E®mova et al., 1998). These data grin gene in epidermal keratinocytes depends on c-Jun/ suggest that at least one route of the stress signal c-Fos heterodimers (Jang et al., 1996), whereas co- transduction pathway may also be involved in the operative action of AP-1 and Sp1 is required for regulation of keratinocyte di€erentiation. maximal expression of the human involucrin promoter An additional argument for the involvement of AP-1 (Lopez-Bayghen et al., 1996). JunD, Fra-1 and Fra-2 in skin biology is the repression of involucrin and K1, proteins, whose levels are a€ected by changes in the K5 and K14 by retinoids and steroid concentration of extracellular calcium, preferentially hormones, which are the most commonly used bind to the calcium response element in this promoter therapeutic agents in dermatology (Lu et al., 1994; (Ng et al., 2000). However, Fra-1, JunB and JunD Monzon et al., 1996; Radoja et al., 2000). Although in appear to be responsible for the regulation of each case repression is mediated through an AP-1 site, involucrin promoter activity by phorbol esters (Welter loss of K1 expression might be explained through et al., 1995). Functional synergism between AP-1 and competitive binding of AP-1 and steroid hormone ETS proteins was found to mediate expression of the receptors to a composite AP-1/steroid hormone keratinocyte terminal di€erentiation markers small receptor element (Lu et al., 1994). Repression of the

Oncogene AP-1 in skin biology P Angel et al 2416 other genes is likely to be mediated by physical that AP-1 activity may be required under conditions interaction of AP-1 with the retinoic acid or where the balance of keratinocyte proliferation and receptor resulting in mutual inactivation di€erentiation has to be rapidly and temporally altered. of their transactivation functions (see Herrlich, this The best example for the requirement of such a switch issue). of genetic programs is the process of wound repair and tissue regeneration, also known as cutaneous wound healing. The healing of an adult wound is a very Role of AP-1 in wound healing complex, dynamic and interactive process involving Despite this large body of data on the expression soluble mediators, cells, dermal cells (in pattern of AP-1 members and potential AP-1 target particular ®broblasts which are responsible for genes in tissue culture cells and in the mouse, the synthesis of components of the ) phenotypes of mice lacking c-Fos, FosB or JunD in the and keratinocytes of the epidermis (Figure 2; for epidermis did not provide evidence for a critical role of review; Martin, 1997; Singer and Clark, 1999). these proteins in normal skin (see Jochum et al. this The Ras/MAP/AP-1 pathway appears to play an issue). Moreover, speci®c deletion of c-Jun in cells of important role in cell proliferation control in response the stratum basale did not yield an obvious skin to wounding since interference with Ras inhibits DNA phenotype (R Zenz and EF Wagner, personal commu- synthesis, cell migration and induction of AP-1 nication). These data suggest that single subunits (e.g. members including c-Fos in bovine endothelial cells c-Jun, c-Fos) may not be required for skin develop- after mechanical wounding (Sosnowski et al., 1993). ment, or that other members of the protein family may On the other hand, in mice lacking c-Jun in functionally compensate their loss. The process of skin keratinocytes tissue regeneration after wounding is metabolism initiated by signals that trigger undi€er- not signi®cantly disturbed (R Zenz and EF Wagner, entiated, proliferative cells to undergo cell di€erentia- personal communication), excluding the absolute tion and to ®nally become shed material of the requirement of c-Jun in cell-autonomous regulation of corni®ed layer is fairly slow. Therefore, in light of keratinocyte proliferation, migration and di€erentia- the rapid and transient kinetics of expression and tion during wound healing in vivo. Nevertheless, there activity of AP-1 subunits in response to many is strong evidence that AP-1 is critically involved in this extracellular signals (for review Angel and Karin, process, since Jun, Fos and ATF proteins are at the 1991; Karin et al., 1997) it is tempting to speculate receiving end of signalling pathways initiated by

Figure 2 AP-1-dependent players of the cytokine network controlling the process of wound healing. Growth factors and cytokines secreted by various cell types during wound healing are shown. Only those, whose expression is regulated by AP-1, or whose activity in target cells depends, at least in part, on AP-1 activity, are considered. For a more detailed description of the wound healing process, see Martin, (1997) and Singer and Clark (1999). On the left, the double paracrine network of epithelial-mesenchymal interaction established in an in vitro organotypic coculture system is highlighted. After wounding keratinocytes secrete IL-1 which induces expression of KGF and GM-CSF in ®broblasts. C-Jun and JunB regulate expression of both cytokines in ®broblasts in an antagonistic manner. An appropriate balance of KGF and GM-CSF is required for co-ordinated keratinocyte proliferation and di€erentiation during reepithelialization of the epidermis

Oncogene AP-1 in skin biology P Angel et al 2417 cytokines and growth factors in appropriate target cells the stimulation of the TF promoter activity (Felts et and, furthermore, since AP-1 is involved in the al., 1995). Yet, it remains to be determined whether in regulation of synthesis of the factors themselves. addition to c-Fos and JunD other AP-1 subunits are In normal and wounded skin, several growth involved in TF expression. Finally, an ATF/CREB- factors and have been detected, such as binding site in the in¯ammatory protein 1 IL-1, IL-6, IL-8, GM-CSF, TFG-a and TGF-b, beta (MIP-1 beta) seems to control - and LPS- NGF, PDGF as well as members of the FGF family induced expression of this gene in (for review see SchroÈ der, 1995; Martin, 1997; Singer (Prott et al., 1995). and Clark, 1999). First evidence for an involvement AP-1 sites have been found in the promoter region of AP-1 in wound healing was provided by the fact of the ®broblast receptor 1 (Saito et al., that certain factors, such as EGF, FGF, members of 1992), and IL-1 receptor antagonist promoter (Smith et the TGFb, TNF-a and protein families al., 1992), suggesting that AP-1 is also involved in the stimulate AP-1 activity through the activation of the regulation of cytokine receptors thereby modulating MAP kinases JNK and p38, which, in turn the susceptibility of target cells for cytokine action. hyperphosphorylate and thereby activate c-Jun and As illustrated in Figure 2 cytokine-mediated cross ATF-2, the main mediators of c-jun expression in talk involves a variety of cell types in the epidermis and response to cytokines and genotoxic agents. Upregu- in the which makes it very dicult to lated gene expression resulting in enhanced levels of de®ne precisely the source of the cytokine of interest. Jun and Fos proteins triggers alterations in the However, a simpli®ed in vitro tissue engineered skin expression of AP-1 target genes, for example matrix equivalent model mimicking tissue physiology has been metalloproteinases and IL-2 (Muegge et al., 1989; established, in which the regulatory cross talk between Borden and Heller, 1997). keratinocytes and dermal ®broblasts can be investi- Second, a number of cytokines have been suggested gated. In these organotypic cultures keratinocyte to be potential AP-1 target genes. For example proliferation and di€erentiation is maintained under regulation of the human TNF promoter by phorbol the control of co-cultured dermal ®broblasts from esters depends in a variety of cell types on both an human or mouse to form a three-dimensionally AP-1 and a juxtaposed PEA3/ETS-1 site (Kramer et organized (Bell et al., 1981; Fusenig, 1994; al., 1995). In myelomonocytic cells, AP-1 synergizes Choi and Fuchs, 1990). Keratinocytes form a typical with C/EBPb in TNF-a expression. Interestingly, in epidermal tissue architecture expressing essentially all these cells co-operation does not require the transacti- characteristic di€erentiation markers including a base- vation domain of c-Jun but may be explained by ment membrane (Smola et al., 1998). Importantly, this protein/protein interaction between c-Jun and c/EBPb in vitro system mimics many aspects of the re- leading to enhanced DNA binding (Zagariya et al., epithelialization process during wound closure. This 1998). In vitro binding studies and mutational analysis mesenchymal/epithelial interplay via di€usible factors revealed the importance of Jun and Fos proteins in the is initiated by keratinocyte-derived IL-1 acting on expression of mouse M-CSF in ®broblasts and ®broblasts to induce the expression of growth factors monocytes (Konicek et al., 1998). AP-1 sites have been such as KGF and GM-SCF in mouse ®broblasts acting found in the promoter region of human and murine back on human keratinocytes in a paracrine fashion. KGF and GM-CSF genes (Finch et al., 1995; Wang et The speci®c contribution of AP-1-dependent cytokine al., 1994; Ye et al., 1996; Viebig, Szabowski and Angel, expression in ®broblasts regulating keratinocyte pro- unpublished). The importance of AP-1 for the liferation and di€erentiation was investigated using induction of KGF promoter activity during wound ®broblasts from c-jun or junB-de®cient mice (Szabow- healing and repression by (Brauchle et ski et al., 2000). Whereas c-jun7/7 ®broblasts did not al., 1995) has not been analysed in detail. In the case of support keratinocyte growth, junB7/7 ®broblasts the GM-CSF promoter, AP-1 exhibits its regulatory caused enhanced keratinocyte growth and di€erentia- activity through functional synergism with other tion. These phenotypes may be explained by the lack of transcription factors including ETS-1, NF-kB (Wang constitutive and Il-1-induced expression of KGF and et al., 1994; Thomas et al., 1997), a Sp1-related GM-CSF in c-jun7/7 cells and enhanced constitutive complex (Ye et al., 1996) and NFAT (Masuda et al., expression of both genes in junB7/7 cells. Growth- 1993). By contrast, AP-1-depended GM-CSF promoter inhibited thin epithelia in c-jun7/7 ®broblasts contain- activity can be repressed by the nuclear factor YY1 (Ye ing cultures could be partially rescued by KGF to a et al., 1996). Functional synergism between AP-1, NF- proliferative but less di€erentiating epithelium, whereas IL-6 and NF-kB has been observed for the regulation addition of both KGF and GM-CSF completely of IL-8 expression (Roebuck, 1999). Two adjacent restored the wild-type phenotype. On the other hand, AP-1 binding sites recognized by JunD and a Fos- blocking antibodies to GM-CSF and IL-1 reduced the related protein mediate transcriptional activation of phenotype obtained by junB7/7 ®broblasts. These data tissue factor (TF), the cellular initiator of the protease suggest that the relative abundance and activation state cascade leading to blood coagulation, by serum, as well of a given AP-1 subunit in a non-cell autonomous, as of de®ned growth factors, such as PDGF and FGF trans-regulatory fashion directs regeneration of the (Felts et al., 1995). Interestingly, overexpression of c- epidermis and maintenance of tissue homeostasis in Fos and JunD abrogates the requirement for serum in skin (Szabowski et al., 2000).

Oncogene AP-1 in skin biology P Angel et al 2418 -derived KGF and GM-CSF, whose wound healing process. Basal transcription as well as function in skin homeostasis has been con®rmed in activation of MMP promoters in response to phorbol mice (Rubin et al., 1989; Werner et al., 1992; Xing et esters, cytokines, growth factors and cell matrix al., 1997) represent the ®rst members of a potentially interactions and altered cell-cell contacts require the growing list of critical AP-1-regulated cytokines, which speci®c interaction of AP-1 and ETS proteins (for are produced by the various cell types during the review see Benbow and Brinckerho€, 1997). In general, di€erent phases of the wound healing process (for MMPs are not constitutively expressed in skin but are review, Martin, 1997; Singer and Clark, 1999). These induced temporarily in response to the above men- factors very likely co-operate with ctyokines that are tioned exogenous signals to trigger the proteolytic expressed in an AP-1 independent manner, e.g. remodelling of the ECM in physiological and patho- members of the TGF-b family, their receptors (Frank logical situations e.g. tissue morphogenesis, tissue et al., 1996) and downstream targets of the activin A repair but also dermal photoaging and tumour cell pathway (Munz et al., 1999). invasion (for review KaÈ haÈ ri and Saarialho-Kere, 1997). In addition to autocrine and paracrine cytokine and In acute murine excisional skin interstitial growth factor action, there is convincing evidence that collagenase (MMP-1; MMP-13), MMP-9, MMP-3, cell-cell and cell matrix interactions are important MMP-10 and their physiological inhibitor TIMP-1 regulators of keratinocyte proliferation, migration and are strongly induced showing a unique spatial and di€erentiation. AP-1-regulated genes may also a€ect temporal transcription pattern (Madlener et al., 1998). this type of regulatory mechanism. AP-1 binding sites Tissue culture as well as animal studies have provided have been identi®ed in the promoter regions of avian evidence for the importance of the AP-1 target genes beta-3 integrin (Cao et al., 1993), alpha2 (Zutter et al., MMP-1 and MMP-3 during wound healing in 1994), alpha5 (Corbi et al., 2000) alpha6 (Nishida et keratinocyte migration (MMP-1; Lund et al., 1999) al., 1997) and alpha7 integrins (Ziober and Kramer, and wound contraction, respectively (MMP-3; Bullard 1996), laminin B1 (Matsui, 1996), laminin gamma2- et al., 1999). chain (Olsen et al., 2000), (Mauviel et al., 1996) and tenascin-C (Mettouchi et al., 1997). Only in some Involvement of AP-1 subunits in photoaging cases, speci®c AP-1 subunit compositions have been described, which may be responsible for regulation of According to the function of the skin to serve as a these genes, such as JunD regulating expression of protective barrier against the environment, such as laminin gamma2 by HGF (Olsen et al., 2000), and ultraviolet irradiation from sunlight, skin cells actively JunD/Fra-2 modulating basal and TGF-b-dependent respond to such signals by changing their repertoire of laminin alpha 3A transcription (Virolle et al., 1998). gene expression to prevent radiation-induced damage. Moreover, to allow tissue remodelling during wound Long-term exposure to UV causes premature skin healing the composition of the extracellular matrix has aging (photoaging), in the course of which the to be altered. This can be achieved by transcriptional symptoms include leathery texture, mottled pigmenta- regulation of cellular genes encoding ECM components tion and . There is strong evidence that this as well as by proteolytic enzymes (particularly matrix process is driven by major changes in gene expression metalloproteinases) and their inhibitors that control the of ®broblasts in the dermal compartment (Bernerd and ECM turnover on the post-translational level (for Asselineau, 1998). This includes induction of AP-1- review: Borden and Heller, 1997; Vu and Werb, 2000). regulated matrix metalloproteinases, particularly inter- Over the past years, a critical role for AP-1 in the stitial collagenase (MMP-1), stromelysin (MMP-3) and regulation of ECM components has been established. gelatinase B (MMP-9; Fisher et al., 1997). In For example, an AP-1 binding site mediates expression agreement with the critical role of AP-1 in the of human alpha2 (I) (COL1A2) gene by TGF- transactivation of these genes by UV, transcription of b and TNF-a (Chung et al., 1996). Expression of the c-jun, junB and c-fos genes is also enhanced upon syndecan-1, a cell surface heparan sulphate proteogly- UV irradiation (Gillardon et al., 1994; Fisher et al., can that binds growth factors, is activated during 1999; Soriani et al., 2000; Shaulian and Karin, this cutaneous wound healing through a so-called AP-1- issue). However, there is evidence that, depending on driven FGF-inducible response element (FiRE). Inter- the wavelength of the UV light, the eciency of estingly, FiRE activity is selectively upregulated in induction di€ers among the Fos and Jun members migrating keratinocytes at the edge of the wound and (Ariizumi et al., 1996). Importantly, pre-existing and is persistent until completion of the re-epithelialization newly synthesized c-Jun protein becomes eciently process. Although the exact composition of AP-1 hyperphosphorylated, most likely by members of the complexes binding to this element has not yet been JNK/SAPK kinase family (Ramaswamy et al., 1998; identi®ed, modulation of AP-1 complexes is mediated Fisher et al., 1999). Activation of c-Jun seems also to by members of the MAP kinase family including ERKs depend on PKCzeta, because pre-treatment of mouse and p38 (Jaakkola et al., 1998). skin with PKCzeta antisense oligonucleotides impaired AP-1 plays a dominant role in the transcriptional UV induced c-Jun-speci®c gene expression (Huang et activation of the majority of matrix-metalloproteinases al., 2000). Interestingly, pre-treatment of cells with (MMPs) that are required for cell migration, ECM retinoic acid, which diminishes the eciency of degradation and tissue reorganization during the photoaging inhibits UV-dependent transcriptional acti-

Oncogene AP-1 in skin biology P Angel et al 2419 vation of MMPs. The repression seems to be mediated formation depends on obligatory wounding, suggesting by an accelerated breakdown of the c-Jun protein via that, in contrast to BPV, transformation by v-Jun the ubiquitin-proteasome pathway (Fisher et al., 1999). requires co-operative action with other yet unknown However, superfusion of rat skin with c-fos antisense factors. oligonucleotides did not signi®cantly reduce the When targeted to the basal cells of the epidermis, formation of cells in the UV-irradiated expression of human papilloma virus 16 (HPV-16) epidermis (Gillardon et al., 1994). leads to progressive squamous epithelial neoplasia, which is accompanied by alterations in the expression of K5, K10, K14 and ®laggrin (Arbeit et al., 1994). Role of AP-1 in tumourigenesis and other skin diseases Products of HPV (E6, E7) may directly or indirectly a€ect AP-1 activity, resulting in changes in gene The ability of speci®c members of the Jun and Fos expression and keratinocyte proliferation and di€er- protein family, as well as their retroviral derivatives, to entiation (Antinore et al., 1996; Shino et al., 1997). On transform tissue culture cells and to induce tumours in the other hand, transcriptional activity of HPV-16 and the animal (avian, rat, mouse) is well established (see other serotypes, e.g. HPV-18 and HPV-11 depends on van Dam and Castellazzi and Jochum et al., this issue). AP-1 binding sites (Cripe et al., 1990; Thierry et al., There is evidence that changes in AP-1 expression and 1992; Zhao et al., 1997). Exempli®ed by HPV-18 there activity correlate with di€erent stages of melanoma is increasing evidence that speci®c AP-1 subunits di€er development and progression (Rutberg et al., 1994). It in their activity to either activate or trans-repress HPV- was, however, the analysis of AP-1 function in linked carcinogenesis of the uterine cervix (Thierry et keratinocyte cell lines and in epidermal tumours of al., 1992; Soto et al., 1999). the mouse, which has contributed considerably to our The contribution of AP-1 subunits to premalignant current knowledge on the function of AP-1 in conversion and malignant progression of epidermal tumourigenesis. cells is best documented by the initiation-promotion Di€erent tumour model systems of mouse skin have protocol of mouse multistage skin carcinogenesis, become available: which ranks among the best studied in vivo approaches Formation of squamous cell carcinoma can be in experimental cancer research (for review see Bowden induced in hairless mice upon chronical exposure to et al., 1994; Brown and Balmain, 1995; Yuspa, 1998). UV-B irradiation. While a single exposure leads to a Upon treatment of the skin with a single dose of transient upregulation of c-fos,c-jun and c-myc, high mutagen (e.g. DMBA), followed by repeated applica- constitutive expression of c-fos,c-myc and Ha-ras was tion of tumour promoters, such as the phorbol ester observed in the tumour cells (Sato et al., 1997). 12-0-tetradecanoylphorbol-13-acetate (TPA), benign Interestingly, application of the monoterpene perillyl papillomas develop, some of which will enter malignant alcohol (POH) inhibited tumour incidence and UV-B- progression to squamous cell carcinomas. In mice induced AP-1 activity in mouse skin (Barthelman et al., lacking c-fos the development of malignant skin 1998). The speci®c contribution of these proteins in the tumours from papillomas induced by treatment with induction of skin photocarcinogenesis still remains to TPA is blocked at the transition from benign to be con®rmed by functional assays. malignancy (Saez et al., 1995). The eciency of Skin papillomas can be induced with very high formation of papilloma did not di€er from wild-type eciency upon constitutive activation of the Ras mice, but papillomas quickly hyperkeratinized. In pathway in basal keratinocytes (Sibilia et al., 2000). agreement with these data transgenic mice expressing Tumour formation is impaired in mice expressing a c- a transdominant-negative version of c-Jun (TAM67) Jun mutant, which lacks the phosphoacceptor sites for are resistant to DMBA-TPA induced skin tumorigen- JNK (Behrens et al., 2000), which strongly suggests esis (Young et al., 1999). Surprisingly, transgenic mice that activation of c-Jun and c-Jun-dependent target expressing v-Fos under the control of the human genes is critically involved in the development of skin -1 promoter exhibit hyperplasia, papillomas. and squamous papillomas in wounded ears (Green- Expression of bovine papilloma virus (BPV) in halgh et al., 1993), suggesting that both overexpression mouse dermal ®broblasts induces the formation of and loss of Fos activity interferes with skin home- mild and aggressive ®bromatosis, and ®brosarcoma. ostasis. An additional major advantage of this The latter two stages are characterized by strongly carcinogenesis model is the availability of mouse enhanced expression of c-Jun and JunB, but not JunD keratinocyte cell lines that represent each of the and Fos (Bossy-Wetzel et al., 1992). Overexpression of intermediate stages in tumour development. In these c-Jun or JunB, but not JunD, in cells of mild cells constitutive AP-1 binding and transactivating ®bromatosis induced anchorage independence and ability of cells of the malignant, but not benign state changes in the cell shape, suggesting that both proteins of the tumour was observed (Domann et al., 1994). may function as progression factors at intermediate Moreover, high levels of phosphorylated c-Jun, Fra-1, stages of tumorigenesis. Fibrosarcomas have been Fra-2 and ATF-2 proteins and a reduction in JunB observed also in v-Jun transgenic mice, which exhibit expression correlate with malignancy (Joselo€ and high basal level expression of the transgene in Bowden, 1997; Zoumpourlis et al., 2000). Overexpres- ®broblasts (Schuh et al., 1990). However, tumour sion of c-Fos in the papilloma cell line seems to be

Oncogene AP-1 in skin biology P Angel et al 2420 sucient for malignant conversion (Greenhalgh and Hanahan and Weinberg, 2000). Moreover, there seems Yuspa, 1988), whereas expression of a transdominant to exist a quantitative requirement or threshold for an negative mutant version of c-Jun in malignant cells acute neoplastic response and its progression to inhibited expression of AP-1-dependent reporter genes malignant stages which in addition can depend on and the ability of the cells to form tumours in nude the nature of the target cell as it has been mice (Bowden et al., 1994). These results are in good demonstrated for v-Jun-mediated wound tumorigenesis agreement with data obtained in two variants of the (Shalaby et al., 1994). mouse keratinocyte cell line JB6, which are either Evidence for trans-regulatory functions of cellular promotion-sensitive (P+) or promotion resistant (P7) Jun proteins in the regeneration of the epidermis and to TPA-induced transformation. TPA-induced expres- maintenance of tissue homeostasis comes from the sion of c-Jun is reduced in P7 cells and overexpression analysis of a reconstituted skin by combining primary of c-Jun increased the probability of progression in human keratinocytes and mouse wild-type, c-jun7/7 or P+, but not in P7 cells (Watts et al., 1995). junB7/7 ®broblasts described above (Szabowski et al., Overexpression of a dominant negative c-Jun mutant 2000; Figure 2). An aberrant or disturbed balance blocked TPA-induced AP-1 activity, cell transforma- between cytokines may also be implicated in patholo- tion and invasion (Dong et al., 1994, 1997). Block of gical diseases in human, such as , tumorigenesis is accompanied by a loss of TPA- psoriasis or dermato®brosis (Lever, 1983). Histologi- induced expression of MMPs, such as interstitial cally cutaneous lichen planus is characterized by collagenase (MMP-13), stromelysin-1 (MMP-3, stro- epidermal hypergranulosis (a pronounced stratum melysin-2 (MMP-10), gelatinase A (MMP-2) and MT1- granulosum with high amounts of keratohyalin MMP (MMP-14; Dong et al., 1997). The TPA-induced granula), irregular acanthosis, hyperkeratosis, dermal cellular response is mediated by MAP kinases, since dibrosis and a dense in®ltrate (Stefanidou et al., 1999). expression of transdominant negative version of ERK2 By contrast, absence of granular cells, hyperprolifera- inhibits AP-1-dependent gene expression and neoplastic tion and parakeratosis is observed in psoriatic transformation (Watts et al., 1998). epidermis (Lever, 1983). In vitro, normal keratinocytes Co-treatment with retinoic acid (Huang et al., 1997) develop psoriatic-skin like epidermal phenotypes when or steroid hormones, particularly glucocorticoids (Bel- grown on ®broblasts from psoriatic lesions (Saiag et man and Troll, 1972), can eciently interfere with al., 1985), providing evidence that the epidermal chemically-induced tumour formation in the mouse. alterations in psoriasis and dermato®broma are caused TPA-dependent transcriptional upregulation of MMP- by changes in the underlying dermal ®broblasts. The 3 and MMP-13 is similarly blocked by glucocorticoids critical interplay between ®broblasts and keratinocytes (Tuckermann et al., 1999). Induction of these genes is can also be exempli®ed in dermato®bromas where a abolished with similar eciency in wild-type and in signi®cant hyperplasia of the epidermis can be GRdim mice expressing a DNA-binding-defective observed overlying the benign ®broblastic tumour mutant version of GR, demonstrating that the DNA nodule. Thereby, the ®brotic cells stimulate the binding-dependent function of GR is fully dispensable epidermis in a fashion similar to that of embryonic for repression of AP-1 activity in vivo and that DNA- mesenchyme (Lever, 1983). binding-independent functions of the GR are respon- Enhanced DNA binding activity of AP-1 was sible for the antitumour promoting activity of observed in ®broblasts from recessive dystrophic glucocorticoids (Tuckermann et al., 1999). Similarly, epodermolysis bullosa patients, which may be respon- the repression function of the retinoic acid receptor, sible for elevated mRNA and protein levels of AP-1 but not the activation of retinoic acid responsive genes target genes, such as MMP-1 and MMP-3 (Unemoria is required for the antitumour promotion e€ect of et al., 1994). In ®broblasts of the tight skin (TSK) retinoic acid (Huang et al., 1997). Remarkable results mouse, representing a model of ®brosis characterized of a recent study suggest that the eciency of anti- by exaggerated accumulation in skin in¯ammatory agents and cancer chemoprevention may and visceral organs, increased levels of alpha 1(I) and also be ascribed to an impaired recruitment and/or alpha 1 (III) chain mRNA were found. This was function of in¯ammatory cells that supply the AP-1 explained by a loss of the negatively acting AP-1 target gene MMP-9. Analysis of the role of MMP-9 complex binding to the promoter of these genes during carcinogenesis in K14-HPV16 transgenic mice (Philips et al., 1995). The identi®cation of the speci®c and in mice lacking MMP-9 revealed that MMP-9 subunits of this complex, however, remains to be expressed by in¯ammatory cells is functionally determined. Similarly, the nature of the AP-1 subunits involved in the regulation of oncogene-induced exhibiting enhanced DNA binding to the collagenase keratinocyte hyperproliferation, progression to inva- promoter in ®broblasts derived from patients with sive cancer and end-stage malignant grade epithelial laxa (Hatamochi et al., 1996) is yet unknown. carcinomas (Coussens et al., 2000). Thus, tumour Enhanced mRNA and protein levels of c-Jun and c- development and progression are complex multi- Fos were found in keloids and hypertrophic cellular processes, in which normal cells, such as representing a model of altered wound healing in¯ammatory cells, or normal constituents of wound characterized by hyperproliferation of dermal ®bro- repair are conscripted to signi®cantly contribute to the blasts and accelerated production of components of the tumour phenotype (Boudreau and Bissell, 1998; extracellular matrix (Teofoli et al., 1999).

Oncogene AP-1 in skin biology P Angel et al 2421 Summary and outlook ization of AP-1 subunit-speci®c target genes and genetic programs within a given cell type at a certain AP-1 participates in key physiological and pathophy- di€erentiation state. The method of choice will be the siological processes due to its central role as a cellular use of comprehensive array and bioinformatic tools to switch of genetic programs in response to extracellular compare the gene expression patterns for example of signals. The distinct expression pattern of AP-1 keratinocytes located in the di€erent epidermal layers, subunits in the skin as well as the large number of cells from non-treated and UV-treated skin, or cancer AP-1 target genes in epidermal cells indicate that AP-1 cells of di€erent stages of tumour progression. The plays a pivotal role in normal and pathological skin major challenge, however, will be identi®cation of physiology. Even though the loss of single AP-1 those changes that are important, e.g. for cancer subunits in mice did not result in obvious skin development and progression. Clearly, the availability phenotypes, experiments with in vitro reconstituted of the broad spectrum of both in vivo and in vitro skin provided direct evidence for the orchestrated experimental approaches described above represents a antagonistic action of c-Jun and JunB to control powerful selection system to rapidly ®lter the enormous cytokine-regulated mesenchymal-epidermal interaction number of di€erentially expressed genes and to focus in normal skin. Moreover, the regulatory function of on the most promising tumour-associated genes. The AP-1 in wound healing, photoaging and tumorigenesis detailed analysis of known and newly identi®ed AP-1 is demonstrated by numerous studies in tissue culture target genes in such model systems o€ers the unique cells and mouse models. Taken together, AP-1 opportunity to con®rm the importance of these genes transactivation of target genes contributes to both as potential drug targets and will proved a molecular protective and pathological responses in individual cells basis by which alterations in AP-1 subunit composition or tissues, including the skin. and activity may act together in regulating key aspects The analysis of transgenic mouse models and of in of normal or pathological phenotype development and vitro tissue engineered skin equivalent models using maintenance. genetically altered AP-1 subunit-de®cient cell types will be the focus of future studies. As more data will be generated, our current knowledge on the individual functional involvement of AP-1 subunits in skin homeostasis, wound healing and skin carcinogenesis Acknowledgments will be enhanced. We thank Erwin F Wagner for proof-reading of the manuscript. Our laboratory is supported by grants from The design of novel therapeutic strategies and the Deutsche Forschungsgemeinschaft, by the Cooperation potential clinical applications for skin diseases and Program in Cancer Research of the DKFZ and Israeli's cancer will depend on the scienti®c progress made in Ministry of Science, and by the BioMed-2 and Training de®ning cell-type and stimulus-speci®c activation and Mobility of Researchers (TNR) Programs of the modes of individual AP-1 subunits, on the character- European Community.

References

Angel P and Karin M. (1991). Biochim. Biophys. Acta., 1072, Boudreau N and Bissell MJ. (1998). Curr. Opin. Cell Biol., 129 ± 157. 10, 640 ± 646. Antinore MJ, Birrer MJ, Patel D, Nader L and McCance DJ. Bowden GT, Schneider B, Domann R and Kulesz-Martin M. (1996). EMBO J., 15, 1950 ± 1960. (1994). Cancer Res., 54, 1882s ± 1885s. Arbeit JM, Munger K, Howley PM and Hanahan D. (1994). Brauchle M, Fassler R and Werner S. (1995). J. Invest. J. Virol., 68, 4358 ± 4368. Dermatol., 105, 579 ± 584. Ariizumi K, Bergstresser PR and Takashima A. (1996). Brown K and Balmain A. (1995). Cancer Metastasis Rev., 14, J. Dermatol. Sci., 12, 147 ± 155. 113 ± 124. Barthelman M, Chen W, Gensler HL, Huang C, Dong Z and Bullard KM, Lund L, Mudgett JS, Mellin TN, Hunt TK, Bowden GT. (1998). Cancer Res., 58, 711 ± 716. Murphy B, Ronan J, Werb Z and Banda MJ. (1999). Ann. Behrens A, Jochum W, Sibilia M and Wagner EF. (2000). Surg., 230, 260 ± 265. Oncogene, 19, 2657 ± 2663. Cao X, Ross FP, Zhang L, MacDonald PN, Chappel J and Bell E, Ehrlich HP, Buttle DJ and Nakatsuji T. (1981). Teitelbaum SL. (1993). Biol. Chem., 268, 27371 ± 27380. Science, 211, 1052 ± 1054. Carrasco D and Bravo R. (1995). Oncogene, 10, 1069 ± 1079. Belman S and Troll W. (1972). Cancer Res., 32, 450 ± 454. Choi Y and Fuchs E. (1990). Cell Regul., 1, 791 ± 809. Benbow U and Brinckerho€ CE. (1997). Matrix Biol., 15, Chung KY, Agarwal A, Uitto J and Mauviel A. (1996). J. 519 ± 526. Biol. Chem., 271, 3272 ± 3278. Bernerd F and Asselineau D. (1998). Cell Death Di€er., 5, Corbi AL, Jensen UB and Watt FM. (2000). FEBS Lett., 474, 792 ± 802. 201 ± 207. Borden P and Heller RA. (1997). Crit.Rev.Eukaryot.Gene Coussens LM, Tinkle CL, Hanahan D and Werb Z. (2000). Expr., 7, 159 ± 178. Cell, 103, 481 ± 490. Bossy-Wetzel E, Bravo R and Hanahan D. (1992). Genes Dev., 6, 2340 ± 2351.

Oncogene AP-1 in skin biology P Angel et al 2422 Cripe TP, Alderborn A, Anderson RD, Parkkinen S, Lohman FP, Gibbs S, Fischer DF, Borgstein AM, van de Bergman P, Haugen TH, Pettersson U and Turek LP. Putte P and Backendorf C. (1997). Oncogene, 14, 1623 ± (1990). New Biol., 2, 450 ± 463. 1627. Di Sepio D, Bickenbach JR, Longley MA, Bundman DS, Lopez-Bayghen E, Vega A, Cadena A, Granados SE, Jave Rothnagel JA and Roop DR. (1999). Di€erentiation, 64, LF, Gariglio P and Alvarez-Salas LM. (1996). J. Biol. 225 ± 235. Chem., 271, 512 ± 520. Domann Jr FE, Levy JP, Finch JS and Bowden GT. (1994). Lu B, Rothnagel JA, Longley MA, Tsai SY and Roop DR. Mol. Carcinog., 9, 61 ± 66. (1994). J. Biol. Chem., 269, 7443 ± 7449. Dong Z, Birrer MJ, Watts RG, Matrisian LM and Colburn Lund LR, Romer J, Bugge TH, Nielsen BS, Frandsen TL, NH. (1994). Proc. Natl. Acad. Sci. USA, 91, 609 ± 613. Degen JL, Stephens RW and Dano K. (1999). EMBO J., Dong Z, Crawford HC, Lavrosky V, Taub D, Watts R, 18, 4645 ± 4656. Matrisian LM and Colburn NH. (1997). Mol. Carcinog., Madlener M, Parks WC and Werner S. (1998). Exp. Cell 19, 204 ± 212. Res., 242, 201 ± 210. Eckert RL and Welter JF. (1996). Mol. Biol. Rep., 23, 59 ± 70. Martin P. (1997). Science, 276, 75 ± 81. E®mova T, LaCelle P, Welter JF and Eckert RL. (1998). Masuda ES, Tokumitsu H, Tsuboi A, Shlomai J, Hung P, J. Biol. Chem., 273, 24387 ± 24395. Arai K and Arai N. (1993). Mol. Cell. Biol., 13, 7399 ± Felts SJ, Sto¯et ES, Eggers CT and Getz MJ. (1995). 7407. Biochemistry, 34, 12355 ± 12362. Matsui T. (1996). Biochem. Biophys. Res. Commun., 220, Finch PW, Lengel C and Chedid M. (1995). J. Biol. Chem., 405 ± 410. 270, 11230 ± 11237. MauvielA,KorangK,SantraM,TewariD,UittoJand Fischer DF, Sark MW, Lehtola MM, Gibbs S, van de Putte P Iozzo RV. (1996), Biol. Chem., 271, 24824 ± 24829. and Backendorf C. (1999). Genomics, 55, 88 ± 99. Mettouchi A, Cabon F, Montreau N, Dejong V, Vernier P, Fisher GJ, Talwar HS, Lin J and Voorhees JJ. (1999). Gherzi R, Mercier G and Binetruy B. (1997). Mol. Cell Photochem. Photobiol., 69, 154 ± 157. Biol., 17, 3202 ± 3209. Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S and Monzon RI, LaPres JJ and Hudson LG. (1996). Cell Growth Voorhees JJ. (1997). Engl. J. Med., 337, 1419 ± 1428. Di€er., 7, 1751 ± 1759. Frank S, Madlener M and Werner S. (1996). J. Biol. Chem., Muegge K, Williams TM, Kant J, Karin M, Chiu R, Schmidt 271, 10188 ± 10193. A, Siebenlist U, Young HA and Durum SK. (1989). Fusenig NE. (1994). In: The Keratinocyte Handbook, Leigh, Science, 246, 249 ± 251. B Lane and F Watt, eds. (Cambridge: Cambridge Munz B, Smola H, Engelhardt F, Bleuel K, Brauchle M, Lein University Press), pp. 71 ± 94. I, Evans LW, Huylebroeck D, Balling R and Werner S. Gandarillas A and Watt FM. (1995). Oncogene, 11, 1403 ± (1999). EMBO J., 18, 5205 ± 5215. 1407. Navarro JM, Casatorres J and Jorcano JL. (1995). J. Biol. Gillardon F, Eschenfelder C, Uhlmann E, Hartschuh W and Chem., 270, 21362 ± 21367. Zimmermann M. (1994). Oncogene, 9, 3219 ± 3225. Nead MA, Baglia LA, Antinore MJ, Ludlow JW and Greenhalgh DA, Rothnagel JA, Wang XJ, Quintanilla MI, McCance DJ. (1998). EMBO J., 17, 2342 ± 2352. Orengo CC, Gagne TA, Bundman DS, Longley MA, Ng DC, Shafaee S, Lee D and Bikle DD. (2000). J. Biol. Fisher C and Roop DR. (1993). Oncogene, 8, 2145 ± 2157. Chem., 275, 24080 ± 24088. Greenhalgh DA and Yuspa SH. (1988). Mol. Carcinog., 1, NishidaK,KitazawaR,MizunoK,MaedaSandKitazawa 134 ± 143. S. (1997). Biochem. Biophys. Res. Commun., 241, 258 ± Hanahan D and Weinberg RA. (2000). Cell, 100, 57 ± 70. 263. Hatamochi A, Arakawa M, Mori K, Mori Y, Ueki H and Olsen J, Lefebvre O, Fritsch C, Troelsen JT, Orian-Rousseau Yoshioka H. (1996). Dermatol. Sci., 11, 97 ± 103. V, Kedinger M and Simon-Assmann P. (2000). Biochem. Hu L and Gudas LJ. (1994). J. Biol. Chem., 269, 183 ± 191. J., 347, 407 ± 417. HuangC,LiJ,ChenN,MaW,BowdenGTandDongZ. Philips N, Bashey RI and Jimenez SA. (1995). J. Biol. Chem., (2000). Mol. Carcinog., 27, 65 ± 75. 270, 9313 ± 9321. Huang C, Ma WY, Dawson MI, Rincon M, Flavell RA and Prott J, Crabtree G, Grove M, Daubersies P, Bailleul B, Dong Z. (1997). Proc. Natl. Acad. Sci. USA, 94, 5826 ± Wright E and Plumb M. (1995). Gene., 152, 173 ± 179. 5830. Radoja N, Komine M, Jho SH, Blumenberg M and Tomic- Jaakkola P, Maatta A and Jalkanen M. (1998). Oncogene, Canic M, (2000). Mol. Cell Biol., 20, 4328 ± 4339. 17, 1279 ± 1286. Ramaswamy NT, Ronai Z and Pelling JC. (1998). Oncogene, Jang SI, Steinert PM and Markova NG. (1996). J. Biol. 16, 1501 ± 1505. Chem., 271, 24105 ± 24114. Rhodes K and Oshima RG. (1998). J. Biol. Chem., 273, Joselo€ E and Bowden GT. (1997). Mol. Carcinog., 18, 26 ± 26534 ± 26542. 36. Roebuck KA. (1999). J. Interferon Cytokine Res., 19, 429 ± Kahari VM and Saarialho-Kere U. (1997). Exp. Dermatol., 438. 6, 199 ± 213. Rubin JS, Osada H, Finch PW, Taylor WG, Rudiko€ S and Karin M, Liu Z and Zandi E. (1997). Curr. Opin. Cell Biol., 9, Aaronson SA. (1989). Proc.Natl.Acad.Sci.USA,86, 240 ± 246. 802 ± 806. Konicek BW, Xia X, Rajavashisth T and Harrington MA. Rutberg SE, Goldstein IM, Yang YM, Stackpole CW and (1998). DNA Cell Biol., 17, 799 ± 809. Ronai Z. (1994). Mol. Carcinog., 10, 82 ± 87. Kramer B, Wiegmann K and Kronke M. (1995). J. Biol. Rutberg SE, Saez E, Glick A, Dlugosz AA, Spiegelman BM Chem., 270, 6577 ± 6583. and Yuspa SH. (1996). Oncogene, 13, 167 ± 176. Lever WF. (1983). In: Histopathology of the skin, 6th edition, Rutberg SE, Saez E, Lo S, Jang SI, Markova N, Spiegelman Lever WF and Schaumberger-Lever G (eds). (Philadel- BM and Yuspa SH. (1997). Oncogene, 15, 1337 ± 1346. phia: JB Lippincott), pp 139 ± 622.

Oncogene AP-1 in skin biology P Angel et al 2423 Saez E, Rutberg SE, Mueller E, Oppenheim H, Smoluk J, Thomas RS, Tymms MJ, McKinlay LH, Shannon MF, Seth Yuspa SH and Spiegelman BM. (1995). Cell, 82, 721 ± 732. A and Kola I. (1997). Oncogene, 14, 2845 ± 2855. Saiag P, Coulomb B, Lebreton C, Bell E and Dubertret L. Tuckermann JP, Reichardt HM, Arribas R, Richter KH, (1985). Science, 230, 669 ± 672. Schutz G and Angel P. (1999). J. Cell. Biol., 147, 1365 ± Saito H, Kouhara H, Kasayama S, Kishimoto T and Sato B. 1370. (1992). Biochem. Biophys. Res. Commun., 183, 688 ± 693. Unemoria EN, Mauch C, Hoe‚er W, Kim Y, Amento EP SarkMW,FischerDF,deMeijerE,vandePuttePand and Bauer EA. (1994). Exp. Cell. Res., 211, 212 ± 218. Backendorf C. (1998). J. Biol. Chem., 273, 24683 ± 24692. Virolle T, Monthouel MN, Djabari Z, Ortonne JP, Sato H, Suzuki JS, Tanaka M, Ogiso M, Tohyama C and Meneguzzi G and Aberdam D. (1998). J. Biol. Chem., Kobayashi S. (1997). Photochem. Photobiol., 65, 908 ± 914. 273, 17318 ± 17325. SchroÈ der JM. (1995). J. Invest. Dermatol., 105, 20S ± 24S. Vu TH and Werb Z. (2000). Genes Dev., 14, 2123 ± 2133. Schuh AC, Keating SJ, Monteclaro FS, Vogt PK and Wang CY, Bassuk AG, Boise LH, Thompson CB, Bravo R Breitman ML. (1990). Nature, 346, 756 ± 760. and Leiden JM. (1994). Mol. Cell. Biol., 14, 1153 ± 1159. Shalaby F, Schuh AC and Breitman ML. (1994). Oncogene, WattsRG,Ben-AriET,BernsteinLR,BirrerMJ,Winter- 9, 2579 ± 2588. stein D, Wendel E and Colburn NH. (1995). Mo. Shino Y, Shirasawa H, Kinoshita T and Simizu B. (1997). Carcinog., 13, 27 ± 36. J. Virol., 71, 4310 ± 4318. Watts RG, Huang C, Young MR, Li JJ, Dong Z, Pennie WD Sibilia M, Fleischmann A, Behrens A, Stingl L, Carroll J, and Colburn NH. (1998). Oncogene, 17, 3493 ± 3498. Watt FM, Schlessinger J and Wagner EF. (2000). Cell, Welter JF, Crish JF, Agarwal C and Eckert RL. (1995). 102, 211 ± 220. J. Biol. Chem., 270, 12614 ± 12622. Singer AJ and Clark RA. (1999). N. Engl. J. Med., 341, 738 ± Welter JF and Eckert RL. (1995). Oncogene, 11, 2681 ± 2687. 746. Werner S, Peters KG, Longaker MT, Fuller-Pace F, Banda Sinha S, Degenstein L, Copenhaver C and Fuchs E. (2000). MJ and Williams LT. (1992). Proc. Natl. Acad. Sci. USA, Mol. Cell. Biol., 20, 2543 ± 2555. 89, 6896 ± 6900. Smith Jr MF, Eidlen D, Brewer MT, Eisenberg SP, Arend Wilkinson DG, Bhatt S, Ryseck RP and Bravo R. (1989). WP and Gutierrez-Hartmann A. (1992). J. Immunol., 149, Development, 106, 465 ± 471. 2000 ± 2007. Xing Z, Gauldie J, Tremblay GM, Hewlett BR and Addison SmolaH,StarkHJ,ThiekotterG,MiranceaN,KriegTand C. (1997). Lab. Invest., 77, 615 ± 622. Fusenig NE. (1998). Exp. Cell. Res., 239, 399 ± 410. Ye J, Zhang X and Dong Z. (1996). Mol. Cell. Biol., 16, 157 ± Soriani M, Hejmadi V and Tyrrell RM. (2000). Photochem. 167. Photobiol., 71, 551 ± 558. Young MR, Li JJ, Rincon M, Flavell RA, Sathyanarayana Sosnowski RG, Feldman S and Feramisco JR. (1993). BK, Hunziker R and Colburn N. (1999). Proc. Natl. Acad. J. Cell. Biol., 121, 113 ± 119. Sci. USA, 96, 9827 ± 9832. Soto U, Das BC, Lengert M, Finzer P, zur Hausen H and Yuspa SH. (1998). J. Dermatol. Sci., 17, 1±7. Rosl F. (1999). Oncogene, 18, 3187 ± 3198. Zagariya A, Mungre S, Lovis R, Birrer M, Ness S, Stefanidou MP, Ionnidou DJ, Panayiotides JG and Tosca Thimmapaya B and Pope R. (1998). Mol. Cell. Biol., 18, AD. (1999). Br. J. Dermatol., 141, 1040 ± 1045. 2815 ± 2824. Szabowski A, Maas-Szabowski N, Andrecht S, Kolbus A, Zhao W, Chow LT and Broker TR. (1997). J. Virol., 71, Schorpp-Kistner M, Fusenig NE and Angel P. (2000). 8832 ± 8840. Cell, 103, 745 ± 755. Ziober BL and Kramer RH. (1996). J. Biol. Chem., 271, Takahashi H, Asano K, Manabe A, Kinouchi M, Ishida- 22915 ± 22922. Yamamoto A and Iizuka H. (1998). J. Invest. Dermatol., Zoumpourlis V, Papassava P, Linardopoulos S, Gillespie D, 110, 218 ± 223. Balmain A and Pintzas A. (2000). Oncogene, 19, 4011 ± Teofoli P, Bardaugni S, Ribu€o M, Campanella A, De Pita O 4021. and Puddu P. (1999). J. Dermatol. Sci., 22, 31 ± 37. Zutter MM, Santoro SA, Painter AS, Tsung YL and Ga€ord Thierry F, Spyrou G, Yaniv M and Howley P. (1992). A. (1994). J. Biol. Chem., 269, 463 ± 469. J. Virol., 66, 3740 ± 3748.

Oncogene