Keratinocyte differentiation and activation 
Review paper 
KERATINOCYTE 
DIFFERENTIATION AND ACTIVATION 
Miroslav Blumenberg 
SUMMARY 
To understand properly the various phenotypes associated with hereditary disorders due to abnormal 
keratinization, we need to understand the physiology of keratinocytes and the role of the proteins that 
keratinocytes synthesize to perform their function. There are two physiologic pathways open to keratinocytes, 
differentiation and activation, each with characteristic function and battery of proteins produced. The 
biologically active substances can be far didactic purposes categorized into four groups: signaling molecules, 
receptors, transducing molecules and transcription factors. 
KEY WORDS 
keratinocyte, differentiation, activation, signaling molecules, receptors, transducing molecules, transcription 
factors 
To understand properly the various phenotypes 
associated with hereditary disorders due to abnormal 
keratinization, we need to understand the physiology 
of keratinocytes and the roles of the proteins that 
keratinocytes synthesize to perform their function. 
There are two physiologic pathways open to kera-
tinocytes, differentiation and activation, each with 
characteristic function and battery of proteins pro-
duced. 
Keratinocyte differentiation is associated with changes 
in gene expression, specifically of keratin genes, 
keratins being the most abundant epidermal proteins. 
The epidermis is composed of ten to twenty layers 
of keratinocytes, the predominant celi type of this 
tissue. During normal epidermal differentiation, four 
types of keratinocytes can be distinguished through 
acta de1matovenerologica A.P A. Vol 6, 97, No 4 
their phenotypic and biochemical properties: basal, 
spinous, granular, and cornified [1][2]. Basal cells 
are characterized by their contact with the basement 
membrane, mitotic activity, and the expression of 
keratins K5 and K14 [3). In response to unknown 
stimuli, the basal keratinocytes are triggered to 
differentiate terminally. They detach from the basement 
membrane, stop dividing, become spinous, and initiate 
their migration and maturation through the suprabasal 
layers. Concomitantly, they start to express the earliest 
markers of terminal differentiation, keratins Kl and 
KlO, which are fully expressed only in the spinous 
and granular layers [4] [5][6). In the granular layers, 
filaggrin and precursors of the cornified envelopes 
such, as loricrin and involucrin, as well as epidermal 
transgulatminase are expressed [7][8][9][10). The fina! 
127 
Keratinocyte diff erentiation and activation 
stages of the process of differentiation occur after 
the dissolution of nuclei and organelles and the 
formation of cornified envelopes that are assembled 
into a metabolically inert stratum corneum. 
The role of epidermal keratinocytes in defense 
from mechanical injury and desiccation bas been 
appreciated for a long tirne, but their role in 
immunological defense became apparent only recently, 
when it was realized that keratinocytes can produce 
a cornucopia of growth factors, chemoattractants and 
cytokines [l 1][12][13]. Furthermore, keratinocytes 
express receptors for many polypeptide factors, respond 
to autocrine stimulation, and also respond to the 
signals produced by the immune system. In response 
to epidermal injury, keratinocytes become "activated": 
they produce and respond to growth factors and 
cytokines, become migratory and can produce compo-
nents of the basement membrane. Activated keratino-
cytes express a specific pair of keratin proteins, 
distinct from the keratins in the healthy epidermis. 
In healthy epidermis, basal keratinocytes express K5 
and Kl4, whereas suprabasal, differentiating keratino-
cytes express Kl and KlO. However, in suprabasal 
keratinocytes of the activated epidermis, the expression 
of Kl and KlO is suppressed and replaced by K6 
and K16. Thus, expression of K6 and K16 marks 
keratinocyte activation [14][15, 16]. In certain infla-
mmatory processes, especially those characterized by 
Table l. The list of most 
biologically active molecules 
molecular biology. 
frequently mentioned abbreviations. An attempt has been made to categorize the 
in order to facilitate the understanding of the text f or the readers les s f amiliar with 
IFNa, IFN~, IFNy 
EGF 
TNFa 
IL-1 to IL-12 
JAK 
STAT (1-6) 
Rafl 
ERK 
MEK 
TRADD 
TRAF2 
APl 
C/EBP~ 
Elkl 
NFKB 
SAPl 
interferons 
epidermal growth factor 
tumor necrosis factor a 
interleukins 
Janus activated kinase, transduces IFN signals 
signal transducing activator of transcription (responsive to IFNs inter alia) 
Ras activated factor 1 
extracellular signal responsive kinase (responds to EGF inter alia) 
mitogen activated ERK kinase (activates ERK) 
TNFR associated death domain (involved in apoptosis) 
TNFR associated factor 2 (activates transcription) 
Especially relevant review articles are references [19), [23) and [40). 
128 acta dennatovenerologica A.P.A. Vol 6, 97, No 4 
Keratinocyte differentiation and activation 
the infiltration of Th-1 type lymphocytes, such as 
psoriasis, the Kl 7 keratin is also present [17]. 
The extracellular signals that induce keratinocytes 
to start differentiating or to become activated are at 
present the subject of intensive investigation. One of 
the initial signals for activation of keratinocytes may 
be the release of pre-stored IL-1. Once activated, 
keratinocytes synthesize additional signaling growth 
factors and cytokines. Severa! extracellular markers 
are specifically expressed by the activated keratinocytes. 
The various signaling molecules may be synergistic 
or antagonistic with each other. This allows the 
activated phenotype to be specifically modified, which 
can lead to different activated phenotypes. (Table 1). 
Signals from the extracellular environment initiate 
enzymatic cascades which lead to the activation of 
transcription factors. Activated transcription factors 
then regulate gene expression by diverse mechanisms 
that include binding to specific DNA sequences and 
interaction with other transcription factors or nuclear 
receptors. They can also induce expression of additional 
regulatory factors as well as of the differentiation or 
activation markers. Three such pathways, IFNy, the 
EGF family and TNFcx/IL-1, are known to be 
important in keratinocyte activation and we have 
shown that they regulate expression of keratin genes. 
The most extensively studied signaling molecules 
of the immune system are the interferons, IFNcx, 
IFN~, and IFNy, a subset of cytokines originally 
described as factors that protect cells from vira! 
infections [18] [19]. IFN cx and IFN~ share a cell 
surface receptor, whereas IFNy binds to a different 
receptor and has distinct effects. Certain diseases, 
such as psoriasis, are associated with high levels of 
IFNy in epidermis [20]. Although the role of interferons 
in pathologic processes has not been clearly defined, 
they have been used in therapeutic trials for severa! 
dermatologic diseases [21]. 
Activation of IFN receptors initiates a cascade of 
protein phosphorylation events [18][19]. The receptors 
internet with JAK kinases, which phosphorylate 
tyrosines both on the receptors, and on the STAT 
(for Signal Transducing Activator of Transcription) 
family of transcription factors (Fig. 1). The phospho-
rylation of STATs causes their activation and 
translocation to the nucleus, where ST ATs bind to 
specific DNA sites and activate transcription of 
nearby genes. The regulatory specificity of the cytokine 
signals at the cell surface is mirrored in the nucleus 
by the activity of specific members of the STAT 
family: IFNy leads to activation of STATl, IFNcx of 
STATI and 3, IL-6 and OsM of STAT3, IL-12 of 
acta dennatovenerologica A.P.A. Vol 6, 97, No 4 
STAT3 and 4, IL-3, IL-5 and GMCSF of STAT5, 
while IL-4 of STAT6 [19]. 
Among the most extensively studied cellular receptor 
signaling pathways are those involving epidermal 
growth factor, EGF, and its receptor EGFR [22][23]. 
A simplified scheme of the cascade is shown in Fig. 
2. Severa! ligands can bind to and activate EGFR 
including TGFcx, amphiregulin, HB-EGF and herre-
gulin. The binding of the ligand causes receptor 
dimerization with concomitant activation of its intra-
cellular protein tyrosine kinase. A substrate for this 
kinase is the receptor itself, the two monomers 
phosphorylate each other. The phosphotyrosines serve 
as docking sites for SH2 domain containing proteins 
(such as Grb2 or SHC) that internet with proteins 
capable of activating Ras. Severa! growth factor 
receptors, via different adaptor molecules activate 
Ras, which makes Ras a fulcrum for signal transduction 
pathways (see Fig. 2). Activated Ras, in turn, activates 
a cascade of three protein kinases, Rafl, MEK and 
ACTIVATION OF STATs 
OsM IFNY 
p130 RECEPTOR 
Figure l. Activation of the JAK-STAT pathway. Binding 
oj the ligand to the receptor causes its association 
with the JAK/TYK kinases, which, in tum phosporylate 
STATs. STATs, when phosphorylated, dimerize and 
translocate to the nucleus where they activate trans-
cription. 
129 
Keratinocyte differentiation and activation 
Erk. The last one, Erk, translocates to the nucleus 
where it phosphorylates, and thus activates transcription 
factors such as Elkland SAPl. 
Successive activation of a cascade of three protein 
kinases is a recurrent motif in signal transduction. 
Stress, exemplified by osmotic shock and UV irra-
diation, or proinflammatory cytokines, exemplified 
by TNFa and IL-1, can activate two parallel cascades 
(see below), thus activating partially overlapping sets 
of transcription factors (Fig. 2). Specifically, UV 
irradiation primarily activates JNK, which results in 
activation of Jun and ATF2, whereas osmotic shock 
activates p38 and consequently ATF2 and Max. 
There can be significant crosstalk among the cascades. 
For example UV can activate the p38 pathway and 
in certain cell types, EGF can activate JNK. All 
three cascades are present and functional in kera-
tinocytes. 
TNFa has been discovered from two independent 
lines of research, first as an inducer of necrosis in 
some tumor cells and second as a cause of cachexia 
in septic animals. Subsequently it has been established 
that TNFa is one of the proinflammatory cytokines 
that induce many inflammatory effects, such as fever 
and shock. In response to infection or injury a wide 
variety of cells produce TNFa, primarily macrophages 
and monocytes but also epithelial cells including 
keratinocytes [24]. 
A low level of TNFa is present in the upper 
layers of the healthy epidermis, but its synthesis and 
release from keratinocytes are greatly augmented 
under a variety of conditions, such as allergic and 
MAP CASCADES 
cell 
membrane 
nuclear 
membrane 
GROWTH 
FACTORS 
RECEPTOR 
MAPKKK 
MAPKK 
MAPK 
Raf1 
-1-
MEK 
-1-
ERK 
SAP1 Elk1 
uv STRESS 
MEKK1 ?? 
-1- -1-
MKK1 MKK3, 6 
-1- -1-
JNK1, 2, 3 RK/p38 
/J_ 
cJun ATF2 Max 
Figure 2. The MAPK signal transduction cascades. Growth factors, such as EGF, bind to their receptor activating 
Ras. Ras activates Rafl, which is a MAPKKK Rafl activates MEKs, which activate ERKs. When activated, 
ERKs translocate to the nucleus, where they phosphorylate and thus activate transcription factors, such as SAPI 
and Elkl. Stress, such as heat, UV, or TNFa and IL-1, activate their own sets of MAPKKKs. These, in turn 
activate specific MAPKKs, which activate JNKs and p38. The last two MAPKs (presumably in the nucleus) 
phosphorylate and thus activate transcription factors shown on the bottom. White there is crosstalk at the top 
and the bottom of the cascades, the phosphorylation by MAPKKs and MAPKs is quite specific. Most of the 
initial events that sense stress signals have not been elucidated so far. 
130 acta dennatovenerologica A.P.A. Vol 6, 97, No 4 
Keratinocyte differentiation and activation 
irritant contact dermatitis, infection, and UV irradiation 
[11]. In these pathological conditions TNFa activates 
immune responses by inducing production of additional 
signaling molecules, cytokines, growth factors, their 
receptors and adhesion proteins [25]. 
The signal transduction pathway triggered by TNFa 
appears to be much more complicated than the 
EGF-triggered one [26][27]. A currently known version 
of the cascade is shown in Fig. 3. There are two 
TNFa receptors, but keratinocytes express mainly 
the Type 1 receptor (55kd). There are three major 
intracellular effects of TNFa. One is the induction 
of apoptosis (Box 1 in Fig. 3). The second involves 
production of ceramides, which in turn act as second 
messengers activating arachidonic acid synthesis and 
regulating downstream effects (Box 2 in Fig. 3). The 
third signaling pathway involves proteins TRADD 
and TRAF2, which activate transcription factors 
NFKB and C/EBP~ (Box 3 in Fig. 3). 
Environmental signals, such as growth factors and 
cytokines, modulate the activity of nuclear transcription 
factors, thus regulating gene expression. Modulated 
transcription factors fall into well characterized classes. 
The best studied of these are the STAT proteins, the 
APl family and the NFKB family. First discovered 
as mediators of interferon signaling, STATs are 
unusual because they can convey the signal directly 
from the plasma membrane into the nucleus without 
second messengers or cytoplasmic kinase cascade 
intermediates. STATs range in size from 80 to 110 
kD [19]. STAT proteins are cytoplasmic in their 
ground state, but upon activation of appropriate 
THE SIGNAL TRANSDUCTION PATHWAYS 
IL-1 
celi \ 
membrane 
(1) 
APOPTOSIS 
nuclear 
membrane 
TNFU TNFU 
OVEREXPRESSION 
CAUSES 
HYPERKERA TOSIS 
✓ 
(2) 
Figure 3. The TNFa signal transduction pathways. There are two receptors, although only the p55 seems to be 
expressed in keratinocytes. There are three principal signal transduction pathways: (1) the apoptosis pathway, (2) 
the ceramide pathway and (3) the TRAF2 pathway. The apoptosis pathway proceeds through "death domain" 
containing proteins TRAD and FADD. Through TRAK, and independently through PKC the other two MAPK 
pathways can get activated as well. Mechanisms by which INK and NFkB are activated have not been fully 
characterized. Interestingly, the effects of IL-1 partially overlap those of TNF a. 
acta dennatovenerologica A.P.A. Vol 6, 97, No 4 131 
Keratinocyte differentiation and activation 
receptors, STATs become phosphorylated and, through 
their SH2 domains, dimerize and translocate into 
the nucleus. In the nucleus STATs bind to specific 
DNA recognition elements and activate transcription 
of nearby genes. 
Perhaps the most widely studied regulated trans-
cription factors are those belonging to the AP-1 
family. AP-1 is a nuclear transcription complex 
composed of dimers encoded by the fos and jun 
families of proto-oncogenes [28]. Whereas Fos proteins 
only heterodimerize with members of the Jun family, 
Jun proteins may homo- or heterodimerize with 
both Fos and other Jun proteins. The AP-1 activity 
is induced by growth factors such as serum, EGF, 
and TGFa, by cytokines such as IL-1 and TNFa, as 
well as tumor promoters such as TP A and UV light 
[28][29]. 
In the epidermis, AP-1 regulates cell growth, 
differentiation and transformation [30][31][32][33]. 
However, the expression of individual APl proteins 
A 
733bp ! t k K#1 
2,2, utt zs It K#3 
832 ZJS ! I K#S 
381 K#6 
395 t ~ sia:: K#7 
1115 t s I s K#S 
1676 ! ! l m: K#10 
TFIID AP-1 AP-2 CTF NF-1 Sp1 335 !iz tt sH K#14 
T X .6 i t s z., 163 .1.I,_ K#15 
t t gr t K#16 510 l&S 'h zs 
1180~ ! s ~~ s K#17 2sJ. zs 1? zs K#18 
390 ll zs sr K#19 
K #5 
~ @~ K#161):eisiiCI 2so6p ~
0S0?f?~ K #17 1c===~t~G;;.i:;;''J~~~:::;~::~:::J-~;;:ciu:;;:'.::r:=========i 
K #14 1 1sobp 
Figure 4. (A) Computer analysis of transcription 
factor binding sites in the sequences of the promoters 
of keratin genes. (B) Gel shift analysis results showing 
clusters of transcription factor binding sites in keratin 
gene promoters. 
132 
in epidermal layers is a controversial issue that 
awaits resolution. Certain authors find c-Fos in 
lower layers of the epidermis [34][30][35] while 
others do not find any cFos [33] , which agrees with 
the Jack of an epidermal phenotype in fos knockout 
mice [32]. The differing results could be explained 
by varied different epitopes of the antibodies used, 
or functional redundancy of Fos family members. Be 
that as it may, it is clear that the AP-1 proteins in 
keratinocytes can regulate the expression of differen-
tiation markers [36][37][38] and may convey the 
calcium- and PKC-dependent signals [35][33]. Functi-
onal AP-1 sites have been found in many keratin 
genes (see below), including in the first intron of the 
human and murine K18 and in the KS gene [39]. 
The NFKB family includes proteins p65, p50 and 
c/rel, which both homo- and heterodimerize amongst 
themselves [ 40] . Activation of these proteins is not 
dependent upon new protein synthesis, rather, they 
are stored in the cytoplasm bound to the inhibitory 
protein, 1-KB. Inflammatory processes that induce 1-
KB phosphorylation and degradation result in the 
nuclear translocation and activation of the NFKB 
complex. Signaling by EGF, TNFa and IL-1 results 
in NFKB activation. 
Severa! transcriptional factors were found to be 
specific for epidermal keratinocytes. Among these is 
Basonuclin, an unusual transcription factor that contains 
many pairs of Zn fingers and a serine stripe running 
down its alpha-helical segment [41]. Importantly, 
this protein is found exclusively in the nuclei of the 
basal and the first suprabasal layer of epidermal 
keratinocytes and it is possible that it plays a role 
in specifying basal layer specific transcription. Sknl 
and Skn2 are also specifically found in skin. They 
are functionally distinct and belong to a family of 
transcription factors that specify differentiation pathways 
of various cell types. It is not yet known whether 
Sknl and Skn2 play a similar role in epidermal 
differentiation. 
AP2 binding sites have been found in most keratin 
gene promoters analyzed. Although not the sole 
determinant of epithelia-specific expression [ 42] they 
are essential for appropriate transcription of many 
keratin genes [43]. The promoters of KS, K6, K14, 
K16 and Kl 7 keratin genes contain functional AP2 
sites. One of the first transcription factors to be 
purified and cloned [44], Spl also belongs to a gene 
family. Different members of the Spl family can 
exert opposite regulation of target promoters. Inte-
restingly, the differentiation-specific keratin genes do 
not have Spl sites in their promoters, whereas the 
acta dennatovenerologica A .P.A. Vol 6, 97, No 4 
Keratinocyte differentiation and activation 
basal and activation-specific ones do. Spl interacts 
with other transcription factors, such as NFl and 
Ets, which often have adjacent or overlapping binding 
sites in DNA Spl protein has several trans-activation 
domains and can multimerize while bound to distant 
sites on DNA, looping out sequences between the 
Spl sites and bringing additional factors into proximity 
of each other [45, 46]. This, process seems important 
for expression of keratin genes [ 47]. Several NFl 
binding sites have been found using computer analysis 
of available keratin gene promoter sequences [ 48]. It 
is important to note however that the NFl transcription 
factor interacts with members of the STAT trans-
cription factor family [ 49] and thus may be important 
for the interferon-dependent induction of Kl 7 keratin 
expression. 
Regulation of keratin gene expression occurs 
predominantly, if not exclusively at the level of 
transcription initiation [6]. As expected, most of the 
important sites for regulation are found in the 
upstream region although in several instances introns 
and even the downstream sequences contain regulatory 
elements. 
The first cell type specific element in keratin 
genes was described by Blessing et al. [50] for the 
bovine K6 gene. Within a 650 bp sequence upstream 
from the gene exists an enhancer functional in 
proliferating cells of stratified epithelial origin, but 
nonfunctional in simple epithelial cells. This enhancer 
may be specific for either stratified or hyperproliferating 
cells, or both. It can confer enhancement of trans-
cription to other promoters including those for Kl 
and KlO keratins, which are expressed only in 
differentiating cells and thus are not expressed without 
the K6 gene enhancer in cells in culture. 
The upstream sequences for the following human 
keratin genes are known: Kl, K3, KS, K6, K7, KS, 
KlO, K14, K16, K17, KIS, K19 and a hair keratin 
(Fig. 4). Work from our laboratory and several 
others has characterized many of the transcription 
factors and DNA sites that play important roles in 
regulation of keratin gene expression. All promoters 
have a canonical TATA box, or a variant of it. 
Thus, the transcription factor TFIID, which binds 
the TATA box, is essential for the transcription 
initiation of keratin genes. This is apparently the 
only transcription factor common to all keratin 
genes. In addition to the TATA box, keratin promoters 
contain several consensus sequences recognized by 
other transcriptional factors. The CAA T box is 
present in Kl, K6, K7, KlO and K19 genes in the 
upstream region. NF-1 half-sites are present in Kl, 
acta dennatovenerologica A.P.A. Vol 6, 97, No 4 
K3, KS, KS, KlO, K14, K16 and KIS genes. Also 
common are the retinoic acid responsive elements, 
RAREs. Functional interactions have been demon-
strated between AP-2 and epidermal keratin genes. 
The consensus sequence for AP-2 is GCCNNNGCC 
and similar sequences have been found in Kl, KS, 
K6, KlO, K14 and K16 genes [51]. The importance 
of AP-2 sites in regulating keratin gene transcription 
is not fully understood because disruption of the 
AP-2 site in the K14 gene promoters results in only 
a twofold reduction of transcriptional activity [51]. 
Keratin promoters also contain binding sites for 
less well known or even hitherto uncharacterized 
transcription factors. Transcription factors often bind 
to keratin genes at adjacent sites in tight clusters. 
Specifically, in the promoter of the KS keratin gene, 
we find a complex protein binding site that binds 
multiple transcription factors [ 47]. Five different 
proteins, including Spl and AP2 independently bind 
to the complex. The complex is functional, as shown 
by point-mutagenesis and transfection assays. Inte-
restingly, some of the same five proteins also bind 
to complex sites in several other keratin genes, 
however, while the binding proteins are the same, 
the sequences and the structures of the complex sites 
are completely different. It is as if each of these 
keratin gene promoters assembled a complex trans-
cription regulatory site appropriate for the transcription 
factors present in epithelial cells. It is possible that 
such clusters confer cell type specificity to the 
expression of keratin genes. 
Mutations currently known to cause hereditary 
disorders due to abnormal keratinization have all 
been found in genes encoding structural proteins in 
keratinocytes, or the enzymes that cross-link these. It 
is to be expected that additional mutations will be 
found in the regulatory circuits that govem their 
expression. 
ACKNOWLEDGMENTS 
Our research is supported by National Institutes of 
Health grants AR30682, AR39176, AR40522, AR41850 
and DK16636. Special thanks go to V Milisavljevic 
far the early gel shift assays. We also thank members 
of our laboratory far advice, reagents and enco-
uragement. 
133 
Keratinocyte differentiation and activation 
REFERENCES 
l. Eckert RL. Structure, function, and differentiation of 
the keratinocyte. [Review]. Physiological Reviews, 1989; 
69(4): 1316-46. 
2. Fuchs E. Epidennal differentiation: The bare essentials. 
Joumal of Cel! Biology, 1990; 111: 2807-14. 
3. Nelson WG, Sun TT. The 50- and 58-kdalton keratin 
classes as molecular markers for stratified squamous epithelia: 
cel! culture studies. Joumal of Cel! Biology, 1983; 97(1): 
244-51. 
4. Fuchs E, Green H Changes in keratin gene expression 
during terminal diff erentiation of the keratinocyte. Cel!, 
1980; 19(4): 1033-42. 
5. Schweizer J et al., Sequential expression of mRNA-
encoded keratin sets in neonatal mouse epidennis: basal 
cells with properties of terminally differentiating cells. Cel!, 
1984; 37(1): 159-70. 
6. Roop DR et al., Transcriptional control of high molecular 
weight keratin gene expression in multistage mouse skin 
carcinogenesis. Cancer Research, 1988; 48(11): 3245-52. 
7. Simon M, Green H Participation of membrane-
associated proteins in the fonnation of the cross-linked 
envelope of the keratinocyte. Cel!, 1984; 36(4): 827-34. 
8. Dale BA et al. Expression of epidennal keratins and 
filaggrin during human fetal skin development. Joumal of 
Cel! Biology, 1985; 101(4): 1257-69. 
9. Hohl D et al. Transcription of the human loricrin gene 
in vitro is induced by calcium and cel! density and 
suppressed by retinoic acid Joumal of Investigative Dennatology, 
1991; 96(4): 414-8. 
1 O. Magnaldo T et al. Expression of loricrin is negatively 
controlled by retinoic acid in human epidennis reconstructed 
in vitro. Differentiation, 1992; 49: 39-46. 
11. Barker JNWN et al. Keratinocytes as initiators of 
inflammation. Lancet, 1991; 337: 211-214. 
12. Nickoloff BI, Turka LA. Keratinocytes: key immunocytes 
of the integument [editorial ]. [Review J [53 refs J American 
loumal of Pathology, 1993; 143(2): 325-31. 
13. Kupper TS, Groves RW. The interleukin-1 axis and 
cutaneous inflammation. [Review J [110 refs]. Joumal of 
Investigative Dennatology, 1995; 105(1 Suppl): 62S-66S. 
14. Weiss RA, Eichner R, Sun TT. Monoclonal antibody 
analysis of keratin expression in epidennal diseases: A 48-
and 56-kDalton keratin as molecular markers for 
hyperproliferative keratinocytes. Joumal of Cel! Biology, 
1984; 98(1397-1406). 
15. Jiang CK et al Epidennal growth factor and transfonning 
growth factor alpha specifically induce the activation- and 
134 
hyperprolif eration-associated keratins 6 and 16. Proceedings 
of the National Academy of Sciences of the United States 
of America, 1993; 90(14): 6786-90. 
16. Jiang CK et al. Disease-activated transcription factor: 
allergic reactions in human skin cause nuclear transcription 
of STAT-91 and induce synthesis of keratin Kl7. Molecular 
and Cellular Biology, 1994; 14: 4759-69. 
17. Kamine M, Freedberg IM, Blumenberg M Regulation 
of epidennal expression of keratin KI 7 in inflammatory 
skin diseases. Joumal of Investigative Dennatology, 1996; 
107(4): 569-75. 
18. Dame!! J, Jr, Kerr IM, Stark GR. Jak-STAT 
pathways and transcriptional activation in response to IFNs 
and other extracellular signaling proteins. Science, 1994; 
264(5164): 1415-21. 
19. Schindler C, Dame!! J, Jr. Transcriptional responses to 
polypeptide ligands: the JAK-STAT pathway. [Review] [145 
refs]. Annual Review of Biochemistry, 1995; 64: 621-51. 
20. Nickoloff BI, Griffiths CE, Barker l. The role of 
adhesion molecules, chemotactic factors, and cytokines in 
inflammatory and neoplastic skin disease-1990 update. 
[Review]. Joumal of Investigative Dennatology, 1990; 94(6 
Suppl): 151S-157S. 
21. Eron LI et al. Therapy of genital herpes with topically 
applied inte,feron. Antimicrobial Agents & Chemotherapy, 
1987; 31 (7): 1137-9. 
22. Ullrich A , Schlessinger l. Signal transduction by 
receptors with tyrosine kinase activity. [Review]. Cell 1990; 
61(2): 203-12. 
23. Hill CS, Treisman R. Transcriptional regulation by 
extracellular signals: mechanisms and specificity. [Review J 
[129 refs]. Cell, 1995; 80(2): 199-211. 
24. Kock A et al. Human keratinocytes are a source for 
tumor necrosis factor alpha: evidence for synthesis and 
release upon stimulation with endotoxin or ultraviolet light. 
Joumal of Experimental Medicine, 1990; 172(6): 1609-14. 
25. Griffiths TW, Griffiths CE, Voorhees JI, Immuno-
pathogenesis and immunotherapy of psoriasis. [Review J [159 
refs]. Dennatologic Clinics, 1995; 13(4): 739-49. 
26. Natoli G et al. Activation of SAPK/JNK by TNF 
receptor 1 through a noncytotoxi,c TRAF2-dependent pathway. 
Science, 1997; 275(5297): 200-3. 
27. Rothe M et al. TRAF2-mediated activation of NF-
kappa B by TNF receptor 2 and CD40. Science, 1995; 
269(5229): 1424-7. . 
28. Angel P, Karin M The role of lun, Fos and the AP-
1 complex in cell-proliferation and transfonnation. [Review J 
acta dennatovenerologica A.P.A. Vol 6, 97, No 4 
Keratinocyte differentiation and activation 
[276 refs] Biochimica et Biophysica Acta, 1991; 1072(2-3): 
129-57. 
29. Klampfer L et al. NF-IL6 and AP-1 cooperatively 
_modulate the activation of the TSG-6 gene by tumor 
necrosis factor alpha and interleukin-1. Molecular & 
Cellular Biology, 1994; 14(10): 6561-9. 
30. Basset-Seguin N et al. Comparative analysis of cellular 
and tissular expression of c-fos in human keratinocytes: 
evidence of its role in cel! differentiation. Oncogene, 1994; 
9(3): 765-71. 
31. Bemerd F et al. Expression of the carcinoma-associated 
keratin K6 and the role of AP-1 proto-oncoproteins. Gene 
Expression, 1993;. 3: 187-99. 
32. Saez E et al. c-fos is required far malignant progression 
of skin tumors. Cel!, 1995; 82(5): 721-32. 
33. Rutberg SE et al. Differentiation of mouse keratino-
cytes is accompanied by PKC-dependent changes in AP-1 
proteins. Oncogene, 1996; 13(1): 167-76. 
34. Fisher C et al., Pattems of epithelial expression of Fos 
protein suggest important role in the transition from viable 
to comified cel! during keratinization. Development, 1991; 
111(2): 253-8. 
35. Welter JF et al. Fos-related antigen (Fra-1), junB, and 
junD activate human involucrin pramater transcription by 
binding to proximal and distal AP 1 sites to mediate phorbol 
ester effects on pramater activity. Joumal of Biological 
Chemistry, 1995; 270(21): 12614-22. 
36. Lu B, Rothnagel JA, Roop DR, Human keratin 1 is 
regulated by AP-1 factors and coup-TF through a composite 
element [abstract] Joumal of Investigative Dermatology, 
1995; 102: 524. 
37. Lohman FP et al. Expression of the SPRR comification 
gene s is differentially affected by carcinogenic transf ormation. 
Experimental Cel! Research, 1997; 231 (1): 141-8. 
38. Presland RB et al. Characterization of the human 
epidermal profilaggrin gene. Genomic organization and 
identification of an S-100-like calcium binding domain at 
the amina terminus. Joumal of Biological Chemistry, 1992; 
267(33): 23772-81. 
39. Oshima RG, Abrams L, Kulesh D. Activation of an 
intron enhancer within the keratin 18 gene by expression 
of c-fos and c-jun in undifferentiated F9 embryonal 
carcinoma cells. Genes & Development, 1990; 4: 835-848. 
40. Miyamoto S, Verma IM. Rel/NF-kappa Bil kappa B 
story. [R.eview J [236 refs]. Advances in Cancer Research, 
1995; 66: 255-92. 
41. Tseng H, Green H. Association of basonuclin with 
ability of keratinocytes to multiply and with absence of 
terminal differentiation. Joumal of Cel! Biology, 1994; 
126(2): 495-506. 
42. Magnaldo T et al. On the role of AP2 in epithelial-
specific gene e.xpression. Gene &pression, 1993; 3(3): 307-15. 
43. Ohtsuki M et al. A cluster of five nuclear proteins 
regulates keratin transcription. Gene Expression, 1993; 3: 
201-13. 
44. Kadonaga IT and Tjian R. Affinity purification of 
sequence-specific DNA binding proteins. Proceedings of the 
National Academy of Sciences of the United States of 
America, 1986; 83(16): 5889-93. 
45. Pascal E, Tijan R. Different activation domains of Spi 
go vem f ormation of multimers and mediate transcriptional 
synergism. Genes & Development, 1991; 5: 1646-56. 
46. Mastrangelo 1A et al. DNA looping and Spi multimer 
links: A mechanism far transcriptional synergism and 
enhancement. Proceedings of the National Academy of 
Sciences of the United States of America, 1991; 88: 5670-4. 
47. Ohtsuki M et al. A cluster of five nuclear proteins 
regulates keratin gene transcription. Gene Expression, 1993; 
3(2): 201-13. 
48. Blumenberg M. Molecular biology of human keratin 
genes, in Molecular Biology oj the Skin: The Keratinocyte, 
M. Darmon and M. Blumenberg, Editors. 1993; Academic 
Press, lnc.: New York. 1-24. 
49. Li S, Rosen JM. Nuclear factor I and mammary 
gland jactor (STAT5) play a critical role in regulating rat 
whey acidic protein gene expression in transgenic mice. 
Molecular & Cellular Biology, 1995; 15: 2063-70. 
50. Blessing M, Zentgraf H, Jorcano JL. Differentially 
expressed bovine cytokeratin genes. Analysis oj gene linkage 
and evolutionary conservation oj 5'-upstream sequences. 
Embo Joumal, 1987; 6(3): 567-75. 
51. Leask A , Byme C, Fuchs E. Transcription jactor AP2 
and its role in epidennal-specific gene expression. Proceedings 
oj the National Academy oj Sciences oj the United States 
oj America, 1991; 88: 7948-52. 
AUTHORS' ADDRESS 
Miroslav Blumenberg, PhD, professor of biochemistry and dermatology, R. O. Perelman Department nf 
Dermatology, and Department of Biochemistry, and the Kaplan Cancer Research Center, New York 
University Medical Center, 550 First Avenue, New York, 10016 USA. 
acta dennatovenerologica A.P.A. Vol 6, 97, No 4 135