Roles of AP-2 transcription factors in the regulation ofcartilage and skeletal development Ann-Kathrin Wenke and Anja K.. AP-2a, AP-2b and AP-2c show partially overlap-ping expression pa
Trang 1Roles of AP-2 transcription factors in the regulation of
cartilage and skeletal development
Ann-Kathrin Wenke and Anja K Bosserhoff
Institute of Pathology, University of Regensburg, Germany
The AP-2 family
AP-2a was first identified by its ability to bind to
enhan-cer regions of SV40 and human metallothionein IIA [1]
The AP-2 family of transcription factors is composed of
five members: AP-2a, AP-2b, AP-2c, AP-2d, and AP-2e
[2–7], described for humans and mice Orthologs of
some AP-2s have also been found in frogs and fish, and
homologs occur in invertebrates All AP-2s have a
highly conserved basic helix–span–helix DNA-binding
and dimerization domain at their C-terminus, and a less
conserved proline-rich and glutamine-rich
transactiva-tion domain at their N-terminus [8–10] Most isoforms
also have a PY-motif (XPPXY) in the N-terminal
trans-activation domain that is important for their role as
transcriptional activators [9] The AP-2 factors form
homodimers and heterodimers for their transcriptional
activity A multiple alignment of all five human AP-2s,
illustrating their domain structure, is shown in Fig 1
A detailed and extensive overview of the AP-2 family
is given in the review of Eckert et al., [11] which also contains a schematic illustration of the AP-2 structure
Expression patterns of AP-2 molecules and functional implications
The expression and function of AP-2 isoforms have been systematically analyzed during murine embryo-genesis and in studies of the corresponding knockout mice
AP-2a, AP-2b and AP-2c show partially overlap-ping expression patterns in neural crest cells (NCCs), the peripheral nervous system, the facial mesenchyme, the limbs, various epithelia of the developing embryo,
Keywords
AP-2; cartilage; chondrogenesis; limb;
transcriptional regulation
Correspondence
A.-K Bosserhoff, Institute of Pathology,
University of Regensburg,
Franz-Josef-Strauss-Allee 11, D-93053
Regensburg, Germany
Fax: +49 941 944 6602
Tel: +49 941 944 6705
E-mail: anja.bosserhoff@klinik.uni-regens
burg.de
(Received 12 October 2009, revised 13
November 2009, accepted 20 November
2009)
doi:10.1111/j.1742-4658.2009.07509.x
During embryogenesis, most of the mammalian skeletal system is preformed
as cartilaginous structures that ossify later The different stages of cartilage and skeletal development are well described, and several molecular factors are known to influence the events of this enchondral ossification, especially transcription factors Members of the AP-2 family of transcription factors play important roles in several cellular processes, such as apoptosis, migra-tion and differentiamigra-tion Studies with knockout mice demonstrate that a main function of AP-2s is the suppression of terminal differentiation during embryonic development Additionally, the specific role of these molecules as regulators during chondrogenesis has been characterized This review gives
an overview of AP-2s, and discusses the recent findings on the AP-2 family,
in particular AP-2a, AP-2b, and AP-2e, as regulators of cartilage and skeletal development
Abbreviations
NCC, neural crest cell; RA, retinoic acid; ZPA, zone of polarizing activity.
Trang 2and the extraembryonic trophectoderm [4,12,13] In
contrast to the other AP-2s, AP-2d is specifically
expressed in the central nervous system, retina, and
developing heart [6] AP-2e expression has been
detected in the developing olfactory bulb, neural
tis-sue, especially the midbrain and hindbrain [7,14], and hypertrophic chondrocytes during chondrogenesis [15] Winger et al [16] analyzed the expression of all five mouse AP-2 family members in the unfertilized oocyte and from zygote formation to the blastocyst
Alpha -MLWKLTDNIKYEDC-EDRHDGTSNGTARLPQLGTVGQSPYTSAPPLSHT
Beta MHSPPRDQAAIMLWKLVENVKYEDIYEDRHDGVPSHSSRLSQLGSVSQGPYSSAPPLSHT
Gamma -MLWKITDNVKYEEDCEDRHDGSSNGNPRVPHLSSAGQHLYSPAPPLSHT
Epsilon -MLVHTYSAME -RPDGLG-AAAGGARLSSLPQAAYGPAPPLCHT
Delta -MSTTFPGLVHDAEIRHDGSNSYRLMQLGCLESVANSTVAYSSSSPLTYS
* : : : * :.** ::
Alpha PNA DFQPP-YFPPPY QPI-YPQSQDP -YSHVN-DPYS LNPLHAQPQP Q Beta PSS DFQPP-YFPPPY QPLPYHQSQDP -YSHVN-DPYS LNPLHQ-PQ -Q Gamma GVA EYQPPPYFPPPY QQLAYSQSADP -YSHLG-EAYAAAINPLHQPAPTGSQ Epsilon
PAATAAAEFQPP-YFPPPYPQPPLPYGQAPDAAAAFPHLAGDPYGG-LAPLAQPQPP -Delta TTG -TEFASP-YFSTNHQYTPL-HHQSFHYEFQHSHPAVTPDAYSLNSLHHSQQYYQQ :: * ** : : : *: * : *
Alpha HPGWPGQRQ -SQESGLLHTHRGLPHQLSG-LDP -RRDY -RRHEDLLHGP-HA Beta HPWGQRQRQEVGSEAGSLLPQPRAALPQLSG-LDP -RRDYHSVRRPDVLLHSAHHG Gamma QQAWPGRQSQEGAGLPSHHGRPAGLLPHLSG-LEAGAVSARRDAY RRSDLLLPHAHAL Epsilon QAAWAAPRAAARAHEE PPGLLAPPARALG-LDP -RRDYA TAVPRLLHGLADG Delta IHHGEPTDFINLHNARALKSSCLDEQRRELGCLDAYR -RHDLS LMSHGSQYGMHPD : * *: *:*
Alpha LSSGLGD-LSIHSLPH AIEEVPHVEDP -GINIPDQT-VIKKGPVSLSKSNSNAVSA Beta LDAGMGDSLSLHGLGHP-GMEDVQSVEDANNSGMNLLDQS-VIKKVPVPP -KSVTS Gamma DAAGLAENLGLHDMPH QMDEVQNVDDQ -HLLLHDQT-VIRKGPISMT KNPLN Epsilon AHGLADAPLGLPGLAAAPGLEDLQAMDEP -GMSLLDQS-VIKKVPIPSK -ASSLSA Delta
*.: ::: : : : * **::
Alpha IPINKDNLFGGV-VNPNEVFCSVPGRLSLLSSTSKYKVTVAEVQRRLSPPECLNASLLGG Beta LMMNKDGFLGGMSVNTGEVFCSVPGRLSLLSSTSKYKVTVGEVQRRLSPPECLNASLLGG Gamma LPCQKE LVGAVMNPTEVFCSVPGRLSLLSSTSKYKVTVAEVQRRLSPPECLNASLLGG Epsilon LSLAKDS-LVGGITNPGEVFCSVPGRLSLLSSTSKYKVTVGEVQRRLSPPECLNASLLGG Delta -GTCVVNPTDLFCSVPGRLSLLSSTSKYKVTIAEVKRRLSPPECLNASLLGG * ::********************:.**:****************
Alpha VLRRAKSKNGGRSLREKLDKIGLNLPAGRRKAANVTLLTSLVEGEAVHLARDFGYVCETE Beta VLRRAKSKNGGRSLRERLEKIGLNLPAGRRKAANVTLLTSLVEGEAVHLARDFGYICETE Gamma VLRRAKSKNGGRSLREKLDKIGLNLPAGRRKAAHVTLLTSLVEGEAVHLARDFAYVCEAE Epsilon VLRRAKSKNGGRCLRERLEKIGLNLPAGRRKAANVTLLTSLVEGEAVHLARDFGYVCETE Delta ILRRAKSKNGGRCLREKLDRLGLNLPAGRRKAANVTLLTSLVEGEALHLARDFGYTCETE :***********.***:*:::************:************:******.* **:*
Alpha FPAKAVAEFLNRQHSD-PNEQVTRKNMLLATKQICKEFTDLLAQDRSPLGNSRPNPILEP Beta FPAKAVSEYLNRQHTD-PSDLHSRKNMLLATKQLCKEFTDLLAQDRTPIGNSRPSPILEP Gamma FPSKPVAEYLTRPHLGGRNEMAARKNMLLAAQQLCKEFTELLSQDRTPHGTSRLAPVLET Epsilon FPAKAAAEYLCRQHAD-PGELHSRKSMLLAAKQICKEFADLMAQDRSPLGNSRPALILEP Delta FPAKAVGEHLARQHME-QKEQTARKKMILATKQICKEFQDLLSQDRSPLGSSRPTPILDL **:* *.* * * : :**.*:**::*:**** :*::***:* *.** :*:
Alpha GIQSCLTHFNLISHGFGSPAVCAAVTALQNYLTEALKAMDKMYLS -NNP-NSHTDN Beta GIQSCLTHFSLITHGFGAPAICAALTALQNYLTEALKGMDKMFLN -NTTTNRHTSG Gamma NIQNCLSHFSLITHGFGSQAICAAVSALQNYIKEALIVIDKSYMN -PGD-QSPADS Epsilon GVQSCLTHFSLITHGFGGPAICAALTAFQNYLLESLKGLDKMFLS -SVG-SGHGET Delta DIQRHLTHFSLITHGFGTPAICAALSTFQTVLSEMLNYLEKHTTHKNGGAADSGQGHANS .:* *:**.**:**** *:***::::* : * * ::*
Alpha N AKSSDKEEKHRK -
Beta EGP-GSKTGDKEEKHRK -
Gamma N -KTLEKMEKHRK -
Epsilon K -ASEKDAKHRK -
Delta EKAPLRKTSEAAVKEGKTEKTD : : : * *
Fig 1 Multiple alignment of AP-2a, AP-2b, AP-2c, AP-2d, and AP-2e The proline-rich and glutamine-rich N-terminus, which is important for transactivation, is shown in yellow, and contains the PY-motif (green) The helix–span–helix domain at the C-terminus shown in blue medi-ates dimerization and, together with the basic domain, (red) DNA-binding ‘*’, amino acids that are identical in all sequences in the align-ment; ‘:’, conserved substitutions have been observed; ‘.’, semiconserved substitutions.
Trang 3stage of development They found that AP-2a,
AP-2b, AP-2c and AP-2e are differentially expressed
during the preimplantation period, and, with the
exception of AP-2a, also in unfertilized oocytes
Furthermore, they determined that functional
redun-dancy occurs between these proteins during at least
the preimplantation period [16]
However, gene knockout experiments indicate that
the AP-2s perform individual and nonredundant
functions during mouse development Analyses of
AP-2a-null mice have demonstrated that AP-2a is a
fundamental regulator of mammalian craniofacial
development AP-2a knockout mice die perinatally
with craniofacial defects, thoracoabdominoschisis, and
severe skeletal defects in the head and trunk region
[17,18] Studies of earlier embryonic stages of these
mice indicate a failure of cranial neural tube closure
and defects in cranial ganglia development Another
role of AP-2a previously masked in the knockout mice
became apparent in chimeric mice composed of both
wild-type and AP-2a-null cells [19] These chimeras
reveal the major influence of AP-2a on eye
forma-tion and limb pattern formaforma-tion typified by limb
duplications
In contrast to these defects, the lack of AP-2b
leads to enhanced apoptotic cell death of renal
epi-thelial cells AP-2b knockout mice die shortly after
birth because of polycystic kidney disease and
termi-nal retermi-nal failure [20,21] The targeted deletion of
AP-2c also has severe consequences The loss of
AP-2c is already lethal in early embryogenic
develop-ment directly after implantation during gastrulation,
because AP-2c controls proliferation and
differentia-tion of extraembryonic trophectodermal cells [22,23]
So far, nothing is known about chondrogenic defects
mediated by knocking out AP-2b or AP-2c
However, all these types of grave damage after
deletion of AP-2 transcription factors demonstrate
the importance of the AP-2s for several functions
during embryonic development To date, knockout
studies concerning AP-2d or AP-2e have not been
published
Regulation of AP-2 and AP-2 target
genes
The expression of the AP-2a transcription factor is
induced by different signal-transducing agents, such as
retinoic acid (RA), cAMP, phorbol ester, UV light, and
singlet oxygen [2,24–26] RA plays an important role in
the process of chondrocyte differentiation [27] AP-2
mediates transcriptional activation in response to two
different signal transduction pathways, the phorbol
ester-activated protein kinase C pathway, or the cAMP-dependent protein kinase A pathway [28] Here, cAMP may modulate AP-2 activity by protein kinase A-induced phosphorylation of the transcription factor [29]
So far, interactions with AP-2 have been described for many proteins For example, CBP⁄ p300-interacting transactivator with ED-rich tail 2 interacts with and co-activates all isoforms of AP-2, and the interaction with AP-2a is suggested to be necessary for normal neural tube and cardiac development [30,31] The Kru¨ppel-related zinc finger protein AP-2rep (Klf12) has been characterized as a repressor of AP-2a Repression of AP-2a transcription by AP-2rep is dependent on an N-terminal PVDLS motif that interacts specifically with the corepressor CtBP1 [32,33] Recently, it was shown that the broad-complex, tramtrack and bric-a-brac domain containing protein KCTD1 directly binds to AP-2a and acts as a negative regulator for AP-2a trans-activation [34] It was also demonstrated in other studies that the nuclear protein poly(ADP-ribose) polymerase-1 interacts with the C-terminus of AP-2a and enhances its transcriptional activity in normal circumstances, whereas its enzymatic activity is used as a temporary shut-off mechanism during unfavorable conditions [35,36] Little is known about the interaction of AP-2 and its binding partners in cartilage However, at least CBP⁄ p300-interacting transactivator with ED-rich tail 2 and protein poly(ADP-ribose) polymerase-1 are expressed in this tissue [37–40] It would be interesting
to further analyze their interactions with AP-2 and the functional role of these in chondrocytes
Furthermore, it is speculated that in melanoma, where AP-2a acts as a tumor suppressor, the loss of AP-2a is caused by a failure in post-transcriptional processing of the protein [41] Additionally, it is evi-dent that AP-2 transcription factors can indirectly modulate genes by functional interactions with other transcription factors, e.g c-myc, rBP, and p53 [42–44] The formation of AP-2 homodimers and heterodimers could also be important for their regulatory activity, but no studies have been published so far
For the regulation of target gene expression, the AP-2 transcription factors bind to the palindromic recognition sequence 5¢-GCCN3GGC-3¢ or variations
of this GC-rich sequence within multiple gene promot-ers [45] AP-2s play a dual role as transcriptional acti-vators and repressors By regulating target genes with AP-2-binding sites within their promoter sequences, the AP-2 transcription factors play important roles in cellular processes, such as morphogenesis, in particular proliferation, differentiation, cell cycle regulation, and apoptosis [11,45,46] Through suppression of genes inducing terminal differentiation, apoptosis, and
Trang 4growth retardation, AP-2s play vital roles in cell
prolif-eration Besides the functions of AP-2s in physiological
processes, they have also crucial roles in pathological
processes such as tumorigenesis and genetic diseases
[47]
Most analyses of the regulation of AP-2 and the
interactions of the transcription factor with binding
partners, as well as of the regulation of target gene
expression, have been performed for AP-2a Up to
now, there have been no similar studies for the other
AP-2 isoforms
Chondrogenesis and skeletal
development
Most elements of the vertebrate skeleton are built
through enchondral ossification This is a complex
pro-cess beginning with the migration of undifferentiated
mesenchymal cells to regions determined to
differenti-ate into bone, followed by aggregation and the
forma-tion of mesenchymal condensaforma-tion [48,49] These
resting and proliferating chondrocytes produce an
extracellular matrix mainly consisting of aggrecan and
type II collagen As skeletogenesis proceeds,
proliferat-ing chondrocytes exit the cell cycle, become
hypertro-phic, express type X collagen, and reduce the
expression of type II collagen [50] Hypertrophic
chon-drocytes undergo terminal differentiation before they
finally become apoptotic Through the invasion of
blood vessels from the perichondrium, the cartilage
becomes vascularized Additionally, osteoblasts invade
the cartilage and start to replace it with mineralized
bone [48]
Many molecules and signaling cascades are
neces-sary to regulate these molecular processes of
chondro-genic and skeletal development, including transcription
factors Essential transcription factors in chondrocyte
differentiation are Sox9 and Runx2 Sox9 plays a key
role in chondrogenesis, as an inactivating mutation in
the gene encoding Sox9 leads to severe cartilage
abnor-malities called campomelic dysplasia [51,52] The effect
of a complete loss of Sox9 during chondrogenesis was
analyzed using a model of mice chimeras injected with
homozygous embryonic Sox9) ⁄ ) stem cells into
wild-type blastocysts, because Sox9 knockout mice are not
viable [53] The Sox9) ⁄ )cells were excluded from
mes-enchymal condensation and had no expression of the
chondrocytic markers type II collagen, type IX
colla-gen, type X collacolla-gen, and aggrecan Besides type II
collagen and aggrecan, Sox9 also regulates the
expres-sion of the cartilage-derived retinoic acid-sensitive
pro-tein [54,55] Sox5 and Sox6, members of the Sox
family, are also important for chondrocyte
differentia-tion, as embryos lacking Sox5 and Sox6 die at embry-onic day 16.5 and display a failure of chondrocyte progenitor cells to differentiate into hypertrophic chon-drocytes [56]
Two members of the Runx family of transcription factors, Runx2 and Runx3, are positive regulators of chondrocyte hypertrophy Runx2 is transiently expressed in prehypertrophic chondrocytes, and enforced expression of Runx2 in these cells in trans-genic mice leads to ectopic chondrocyte hypertrophy [57] Mice lacking both Runx2 and Runx3 do not have hypertrophic chondrocytes or type X collagen-express-ing cells, showcollagen-express-ing that both Runx2 and Runx3 are important regulators for hypertrophic development of chondrocytes [58] Alongside the important function for chondrogenesis, Runx2 is also a key regulator for osteoblast differentiation In particular, Runx2 is expressed in cells prefiguring the vertebrate skeleton as early as embryonic day 10.5 [59] Runx2 regulates many genes that determine the osteoblast phenotype,
as the forced expression of Runx2 in nonosteoblast cells is sufficient to induce the osteoblast-specific gene osteocalcin[60] The inactivation of both Runx2 alleles
in mice results in a lack of osteoblasts throughout the skeleton [61,62] It has also been shown that deletions resulting in the heterozygous loss of runx2 cause cleid-ocranial dysplasia [63]
Role of AP-2a, AP-2b and AP-2e in chondrogenesis and skeletal development
In addition to Sox and Runx transcription factors, members of the AP-2 family also have important func-tions in chondrogenesis and development of the verte-brate skeleton during embryogenesis Especially for AP-2a, but also for AP-2b and AP-2e, a role as a reg-ulator of cartilage differentiation has been shown [64–69] The functional and important roles of AP-2 transcription factors during chondrogenesis are illus-trated in Fig 2
AP-2a is expressed in the growth plate and in articu-lar cartilage, and has been described as a negative regulator of chondrocyte differentiation [64] The expression of cartilage-derived retinoic acid-sensitive protein and type II collagen is negatively correlated with AP-2a expression, and AP-2a thus acts as a sup-pressor of these two cartilage matrix genes during car-tilage differentiation [64–66] (Fig 2) High expression levels of AP-2a in chondroprogenitor cells maintain these cells in an early differentiation phenotype and inhibit the transition to differentiated chondrocytes The induction of Sox5 and Sox6 as well as that of chondrocytic matrix genes such as type II collagen,
Trang 5aggrecan and type X collagen are also delayed by
AP-2a [64,67]
Reports on AP-2a knockout mice clearly indicate
the importance of this transcription factor in
regulat-ing bone and cartilage development durregulat-ing
embryogen-esis, because of the severe skeletal defects in growth
and the development of face and limbs [17–19]
Don-ner et al tried to link the expression of AP-2a in these
tissues to upstream signaling pathways They assessed
the organization of a cis-regulatory region within the
fifth intron specific for directing AP-2a expression to
the developing frontal nasal process and limb bud
mes-enchyme, which they had previously identified in
trans-genic mice [70,71] The results demonstrate that a
STAT binding site is required for robust AP-2a
expres-sion in the face and limbs In a follow-up study, they
found that this conserved cis-acting sequence serves to
maintain a level of AP-2a expression that limits the
size of the hand plate and the associated number of
digit primordia [72]
AP-2 function was also analyzed in other species
A similar role for AP-2a as a regulator for face and
limb bud development was described in chickens AP-2
expression is completely downregulated after treatment
of the chick face with RA, and this is accompanied by
an increase in apoptosis [73] The authors of this study
ascribe the regulation of outgrowth of limb buds and
patterning of the digits to the chicken AP-2
The role of AP-2a was further studied in zebrafish
It was confirmed that AP-2a is an essential regulator
of the development of neural crest derivates, including embryonic cartilage and neurons, as well as pigmented cells [74–76] Knight et al [77] demonstrated essential functions for zebrafish AP-2a (tfap2a) and also AP-2b (tfap2b) in the development of the facial ectoderm, and for signals from this epithelium that induce skeletogen-esis in NCCs Zebrafish embryos lacking both tfap2a and tfap2b have defects in epidermal cell survival and deficient NCC-derived cartilage The authors propose that AP-2s have two distinct functions in cranial NCCs: they play an early cell-autonomous role in cell specification and survival, and a later nonautonomous role as regulators of ectodermal signals that induce skeletogenesis [77]
Luo et al [78] characterized Inca (induced in the neural crest by AP-2) as a target gene upregulated by AP-2a in Xenopus embryos Knockdown experiments for Inca in frog and fish revealed essential functions in
a subset of NCCs that form craniofacial cartilage Cells deficient for Inca show normal migration but fail
to condense into skeletal primordia This is an interest-ing aspect, as, for murine embryonic development, AP-2a is described as a suppressor of cartilage differ-entiation, maintaining cells in an early differentiated phenotype
For AP-2b, expression in murine limbs has also been demonstrated AP-2b is expressed in the zone of polar-izing activity (ZPA), the signaling center of the devel-oping vertebrate limb [68] A microarray approach comparing gene expression in the ZPA with that in the
Sox9
AP-2ε
Undifferentiated
mesenchymal cells
Differentiated
chondrocytes
Hypertrophic
chondrocytes
Condensed
mesenchymal cells
Sox9
Sox9
Sox5
Sox6
AP-2α
Runx2 Runx3 Runx2
Runx2
Fig 2 Functional role of AP-2a and AP-2e
in chondrogenesis Overview of the differen-tiation stages during chondrogenesis and the involvement of transcription factors (henatoxylin and eosin-stained section of an embryonic cartilaginous limb).
Trang 6rest of the limb showed that AP-2b expression is
increased in the ZPA
The fifth member of the AP-2 family, AP-2e, is
expressed in human articular cartilage, where it has
been shown to be a regulator of integrin a10
expres-sion [15] Recently, it was reported that the
transcrip-tion factor Sox9 induces AP-2e expression in the
hypertrophic stage of chondrocytic
differentia-tion through direct binding to the AP-2e promoter [69]
(Fig 2) Additionally, osteoarthritis chondrocytes show
increased expression of AP-2e as compared with
differentiated chondrocytes [69] Further studies are
required to identify AP-2e target genes other than
integrin a10, to clarify the role of AP-2e in
chon-drocyte differentiation and in the development of
osteoarthritis
Role of AP-2 in chondrocytic diseases
A role for AP-2s as regulators has been shown for
sev-eral chondrogenic diseases For example, mutations in
tfap2a are known to cause branchio-oculo-facial
syn-drome [79] The characteristic craniofacial features of
this disease are dolichocephaly, malformed pinnae,
thick nasal tip, and cleft lip Moreover, it has been
reported that branchio-oculo-facial syndrome has
over-lapping features, such as orofacial clefting and
occa-sional lip pits, with Van der Woude syndrome, in
which disruption of an AP-2a-binding site within an
interferon regulatory factor 6 enhancer is strongly
associated with cleft lip [80] Recently, it has been
demonstrated that AP-2e is overexpressed in
osteoar-thritic chondrocytes, but the exact function of AP-2e
in osteoarthritic development of cartilage is still
unknown [69]
Conclusions
AP-2 proteins, especially AP-2a and AP-2e, are
impor-tant for chondrogenic and skeletal development Many
studies on AP-2a have been performed, analyzing the
role of this transcription factor as a main regulator
of facial and limb development in embryogenesis
Further analyses are required to clarify the regulatory
mechanisms during early chondrocytic differentiation,
because it is still unknown how AP-2a itself is
upregu-lated in chondroprogenitor cells The molecular
rele-vance of AP-2e in hypertrophic cartilage and in the
development of osteoarthritis also still has to be
ana-lyzed in detail It is necessary to obtain more insights
into the transcriptional regulation of AP-2s, to
under-stand the complex story of AP-2s during embryonic
development
References
1 Mitchell PJ, Wang C & Tjian R (1987) Positive and negative regulation of transcription in vitro: enhancer-binding protein AP-2 is inhibited by SV40 T antigen Cell 50, 847–861
2 Williams T, Admon A, Luscher B & Tjian R (1988) Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements Genes Dev 2, 1557–1569
3 Moser M, Imhof A, Pscherer A, Bauer R, Amselgruber
W, Sinowatz F, Hofstadter F, Schule R & Buettner R (1995) Cloning and characterization of a second AP-2 transcription factor: AP-2 beta Development 121, 2779– 2788
4 Chazaud C, Oulad-Abdelghani M, Bouillet P, Decimo
D, Chambon P & Dolle P (1996) AP-2.2, a novel gene related to AP-2, is expressed in the forebrain, limbs and face during mouse embryogenesis Mech Dev 54, 83–94
5 Oulad-Abdelghani M, Bouillet P, Chazaud C, Dolle P
& Chambon P (1996) AP-2.2: a novel AP-2-related transcription factor induced by retinoic acid during dif-ferentiation of P19 embryonal carcinoma cells Exp Cell Res 225, 338–347
6 Zhao F, Satoda M, Licht JD, Hayashizaki Y & Gelb
BD (2001) Cloning and characterization of a novel mouse AP-2 transcription factor, AP-2delta, with unique DNA binding and transactivation properties
J Biol Chem 276, 40755–40760
7 Wang HV, Vaupel K, Buettner R, Bosserhoff AK & Moser M (2004) Identification and embryonic expres-sion of a new AP-2 transcription factor, AP-2 epsilon Dev Dyn 231, 128–135
8 Garcia MA, Campillos M, Ogueta S, Valdivieso F & Vazquez J (2000) Identification of amino acid residues
of transcription factor AP-2 involved in DNA binding
J Mol Biol 301, 807–816
9 Wankhade S, Yu Y, Weinberg J, Tainsky MA & Kan-nan P (2000) Characterization of the activation domains
of AP-2 family transcription factors J Biol Chem 275, 29701–29708
10 Williams T & Tjian R (1991) Analysis of the DNA-binding and activation properties of the human tran-scription factor AP-2 Genes Dev 5, 670–682
11 Eckert D, Buhl S, Weber S, Jager R & Schorle H (2005) The AP-2 family of transcription factors Genome Biol 6, 246, doi:10.1186/gb-2005-6-13-246
12 Moser M, Ruschoff J & Buettner R (1997) Comparative analysis of AP-2 alpha and AP-2 beta gene expression during murine embryogenesis Dev Dyn 208, 115–124
13 Zhao F, Lufkin T & Gelb BD (2003) Expression of Tfap2d, the gene encoding the transcription factor Ap-2 delta, during mouse embryogenesis Gene Expr Patterns
3, 213–217
Trang 714 Feng W & Williams T (2003) Cloning and
characteriza-tion of the mouse AP-2 epsilon gene: a novel family
member expressed in the developing olfactory bulb Mol
Cell Neurosci 24, 460–475
15 Wenke AK, Rothhammer T, Moser M & Bosserhoff
AK (2006) Regulation of integrin alpha10 expression in
chondrocytes by the transcription factors AP-2epsilon
and Ets-1 Biochem Biophys Res Commun 345, 495–501
16 Winger Q, Huang J, Auman HJ, Lewandoski M &
Williams T (2006) Analysis of transcription factor AP-2
expression and function during mouse preimplantation
development Biol Reprod 75, 324–333
17 Zhang J, Hagopian-Donaldson S, Serbedzija G,
Elsemore J, Plehn-Dujowich D, McMahon AP, Flavell
RA & Williams T (1996) Neural tube, skeletal and body
wall defects in mice lacking transcription factor AP-2
Nature 381, 238–241
18 Schorle H, Meier P, Buchert M, Jaenisch R & Mitchell
PJ (1996) Transcription factor AP-2 essential for cranial
closure and craniofacial development Nature 381, 235\–
238
19 Nottoli T, Hagopian-Donaldson S, Zhang J, Perkins A
& Williams T (1998) AP-2-null cells disrupt
morphogen-esis of the eye, face, and limbs in chimeric mice Proc
Natl Acad Sci USA 95, 13714–13719
20 Moser M, Pscherer A, Roth C, Becker J, Mucher G,
Zerres K, Dixkens C, Weis J, Guay-Woodford L,
Buettner R et al (1997) Enhanced apoptotic cell death
of renal epithelial cells in mice lacking transcription
factor AP-2beta Genes Dev 11, 1938–1948
21 Moser M, Dahmen S, Kluge R, Grone H, Dahmen J,
Kunz D, Schorle H & Buettner R (2003) Terminal renal
failure in mice lacking transcription factor AP-2 beta
Lab Invest 83, 571–578
22 Werling U & Schorle H (2002) Transcription factor
gene AP-2 gamma is essential for early murine
development Mol Cell Biol 22, 3149–3156
23 Auman HJ, Nottoli T, Lakiza O, Winger Q, Donaldson S
& Williams T (2002) Transcription factor AP-2gamma is
essential in the extra-embryonic lineages for early
postim-plantation development Development 129, 2733–2747
24 Luscher B, Mitchell PJ, Williams T & Tjian R (1989)
Regulation of transcription factor AP-2 by the
morpho-gen retinoic acid and by second messengers Genes Dev
3, 1507–1517
25 Grether-Beck S, Olaizola-Horn S, Schmitt H, Grewe M,
Jahnke A, Johnson JP, Briviba K, Sies H & Krutmann
J (1996) Activation of transcription factor AP-2
mediates UVA radiation- and singlet oxygen-induced
expression of the human intercellular adhesion molecule
1 gene Proc Natl Acad Sci USA 93, 14586–14591
26 Huang Y & Domann FE (1998) Redox modulation of
AP-2 DNA binding activity in vitro Biochem Biophys
Res Commun 249, 307–312
27 Underhill TM, Sampaio AV & Weston AD (2001) Retinoid signalling and skeletal development Novartis Found Symp 232, 171–185
28 Imagawa M, Chiu R & Karin M (1987) Transcription factor AP-2 mediates induction by two different signal-transduction pathways: protein kinase C and cAMP Cell 51, 251–260
29 Garcia MA, Campillos M, Marina A, Valdivieso F & Vazquez J (1999) Transcription factor AP-2 activity is modulated by protein kinase A-mediated phosphoryla-tion FEBS Lett 444, 27–31
30 Bamforth SD, Braganca J, Eloranta JJ, Murdoch JN, Marques FI, Kranc KR, Farza H, Henderson DJ, Hurst HC & Bhattacharya S (2001) Cardiac malforma-tions, adrenal agenesis, neural crest defects and exen-cephaly in mice lacking Cited2, a new Tfap2 co-activator Nat Genet 29, 469–474
31 Braganca J, Eloranta JJ, Bamforth SD, Ibbitt JC, Hurst
HC & Bhattacharya S (2003) Physical and functional interactions among AP-2 transcription factors, p300⁄ CREB-binding protein, and CITED2 J Biol Chem 278, 16021–16029
32 Roth C, Schuierer M, Gunther K & Buettner R (2000) Genomic structure and DNA binding properties of the human zinc finger transcriptional repressor AP-2rep (KLF12) Genomics 63, 384–390
33 Schuierer M, Hilger-Eversheim K, Dobner T, Bosserhoff AK, Moser M, Turner J, Crossley M & Buettner R (2001) Induction of AP-2alpha expression
by adenoviral infection involves inactivation of the AP-2rep transcriptional corepressor CtBP1 J Biol Chem
276, 27944–27949
34 Ding X, Luo C, Zhou J, Zhong Y, Hu X, Zhou F, Ren
K, Gan L, He A, Zhu J et al (2009) The interaction of KCTD1 with transcription factor AP-2alpha inhibits its transactivation J Cell Biochem 106, 285–295
35 Kannan P, Yu Y, Wankhade S & Tainsky MA (1999) PolyADP-ribose polymerase is a coactivator for AP-2-mediated transcriptional activation Nucleic Acids Res 27, 866–874
36 Li M, Naidu P, Yu Y, Berger NA & Kannan P (2004) Dual regulation of AP-2alpha transcriptional activation
by poly(ADP-ribose) polymerase-1 Biochem J 382, 323–329
37 Yokota H, Goldring MB & Sun HB (2003) CITED2-mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear J Biol Chem 278, 47275–47280
38 Agrawal A, Gajghate S, Smith H, Anderson DG, Albert TJ, Shapiro IM & Risbud MV (2008) Cited2 modulates hypoxia-inducible factor-dependent expres-sion of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc Arthritis Rheum 58, 3798–3808
Trang 839 Zakany R, Bakondi E, Juhasz T, Matta C, Szijgyarto
Z, Erdelyi K, Szabo E, Modis L, Virag L & Gergely P
(2007) Oxidative stress-induced poly(ADP-ribosyl)ation
in chick limb bud-derived chondrocytes Int J Mol Med
19, 597–605
40 Gonzalez-Rey E, Martinez-Romero R, O’Valle F,
Aguilar-Quesada R, Conde C, Delgado M & Oliver FJ
(2007) Therapeutic effect of a poly(ADP-ribose)
poly-merase-1 inhibitor on experimental arthritis by
downre-gulating inflammation and Th1 response PLoS ONE 2,
e1071, doi:10.1371/journal.pone.0001071
41 Karjalainen JM, Kellokoski JK, Mannermaa AJ,
Kujala HE, Moisio KI, Mitchell PJ, Eskelinen MJ,
Alhava EM & Kosma VM (2000) Failure in
post-tran-scriptional processing is a possible inactivation
mechanism of AP-2alpha in cutaneous melanoma Br J
Cancer 82, 2015–2021
42 Batsche E, Muchardt C, Behrens J, Hurst HC &
Cremisi C (1998) RB and c-Myc activate expression of
the E-cadherin gene in epithelial cells through
interac-tion with transcripinterac-tion factor AP-2 Mol Cell Biol 18,
3647–3658
43 Decary S, Decesse JT, Ogryzko V, Reed JC,
Naguibne-va I, Harel-Bellan A & Cremisi CE (2002) The
retino-blastoma protein binds the promoter of the survival
gene bcl-2 and regulates its transcription in epithelial
cells through transcription factor AP-2 Mol Cell Biol
22, 7877–7888
44 McPherson LA, Loktev AV & Weigel RJ (2002) Tumor
suppressor activity of AP2alpha mediated through a
direct interaction with p53 J Biol Chem 277,
45028–45033
45 Hilger-Eversheim K, Moser M, Schorle H & Buettner
R (2000) Regulatory roles of AP-2 transcription factors
in vertebrate development, apoptosis and cell-cycle
con-trol Gene 260, 1–12
46 Pfisterer P, Ehlermann J, Hegen M & Schorle H
(2002) A subtractive gene expression screen suggests
a role of transcription factor AP-2 alpha in control of
proliferation and differentiation J Biol Chem 277,
6637–6644
47 Pellikainen JM & Kosma VM (2007) Activator
protein-2 in carcinogenesis with a special reference to breast
cancer – a mini review Int J Cancer 120, 2061–2067
48 Karsenty G (2008) Transcriptional control of
skeleto-genesis Annu Rev Genomics Hum Genet 9, 183–196
49 Thorogood PV & Hinchliffe JR (1975) An analysis of
the condensation process during chondrogenesis in the
embryonic chick hind limb J Embryol Exp Morphol 33,
581–606
50 Kosher RA, Kulyk WM & Gay SW (1986) Collagen
gene expression during limb cartilage differentiation
J Cell Biol 102, 1151–1156
51 Foster JW, Dominguez-Steglich MA, Guioli S, Kwok
C, Weller PA, Stevanovic M, Weissenbach J, Mansour
S, Young ID, Goodfellow PN et al (1994) Campomelic dysplasia and autosomal sex reversal caused by muta-tions in an SRY-related gene Nature 372, 525–530
52 Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer
J, Pasantes J, Bricarelli FD, Keutel J, Hustert E et al (1994) Autosomal sex reversal and campomelic dyspla-sia are caused by mutations in and around the SRY-related gene SOX9 Cell 79, 1111–1120
53 Bi W, Deng JM, Zhang Z, Behringer RR & de Cromb-rugghe B (1999) Sox9 is required for cartilage forma-tion Nat Genet 22, 85–89
54 Bell DM, Leung KK, Wheatley SC, Ng LJ, Zhou S, Ling KW, Sham MH, Koopman P, Tam PP & Cheah
KS (1997) SOX9 directly regulates the type-II collagen gene Nat Genet 16, 174–178
55 Xie WF, Zhang X, Sakano S, Lefebvre V & Sandell LJ (1999) Trans-activation of the mouse cartilage-derived retinoic acid-sensitive protein gene by Sox9 J Bone Miner Res 14, 757–763
56 Smits P, Li P, Mandel J, Zhang Z, Deng JM, Behringer
RR, de Crombrugghe B & Lefebvre V (2001) The tran-scription factors L-Sox5 and Sox6 are essential for cartilage formation Dev Cell 1, 277–290
57 Takeda S, Bonnamy JP, Owen MJ, Ducy P & Karsenty
G (2001) Continuous expression of Cbfa1 in nonhyper-trophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice Genes Dev 15, 467–481
58 Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito
K, Inoue K, Yamana K, Zanma A, Takada K, Ito Y
et al.(2004) Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog Genes Dev 18, 952–963
59 Ducy P (2000) Cbfa1: a molecular switch in osteoblast biology Dev Dyn 219, 461–471
60 Ducy P, Zhang R, Geoffroy V, Ridall AL & Karsenty
G (1997) Osf2⁄ Cbfa1: a transcriptional activator of osteoblast differentiation Cell 89, 747–754
61 Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki
K, Deguchi K, Shimizu Y, Bronson RT, Gao YH,
Ina-da M et al (1997) Targeted disruption of Cbfa1 results
in a complete lack of bone formation owing to matura-tional arrest of osteoblasts Cell 89, 755–764
62 Otto F, Thornell AP, Crompton T, Denzel A, Gilmour
KC, Rosewell IR, Stamp GW, Beddington RS, Mund-los S, Olsen BR et al (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development Cell
89, 765–771
63 Quack I, Vonderstrass B, Stock M, Aylsworth AS, Becker A, Brueton L, Lee PJ, Majewski F, Mulliken
JB, Suri M et al (1999) Mutation analysis of core binding factor A1 in patients with cleidocranial dysplasia Am J Hum Genet 65, 1268–1278
Trang 964 Huang Z, Xu H & Sandell L (2004) Negative
regulation of chondrocyte differentiation by
transcrip-tion factor AP-2alpha J Bone Miner Res 19, 245–
255
65 Davies SR, Sakano S, Zhu Y & Sandell LJ (2002)
Distribution of the transcription factors Sox9, AP-2,
and [delta]EF1 in adult murine articular and meniscal
cartilage and growth plate J Histochem Cytochem 50,
1059–1065
66 Xie WF, Kondo S & Sandell LJ (1998) Regulation of
the mouse cartilage-derived retinoic acid-sensitive
pro-tein gene by the transcription factor AP-2 J Biol Chem
273, 5026–5032
67 Tuli R, Seghatoleslami MR, Tuli S, Howard MS,
Danielson KG & Tuan RS (2002) p38 MAP kinase
regulation of AP-2 binding in TGF-beta1-stimulated
chondrogenesis of human trabecular bone-derived cells
Ann NY Acad Sci 961, 172–177
68 Rock JR, Lopez MC, Baker HV & Harfe BD (2007)
Identification of genes expressed in the mouse limb
using a novel ZPA microarray approach Gene Expr
Patterns 8, 19–26
69 Wenke AK, Grassel S, Moser M & Bosserhoff AK
(2009) The cartilage-specific transcription factor Sox9
regulates AP-2epsilon expression in chondrocytes FEBS
J 276, 2494–2504
70 Zhang J & Williams T (2003) Identification and
regula-tion of tissue-specific cis-acting elements associated with
the human AP-2alpha gene Dev Dyn 228, 194–207
71 Donner AL & Williams T (2006) Frontal nasal
promi-nence expression driven by Tcfap2a relies on a
con-served binding site for STAT proteins Dev Dyn 235,
1358–1370
72 Feng W, Huang J, Zhang J & Williams T (2008)
Identi-fication and analysis of a conserved Tcfap2a intronic
enhancer element required for expression in facial and
limb bud mesenchyme Mol Cell Biol 28, 315–325
73 Shen H, Wilke T, Ashique AM, Narvey M, Zerucha T, Savino E, Williams T & Richman JM (1997) Chicken transcription factor AP-2: cloning, expression and its role in outgrowth of facial prominences and limb buds Dev Biol 188, 248–266
74 Barrallo-Gimeno A, Holzschuh J, Driever W & Knapik
EW (2004) Neural crest survival and differentiation in zebrafish depends on mont blanc⁄ tfap2a gene function Development 131, 1463–1477
75 O’Brien EK, d’Alencon C, Bonde G, Li W, Schoene-beck J, Allende ML, Gelb BD, Yelon D, Eisen JS & Cornell RA (2004) Transcription factor Ap-2alpha is necessary for development of embryonic melanophores, autonomic neurons and pharyngeal skeleton in zebra-fish Dev Biol 265, 246–261
76 Knight RD, Javidan Y, Nelson S, Zhang T & Schilling
T (2004) Skeletal and pigment cell defects in the lockjaw mutant reveal multiple roles for zebrafish tfap2a in neu-ral crest development Dev Dyn 229, 87–98
77 Knight RD, Javidan Y, Zhang T, Nelson S & Schilling
TF (2005) AP2-dependent signals from the ectoderm regulate craniofacial development in the zebrafish embryo Development 132, 3127–3138
78 Luo T, Xu Y, Hoffman TL, Zhang T, Schilling T & Sargent TD (2007) Inca: a novel p21-activated kinase-associated protein required for cranial neural crest development Development 134, 1279–1289
79 Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker
HJ, Zori RT, Burch MN, Clemens M, Mulliken JB, Smith R et al (2008) TFAP2A mutations result in branchio-oculo-facial syndrome Am J Hum Genet 82, 1171–1177
80 Rahimov F, Marazita ML, Visel A, Cooper ME, Hitchler MJ, Rubini M, Domann FE, Govil M, Chris-tensen K, Bille C et al (2008) Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip Nat Genet 40, 1341–1347