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J. Biol. Chem., Vol. 276, Issue 37, 34355-34358, September 14, 2001
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From the Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029
Krüppel-like factors
(KLFs)1 are DNA-binding
transcriptional regulators that play diverse roles during
differentiation and development. They form a subset of the broad class
of proteins containing Cys2/His2 zinc fingers,
a motif that is the second most abundant seen in the human genome and
the most abundant in transcription factors, estimated to be present in
just under 600 to over 700 proteins (1-3). The nomenclature is based
on the homology of its founding member,
EKLF (erythroid Krüppel-like factor; KLF1), to the
Drosophila Krüppel protein (4). There are numerous
finger proteins with such homology; however, the fact that KLF proteins
contain additional conserved residues between each finger, that their
fingers are three in number, and that these are found at the extreme
carboxyl end serves to further define KLF proteins as a separate family (Fig. 1). Phylogenetic analysis of the 15 human KLF members demonstrates that they form a clade distinct even
from the closely related Sp1 and Krox zinc finger families. Structural
considerations also place these members together, as three amino acids
at specific locations ("XYZ" positions (5)) adjacent to the
coordinating histidines play a determining role in target site
selection and high affinity binding. As a result, all members of the
family bind very similar "GT-box" or "CACCC element" sites on
DNA, although the configuration is such that the site tends to be
C-rich on one strand and G-rich on the other.
INTRODUCTION
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Fig. 1.
Phylogenetic relationship among the 15 KLF family members designated by the Human Gene Nomenclature
Committee. The ClustalX/TreeTop programs (70) were used to align
human KLF proteins and determine their relatedness (murine KLF14 (alias
Sp6) is a partial sequence and was used because the human orthologue is
not available). Murine KLF1 was included for comparison relative to
human KLF1. Complete amino acid sequences were used. Also indicated are
other names seen in the literature for the same proteins. Members are
divided into four related subgroups as discussed in the text.
GenBankTM accession numbers for protein sequences used for
this analysis are as follows: hKLF1, U37106; mKLF1, M97200; hKLF2,
Q9Y5W3; hKLF3, P57682; hKLF4, O43474; hKLF5, XP_007199; hKLF6,
AF001461; hKLF7, XP_002291; hKLF8, NP_009181; hKLF9, XP_005584; hKLF10,
NP_005646; hKLF11, AAF75793; hKLF12, CAB46982; hKLF13, NP_057079;
mKLF14, CAC06698; hKLF15, BAA88561. Developmental expression patterns
of the murine homologues of many of these have also been determined:
KLF1 (36), KLF2 (30, 31), KLF3 (49), KLF4 (71, 72), KLF5 (73), KLF6
(74, 75), KLF7 (24, 25), KLF9 (76), KLF13 (76), KLF15 (77).
The homologies and relationships among KLF family members, as
well as their biological properties, have been the subject of excellent
comprehensive reviews in the past 2 years (6-8). This discussion will
focus on an update of the family and on recent experiments that
demonstrate the wide and diverse range of cellular and molecular
effects that are exerted by selected members (Fig. 2).
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Cellular Regulation of KLF Gene Expression |
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KLF6/ZF9/CPBP is rapidly induced in liver stellate cells that are
activated after injury, leading to fibrogenesis and extracellular matrix formation (9). Consistent with this, KLF6 activates the collagen
1(I) promoter and the TGF-
promoters, establishing a link between
KLF6 activity and cytokine responsiveness to injury (10). This response
is also seen in injured arterial endothelial cells, in which induced
KLF6 expression up-regulates the urokinase plasminogen activator,
leading to proteolytic activation of latent TGF- and subsequent
tissue remodeling (11).
Vascular injury also plays a role in the induction of KLF5/BTEB2/IKLF
expression in smooth muscle cells, and phorbol ester-sensitive protein
kinase pathways (particularly mitogen-activated protein kinase
induction of Egr1 binding to the KLF5 promoter) have been implicated in
directing this response (12). In a similar (but not identical) way,
KLF5 is a downstream target of Wnt1 signaling as judged by its
induction after Wnt1 infection of cultured epithelia and after
comparison of KLF5 levels in transgenic Wnt1 mouse mammary cells to
wild type controls (13). Induction is transcriptional and occurs via a
-catenin/T cell factor-independent mechanism that may involve
protein kinase C activation.
Cytokines have also been implicated in KLF induction. First,
investigation of TGF--driven effects on pancreatic epithelia, prostate, and brain cell growth led to the identification of
KLF10/TIEG1/EGR and KLF11/TIEG2/FKLF (14). These two proteins are
not only most homologous with each other (Fig.
1, subgroup 2), but they are also immediate-early TGF--responsive genes that behave as potent repressors via three uniquely conserved repression motifs (15). Overexpression of KLF10 or -11 in a pancreatic cell line or in transgenic mice reveals that the functional effect of this repression is inhibition of cell growth (14) and induction of apoptosis via
formation of reactive oxygen species (16). Second, KLF4/GKLF is
directly induced by IFN
in a human colon carcinoma cell line, as
mRNA induction is rapid and occurs in the absence of protein synthesis (17). As more fully described below, this link may explain
the antiproliferative effects of IFN.
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Proliferation or Differentiation |
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KLF4/GKLF has been most thoroughly investigated with respect to its role in cellular differentiation, initially within the gastrointestinal tract (18), where its expression is indicative of a growth-arrested state, and in the epidermis, where KLF4 is critical for late stage differentiation of skin cells (19). Three ways in which KLF4 accomplishes this have been proposed. First, it was noted that KLF4 and p21 levels increase upon induction of growth arrest by serum deprivation and that the kinetics of KLF4 expression slightly preceded that of p21 (20). Following the observation that the p21 promoter contains CACCC elements, KLF4 was shown to bind and directly transactivate the p21 promoter via these sites. This induction was dependent on p53 and thus also occurred after DNA damage with methyl methanesulfonate. In addition, KLF4 physically interacts with p53. The resultant synergistic induction by p53 and KLF4 of p21 then leads to its inhibition of cyclin-dependent kinases and subsequent growth arrest. The second set of data demonstrates that the minimal cyclin D1 promoter also contains multiple CACCC elements that bind KLF4 in vitro and that KLF4 binding results in in vivo repression of the promoter, an effect not seen after transfection of Sp1 (21). Finally, KLF4 activates late differentiation genes such as keratin 4 (22). Together these data argue that KLF4 levels play a critical role in the decision between proliferation and cell cycle arrest/differentiation.
A similar role has been postulated for KLF7/ULKF (23), particularly
within developing and adult nervous systems (24). Expression of KLF7 at
specific phases of early development correlated with the time when
neuronal precursors exit the cell cycle and differentiate. Two sets of
data implicate KLF7 in this process. First, KLF7 can modulate cell
cycle regulators, as its induced overexpression results in a decrease
in DNA synthesis, induction of p21 protein, inhibition of cyclin D1,
and G1 arrest (24). Second, KLF7 may directly regulate
expression of TrkA, which, as the receptor for nerve growth factor, is
required for normal maturation and differentiation of sensory and
sympathetic neurons (25).
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Possible Role in Cellular Malignancy |
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The ability of molecules such as KLF4/GKLF to play critical roles
in the proliferative state of the cell raised the issue of whether they
play any role in the development of cancer. Intestinal samples from
patients with familial adenomatous polyposis (FAP) and from multiple
intestinal neoplasm (min) mice (a model of FAP) were
monitored for expression of KLF4 (26). Reverse transcription-polymerase chain reaction analysis revealed an inverse correlation between KLF4
levels and intestinal adenoma tumor size in min mice and decreased levels of KLF4 in colonic adenomas from FAP patients compared
with neighboring normal mucosa. As the KLF4 promoter contains binding
sites for the Cdx-2 protein (27), a model has been proposed whereby
mutated adenomatous polyposis coli can no longer induce Cdx-2, leading
to low levels of KLF4 and accelerated growth in FAP samples. Consistent
with this idea, KLF4 levels remain very low in the RKO colon cancer
cell line, which contains wild-type adenomatous polyposis coli but a
mutated Cdx-2, a variant that also exerts a dominant negative effect on
wild type Cdx-2 activation of the KLF4 promoter (28). Although a
similar negative correlation is seen between KLF4 level and growth in
prostatic carcinoma, the role of KLF4 is not equivalent in all cancers; for example, KLF4 levels are up-regulated during progression of human
oral/pharyngeal and breast carcinomas (29).
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Tissue-specific Versus General Effects |
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The biological roles of three KLF family members have been tested
by genetic ablation. Consistent with its restricted expression and
molecular properties, disruption of KLF1/EKLF leads to a directed effect on -globin expression (see below). However, other members, more generally expressed, exhibit very specific phenotypes upon their
disruption. In addition to expression in various tissues within the gut
(see above), KLF4/GKLF is also expressed at high levels in the
epidermis. However, its ablation leads to a specific deficiency in the
barrier function of the skin resulting in postnatal death (19).
Although these data are consistent with KLF4 function in growth arrest
and differentiation, the extent of normal development seen in its
absence is paradoxical given the expression pattern and postulated role
of KLF4 in the intestine and other endodermal tissues.
Similarly, genetic disruption of KLF2/LKLF, a molecule originally named by virtue of its high level of expression in the lung (30), led to defects in blood vessel organization and early embryonic death (31). Even though angiogenesis and vasculogenesis were normal, recruitment of pericytes and smooth muscle cells was deficient, leading to a vessel wall of low integrity and severe, lethal hemorrhage.
The embryonic lethality of KLF2-null embryos made it difficult to
analyze effects on other tissues. However, two other experimental approaches addressed this. To test the importance of KLF2 in lymphoid differentiation and at the same time avert embryonic lethality, KLF2-deficient embryonic stem (ES) cells were injected to
recombinase-deficient blastocysts to generate chimeric mice (32). B
cell development was normal, but mature, single-positive T lymphocytes
were susceptible to apoptosis and did not survive, implicating a role
for KLF2 in quiescent T cells. To address the role of KLF2 in the lung, ES cells were again used to generate chimeric mice, and the
contribution of the KLF2-deficient cells to a large number of tissues
was determined (33). In this case, KLF2-deficient cells contributed to
all tissues except the lung, and histopathological analysis of lungs from highly chimeric animals that died at birth showed deficiency in
late stages of development and an abnormal pathology. A striking consistency in the KLF1, -2, and -4 knockouts is that they affect late
stages of differentiation within their respective cellular environments.
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Molecular Roles: Transcriptional Activation |
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KLF1/EKLF was originally isolated by a subtractive cloning
approach to identify genes important for erythroid differentiation (4).
At present, it remains the best characterized member of the group (34,
35), as its target binding sequence at the -globin promoter and its
transcriptional activation properties were quickly identified. Its
expression pattern has not, however, been a paradigm for the family, as
KLF1 is restricted in its expression only to blood-forming tissues
during mammalian development (36). Its genetic ablation not only leads
to the absence of adult -globin expression and embryonic death (37,
38) but also the loss of the chromatin hypersensitive site at the
-globin promoter and a diminution of another strong hypersensitive
site (HS3) located more than 50 kilobase pairs away (39).
A molecular explanation for these results has followed from determining that KLF1/EKLF interacts with p300 and CBP (40), transcriptional coactivators that also acetylate histones and KLF1 itself. Such modifications appear to alter the ability of KLF1 to interact with other proteins, such as components of the SWI/SNF, ATP-dependent chromatin remodeling complex (41-43). As a result, KLF1 has provided the clearest example of the role in transcriptional regulation and chromatin assembly that a KLF molecule can integrate.
Interestingly, the basic region adjacent to the zinc finger domain contains one of the KLF1/EKLF acetylation sites, and this region is most highly conserved among KLF1, KLF2/LKLF, and KLF4/GKLF (43). Indeed, KLF4 has also been shown to interact with the p300 and CBP coactivators in vitro, and the residues required for this interaction are also required for KLF4 to exhibit its growth-suppressive effects in vivo (44). As KLF1, -2, and -4 form a closely related subgroup within the KLF family (Fig. 1, subgroup 3), KLF2 and -4 may also be targets for acetylation that alters their ability to interact with other proteins.
Another characteristic common to this subgroup follows from deletion analysis of their transactivation regions. Not surprisingly, in each case it can be whittled down to a minimal activation module (44-47). However, a region adjacent to their zinc fingers behave functionally as inhibitory modules (45-47), implying that the roles of KLF1, -2, and -4 in transcriptional control is complex and may be sensitive to selective modification and protein interactions.
Recently, KLF13/FKLF2 has been shown to interact with coactivators to
stimulate transcription of the human -globin gene (48). Similar to
KLF1, KLF13 is a substrate for acetylation by CBP and p300. However,
unlike KLF1, P/CAF also acetylates KLF13, and this enzymatic activity
is required for enhancement of KLF13 transcription. Part of this
activation likely follows from the strong stimulation of DNA binding by
KLF13 in the presence of CBP or P/CAF. The cumulative data suggest that
KLF factors are selective in their utilization of coactivators to
stimulate transcription.
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Molecular Roles: Transcriptional Repression |
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A considerably different outcome arises from investigating the role of KLF3/BKLF, which primarily behaves as a strong transcriptional repressor. KLF3 was originally isolated by low stringency cDNA library screening with the KLF1 zinc finger region (49). It is highly expressed in hematopoietic cells and the developing central nervous system and to a lesser extent in many (but not all) adult tissues. It achieves repression by recruitment of CtBP2, a general corepressor protein that interacts with KLF3 by means of a Pro-X-(Asp/Asn)-Leu-(Ser/Thr) motif located in the KLF3 repression domain (50). As preliminary data show that genetic ablation of KLF3 gives rise to a myeloproliferative disorder that infiltrates numerous tissues and effectively interferes with their normal growth (51), it appears that its repression function may play a role in preventing unrestrained cell number expansion.
KLF3 is not unique in its interaction with the CtBP2 corepressor, as
KLF8/BKLF3 also contains a region of homology to KLF3 (in addition to
the zinc finger domain) with the appropriate CtBP2 interaction motif
that enables it to repress transcription (52). KLF8 is broadly
expressed, and endogenous target genes have not yet been determined for
either KLF3 or -8. However, KLF12/AP2-rep, whose target promoter is
known, contains the same interaction motif and functions as a repressor
of the AP2 promoter in cotransfection assays (53). Although KLF12
was originally isolated from a brain cDNA library, it is most
highly expressed in the kidney, and induction of KLF12 expression
correlates with down-regulation of AP2 gene expression during kidney
development. Interestingly, KLF3, -8, and -12 are most closely related
to each other simply by comparative sequence analysis in the absence of
functional tests (Fig. 1, subgroup 1). As a result, it was
not unexpected to find that KLF12 interacts with CtBP1 (54). However,
the adenovirus E1A protein also contains the CtBP1 interaction motif,
and recent experiments suggest that the ability of E1A to derepress the
AP2 promoter results from its interaction with CtBP1, which prevents
CtBP1 from productively interacting with KLF12, thus functionally
inactivating KLF12 repression of AP2 (54).
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Antagonistic Regulatory Control by KLF Family Members |
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Given these examples of molecular repressors and activators within
the KLF family, it may not be completely surprising to find examples of
cross-regulation. Three are illustrative. The original screen that had
isolated KLF12/AP2-rep (above) had also identified KLF9/BTEB1 binding
to the AP2 promoter CACCC element (53). Although KLF12 behaved as a
repressor in transfection assays, KLF9 was a strong activator of the
AP2 promoter. Their mutually exclusive binding leads to different
reporter activities that are dependent on the relative levels of each
protein. Unlike KLF12, KLF9 is expressed in many tissues. This provides
an example of KLF factors whose differing modes of action (activation
versus repression) may play a role in regulating target gene
expression from the same site.
KLF4/GKLF/EZF and KLF5/IKLF/BTEB2 have been implicated in the antagonistic regulation of two gene systems. As already described, KLF4 plays a role in reduced proliferation and increased differentiation of the small intestinal epithelium via its effects on cell cycle regulators. Conversely, KLF5 is primarily expressed in the proliferating cells of the crypt epithelium (55). KLF5 is induced by mitogens, and its overexpression in fibroblasts leads to their increased growth and a transformed phenotype. This leads to a model in which KLF4 and KLF5 play opposing roles in differentiation and proliferation in the intestine (55, 56).
The -smooth muscle and SM22 promoters contain CACCC elements that
were used in a yeast one-hybrid screen to isolate KLF4 (57). However,
KLF4 was found to repress TGF- induction of the -smooth muscle
actin and SM22 promoters in transfection assays; indeed, TGF-
treatment of smooth muscle cells in culture leads to a decrease in KLF4
levels. However, KLF5/BTEB2/IKLF (but not KLF2) increased the activity
of the -smooth muscle and SM22 promoters in transient assays. As
KLF5 is abundant in smooth muscle tissues and is preferentially
activated during their proliferation (58), the regulatory model again
is based on opposing effects of KLF4 and KLF5, this time during muscle differentiation.
A more subtle effect may be apparent during blood cell
development, particularly with respect to regulation of globin gene switching (embryonic to fetal to adult) within the -like cluster. As
KLF1/EKLF appears dedicated to consolidating the switch from human
fetal to adult -globin expression, and because the other genes in
the cluster also contain CACCC elements within their promoters, a
search for related members that may play a role in embryonic and fetal
-like globin expression led to the identification of KLF11/FKLF (59)
and KLF13/FKLF2 (60). KLF11 primarily activates the embryonic and KLF13
the fetal globin promoter, although KLF13 also stimulates non-globin
promoters to a lesser extent. However, another factor highly expressed
in erythroid cells is KLF3/BKLF. As discussed above, KLF3 primarily
behaves as a repressor but in addition may be indirectly regulated by
EKLF (61). These data raise the possibility that at different stages of
red blood cell development, KLF11 and/or KLF13 compete with KLF1 to
optimally activate their cognate high affinity targets in the
-globin cluster, and at the same time, expression of KLF3 may serve
to repress the embryonic and fetal members. Clearly, because all of
these CACCC binding factors are present together in the red cell in development when globin gene switching is occurring, the mechanism of
how a particular target globin promoter is specifically induced at the
correct time in the midst of so many effector molecules remains perplexing.
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Final Thoughts |
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This review has concentrated on specific properties of selected
KLF family members; however, it is not meant to imply that their roles
are thereby limited. For example, KLF1 has historically been
characterized as a strong transcriptional activator with specific roles
in -globin transcription and -locus chromatin integrity; however,
recent data indicate that it may also play a role in erythroid cell
proliferation (62) and may even function as a transcriptional repressor
in specific contexts (63).
How do these proteins exert their particular effects, given that they
contain such similar DNA binding regions that bind to virtually
identical sequences? Studies with KLF1 are instructive. At one level,
specificity can follow from tissue-restricted expression. However, not
only are a number of these factors expressed in multiple tissues but
most cells express more than one factor at any time. As a result, the
second level of specificity is via their respective activation/repression domains, which are unique to each member, and
thus likely determine their resultant protein/protein interactions. This has been directly tested for KLF1, where in vivo tests
of -globin promoter activation by transient transfection assays (64)
and in transgenic mice (65) demonstrate that the Sp1 transactivation
domain cannot substitute for the KLF1 transactivation domain. Third,
the zinc finger region can also play a role in KLF/protein
interactions, whether bound to DNA (e.g. KLF1 interaction with DNA and SWI/SNF proteins (66)) or not (e.g. KLF1
behavior as a repressor (63)). Finally, although the KLF DNA binding domains interact with specific nucleotides within the CACCC element that directly affect their binding affinity, it is also clear that the
overall architecture and context within which this element is located
can have a dramatic effect on the ability of KLF factors (e.g. KLF1 (67-69)) to bind and exert their transcriptional effects.
Although this review has focused on the mammalian members of the KLF
family, it is clear from accumulated sequence analyses that large
numbers of Cys2/His2 zinc finger proteins are
also encoded by the Drosophila, Caenorhabditis elegans, and Danio rerio genomes (1-3). Significant
amino acid homologies among KLF family members beyond their DNA binding
regions exist only between very closely related family members, and
even then it is quite low. These families have expanded independently in different species, and thus direct functional analogies may be
unobtainable by comparison of mammalian and non-mammalian KLF proteins.
However, the localization of evolutionarily conserved domains and any
proteins and pathways with which these domains may interact and link
with in non-mammalian systems will prove useful for directing tests of
homologous regions in their mammalian counterparts.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001.
To whom correspondence should be addressed: Dept. of Biochemistry
and Molecular Biology, Mount Sinai School of Medicine, Box 1020, One
Gustave L. Levy Place, New York, NY 10029. Tel.: 212-241-4143; Fax:
212-860-9279; E-mail: james.bieker@mssm.edu.
Published, JBC Papers in Press, July 6, 2001, DOI 10.1074/jbc.R100043200
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ABBREVIATIONS |
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The abbreviations used are:
KLF, Krüppel-like factor;
E, erythroid;
L, lung;
B, basic;
G, gut;
I, intestinal;
U, ubiquitous;
K, kidney;
F, fetal;
BTEB, basic
transcription element binding;
ZF, zinc finger;
CPBP, core
promoter-binding protein;
TIEG, TGF--inducible early gene;
TGF, transforming growth factor;
CBP, cAMP-response element-binding protein
(CREB)-binding protein;
AP2-rep, AP2 repressor;
ES, embryonic stem;
IFN, interferon;
FAP, familial adenomatous polyposis.
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INTRODUCTION
Cellular Regulation of KLF...
), fetal (