stripe
Additional information about Stripe homologs Egr-1 and Egr-2, especially their functions in neural cells, is found in Huckebein. Another Egr family member in Drosophila is Klumpfuss.
Molecular analysis shows that sr encodes a predicted protein containing
a zinc finger motif. This motif is homologous to the DNA binding domains encoded by members of
the early growth response (egr) gene family. The DNA binding domain of the human Egr-1 protein is 92% identical to that of SR. In mammals, expression of egr genes is induced by
intercellular signals. Mice carrying a mutation in egr2 (also known as Krox20) show severe developmental defects in the hindbrain and in cranial nerves (Lee, 1995).
In Caenorhabditis elegans, a well-defined pathway of heterochronic genes ensures the proper timing of stage-specific developmental events. During the final larval stage, an upregulation of the let-7 microRNA indirectly activates the terminal differentiation factor and central regulator of the larval-to-adult transition, LIN-29, via the downregulation of the let-7 target genes lin-41 and hbl-1. This study identifies a new heterochronic gene, mab-10, and shows that mab-10 encodes a NAB (NGFI-A-binding protein) transcriptional co-factor. MAB-10 acts with LIN-29 to control the expression of genes required to regulate a subset of differentiation events during the larval-to-adult transition, and the NAB-interaction domain of LIN-29 is conserved in Kruppel-family EGR (early growth response) proteins.
A similar interaction between Drosophila NAB and the two Drosophila LIN-29 homologs RN and SQZ was reported recently. In mammals, EGR proteins control the differentiation of multiple cell lineages, and EGR-1 acts with NAB proteins to initiate menarche by regulating the transcription of the luteinizing hormone β subunit. Genome-wide association studies of humans and various studies of mouse recently have implicated the mammalian homologs of the C. elegans heterochronic gene lin-28 in regulating cellular differentiation and the timing of menarche. This work suggests that human homologs of multiple C. elegans heterochronic genes might act in an evolutionarily conserved pathway to promote cellular differentiation and the onset of puberty (Harris, 2011).
This study identified mab-10 as a new heterochronic gene that is required for specific aspects of the larval-to-adult transition, specifically molting cycle exit and seam cell exit from the cell cycle. mab-10 encodes the only C. elegans NAB transcriptional co-factor. NAB proteins are thought to physically interact with Kruppel family EGR transcription factors to regulate their activity (Harris, 2011).
Previous work demonstrated that MAB-10 (then known only as the C. elegans NAB protein R166.1) could interact with mammalian EGR proteins in a yeast two-hybrid assay; no corresponding C. elegans EGR protein was identified. This study has demonstrate that MAB-10 interacts with the terminal differentiation factor LIN-29 through an evolutionarily conserved NAB binding domain (R1 domain) and that MAB-10 is required for a subset of LIN-29-dependent activities. This work identifies LIN-29 as a C. elegans EGR-like protein and demonstrates that the C. elegans heterochronic pathway controls the timing of NAB/EGR-mediated differentiation (Harris, 2011).
Several experiments using mammalian tissue culture suggest that NAB proteins negatively regulate EGR activity by binding EGR proteins at specific target genes and preventing EGR-mediated transcription. However, loss of either EGR2 function or NAB function in mice and humans results in hypomyelination, suggesting that EGR and NAB proteins need not act antagonistically in vivo (Harris, 2011).
In C. elegans, MAB-10 and LIN-29 both act to promote terminal differentiation and the onset of adulthood. Furthermore, mab-10 promotes the formation of precocious adult alae in a lin-41 mutant background, suggesting that MAB-10 does not specifically act to control genes required for exit from the molting cycle and seam cell exit from the cell cycle, but more likely acts as a general enhancer of LIN-29 activity (Harris, 2011).
EGR and NAB proteins have been shown to operate in a negative-feedback loop wherein an EGR protein promotes the expression of its NAB co-factor, which then inhibits EGR activity. mab-10 transcription does not depend on LIN-29, despite a dramatic increase of mab-10 transcription during the L4 stage. Thus, mab-10 is not a transcriptional target of LIN-29 (Harris, 2011).
Whereas mab-10 is not a transcriptional target of LIN-29, MAB-10::GFP localization to seam cell nuclei during the L4 stage required LIN-29, indicating that LIN-29 might promote MAB-10 seam cell nuclear localization via a post-transcriptional mechanism or via direct physical interaction (Harris, 2011).
This work demonstrates that MAB-10 and LIN-29 do not operate in a negative-feedback loop. It is proposed that other components of the heterochronic pathway directly regulate mab-10 transcription to temporally regulate MAB-10/LIN-29 activity and that LIN-29 or some factor downstream of LIN-29 controls MAB-10/LIN-29 activity by promoting the accumulation of MAB-10 in seam cell nuclei (Harris, 2011).
By showing that MAB-10 acts with LIN-29 through an evolutionarily conserved EGR R1 domain, LIN-29 and the Drosophila LIN-29 homologs RN and SQZ are identified as EGR-like molecules. It is proposed that NAB proteins and EGR proteins act together in temporal developmental programs to control terminal differentiation. In Drosophila, the LIN-29 homolog SQZ acts with Drosophila NAB to control neuroblast differentiation. In C. elegans, LIN-29 and MAB-10 act together to control the differentiation of a hypodermal stem cell lineage during the transition from larva to adult by regulating the expression of the nuclear hormone receptors nhr-23 and nhr-25 and the cell cycle regulator cki-1. Recently, a study of C. elegans demonstrated that nhr-25 is itself a heterochronic gene and possibly functions with lin-29 to promote aspects of the larval-to-adult transition, including seam cell exit from the cell cycle. Though the mechanism by which nhr-25 regulates seam cell exit from the cell cycle is not known, it is speculated that LIN-29 and NHR-25 might act together to promote cki-1 expression (Harris, 2011).
EGR proteins were originally identified as immediate-early genes and generally have been regarded as differentiation factors. Like mab-10 and lin-29 mutants, Nab and Egr mutant mice are defective in the terminal differentiation of several cell lineages. For example, in Schwann cells, EGR2 promotes the expression of P27, the homolog of C. elegans CKI-1, and acts with NAB proteins to promote terminal differentiation. Mammalian homologs of other C. elegans heterochronic genes also control differentiation. Similar to the role of LIN-28 in C. elegans, mammalian LIN28 and LIN28B promote stem cell identity and prevent differentiation by repressing the let-7 microRNA gene. As in C. elegans, increasing levels of let-7 drive differentiation, and the mouse homolog of LIN-41, LIN41, has been shown to be a let-7 target acting in stem cell niches to prevent premature differentiation (Harris, 2011).
Mammalian LIN-28 controls the timing of the onset of puberty in mice and possibly humans. Mice lacking EGR1 function, like lin-29 mutants of C. elegans, fail to undergo puberty. EGR1 and NAB proteins act with SF1, the homolog of C. elegans NHR-25, in the gonadotrope lineage of the pituitary gland to regulate the expression of luteinizing hormone and the onset of puberty. The molecular mechanism by which mammalian LIN-28 regulates the onset of puberty is not known. This work raises the possibility that homologs of C. elegans heterochronic genes might act in an evolutionarily conserved pathway that controls the terminal differentiation of cell lineages and the onset of adulthood by regulating the activity of NAB and EGR proteins (Harris, 2011).
Although the activation domains within early growth response gene protein 1 (Egr-1) have been
mapped, little is known of the kinases which phosphorylate Egr-1 and how phosphorylation correlates
with the transcriptional activity of Egr-1. Casein kinase II (See Drosophila CkII)
co-immunoprecipitates with Egr-1 from NIH 3T3 cell lysates. The association of Egr-1 and CKII
requires the C terminus of Egr-1 and CKII phosphorylates Egr-1 in vitro. The in vitro phosphorylation
of Egr-1 by CKII as well as that induced by serum in vivo was compared by examining the CNBr-digested
fragments of the phosphorylated Egr-1. CKII strongly phosphorylates fragments 7 and 10, which cover
part of the activation/nuclear localization and DNA binding domains of Egr-1. CKII also
phosphorylates, albeit weakly, fragments 5 and 8, which respectively cover part of the activation domain and the entire
repression domain of Egr-1. Strong phosphorylation on fragment 10 as well as fragment 5
is also observed in Egr-1 immunoprecipitated from serum-induced, 32P-labeled cells. CKII
phosphorylation of Egr-1 results in a decrease of its DNA binding as well as its transcriptional
activities (Jain 1996).
Muscle spindles are skeletal muscle sensory organs that provide axial and limb position information (proprioception) to the central nervous system. Spindles consist of encapsulated muscle fibers (intrafusal fibers) that are innervated by specialized motor and sensory axons. Although the molecular mechanisms involved in spindle ontogeny are poorly understood, the innervation of a subset of developing myotubes (type I) by peripheral sensory afferents (group Ia) is a critical event for inducing intrafusal fiber differentiation and subsequent spindle formation. The Egr family of zinc-finger transcription factors, whose members include Egr1 (NGFI-A), Egr2 (Krox-20), Egr3 and Egr4 (NGFI-C), are thought to regulate critical genetic programs involved in cellular growth and differentiation. Mice deficient in Egr3 were generated by gene targeting and had gait ataxia, increased frequency of perinatal mortality, scoliosis, resting tremors and ptosis. Although extrafusal skeletal muscle fibers appeared normal, Egr3-deficient animals lacked muscle spindles, a finding that is consistent with their profound gait ataxia. Egr3 is highly expressed in developing muscle spindles, but not in Ia afferent neurons or their terminals during developmental periods that coincided with the induction of spindle morphogenesis by sensory afferent axons. These results indicate that type I myotubes are dependent upon Egr3-mediated transcription for proper spindle development (Tourtellotte, 1998).
The Egr family of zinc-finger transcription factors, consisting of Egr1, Egr2, Egr3, and Egr4, are involved in cellular growth and differentiation. Adult Egr3-deficient mice are ataxic and lack muscle spindle proprioceptors that normally develop at the sites of Ia afferent-myotube contacts during embryogenesis. To resolve whether spindles form and then degenerate, or whether they never form in the absence of Egr3, the spatiotemporal expression of Egr3 relative to spindle development was examined. In wild type mice, Egr3 is expressed in developing myotubes shortly after they are innervated by Ia afferents and its expression is controlled by innervation because it dissipates following nerve transection. In Egr3-deficient mice, myotubes receive Ia afferent innervation and assemble normally into spindles during embryogenesis. However, newborn Egr3-deficient spindles have few internal myonuclei in intrafusal fibers and thin capsules. Moreover, slow-developmental myosin heavy chain is not induced in embryonic Egr3-deficient spindles, suggesting that impairments in differentiation are present before they can be detected morphologically. After birth, sensory and motor innervation withdraw from the Egr3-deficient spindles, and the spindles disassemble. In spite of the spindle disassembly and retraction of afferents from muscles, the cell bodies of proprioceptive neurons within dorsal root ganglia are retained. It is concluded that Egr3 has an essential role in regulating genes required for the transformation of undifferentiated myotubes into intrafusal fibers, and hence for the phenotypic differentiation of spindles (Tourtellotte, 2001).
Ia afferents induce the formation of muscle spindles prenatally and maintain them postnatally. To address whether spindles, in turn, regulate the function of Ia afferents, Egr3-null mutant mice (Egr3-/), in which muscle spindles degenerate progressively after birth, were examined. Egr3-/- mice develop gait ataxia, scoliosis, resting tremors, and ptosis, suggesting a defect in proprioception. Despite the normal morphological appearance of peripheral and central sensory projections, a profound functional deficit was observed in the strength of sensory-motor connections in Egr3-/- mice. Muscle spindles in Egr3-/- mice do not express NT3. Intramuscular injections of NT3 to Egr3-/- mice during the postnatal period restore sensory-motor connections. Thus, NT3 derived from muscle spindles regulates the synaptic connectivity between muscle sensory and motor neurons (Chen, 2002).
Growth factor-mediated signaling has been implicated in the regulation of epithelial-mesenchymal
interactions during organogenesis. Bone morphogenetic protein 4 (BMP-4), a member of the
transforming growth factor beta superfamily, is expressed in the presumptive dental epithelium at the
initiation of tooth development. Subsequently, epithelial signaling leads to mesenchymal induction of
BMP-4 expression. To address the role of this factor, BMP-4-releasing agarose beads were added to
dental mesenchyme in culture. These beads induce a translucent mesenchymal zone similar to that induced by dental epithelium. Three transcription factors (Msx-1, Msx-2, and Egr-1) whose expression is governed by epithelial signaling are induced in response to BMP-4. BMP-4 also
induces its own mesenchymal expression. These findings support the hypothesis that BMP-4 mediates
epithelial-mesenchymal interactions during early tooth development (Vainio, 1993).
Neuregulin (NRG) (also known as ARIA, GGF, and other names) is a heparin sulfate proteoglycan secreted into the neuromuscular junction by innervating motor and sensory neurons. An integral part of synapse formation, NRG-induced changes in gene expression were analyzed over 48 h in primary human myotubes. In addition to increasing the expression of acetylcholine receptors on the myotube surface, NRG treatment results in a transient increase of several members of the early growth response (Egr) family of transcription factors. Three Egrs (Egr1, -2, and -3) are induced within the first hour of NRG treatment, with Egr1 and -3 RNA levels showing the most significant increases of approximately 9- and 16-fold, respectively. Also noted was a corresponding increase in protein levels for both of these transcription factors. Previous literature indicates that Egr3 expression is required for the formation of muscle spindle fibers, sensory organs that are distinct from skeletal muscle contractile fibers. At the molecular level, muscle spindle fibers express a unique subset of myosin heavy chains. Two isoforms of the myosin heavy chain, the slow development and neonatal, were found to be increased in myotube cultures after 48 h of treatment with NRG. Taken together, these results indicate that not only can NRG induce the expression of a transcription factor key to spindle fiber development (Egr3), but that a portion of this developmental process can be replicated in vitro (Jacobson, 2004).
Fibroblast growth factor-1 (Drosophila homolog: Branchless), a prototype member of the heparin-binding growth factor family, is
a potent mitogen for vascular endothelial cells and a variety of other cell types. FGF-1 can induce the
expression of the platelet-derived growth factor-A chain (PDGF-A) gene in endothelial cells; however,
the underlying transcriptional mechanisms are not known. A 16-bp element, located 55
to 71 bp upstream of the transcriptional start site, is required for FGF-1-inducible promoter-dependent
expression of PDGF-A. This region contains nucleotide recognition elements for the early growth response gene
product, early growth response factor-1 (Egr-1), and the related zinc-finger transcription factor, Sp1. FGF-1 induces Egr-1 mRNA expression
within 30 minutes. Egr-1 protein accumulates in the nuclei of endothelial cells exposed to the growth factor, whereas
levels of Sp1 do not change. Egr-1 binds to the FGF-1 response element in the proximal PDGF-A
promoter in a specific and time-dependent manner. These findings indicate that Egr-1 plays a key
regulatory role in FGF-1-inducible endothelial PDGF-A expression and implicate this transcription
factor in pathological settings in which these mitogens are both expressed (Delbridge, 1997).
Basic fibroblast growth factor (bFGF) is an important growth factor for neuroectoderm- and
mesoderm-derived cells. In addition bFGF is an important angiogenic factor and appears to contribute
to tumorigenesis. This is exemplified by the fact that bFGF is expressed in a large majority of human
gliomas and that bFGF expression is critical for the growth and tumorigenesis of these cells. It has
been shown previously that bFGF can induce its own expression through an increase in bFGF mRNA. bFGF leads to its own synthesis through an autoregulated transcriptional
response that requires the transcription factor Egr-1 (also known as Krox24, Zif268 and NGFI-A).
Egr-1 binds to two DNA elements in the bFGF promoter and positively regulates transcription.
Mutation of these sites blocks the ability of bFGF to transcriptionally regulate the bFGF promoter.
These data indicate a mechanism to explain how bFGF functions to autoregulate its expression and
demonstrate that Egr-1 is as an essential transcription factor in this process (Wang, 1997).
The mechanisms controlling the proliferation of astrocytes are of great interest but are not well
defined. The endogenous neuropeptides, endothelin-3 (ET-3), and atrial
natriuretic peptide (ANP), modulate the proliferation of astrocytes by positively and negatively
regulating the transcription of the immediate-early gene egr-1 which transactivates basic fibroblast
growth factor (bFGF) by unknown mechanisms. In these studies, the involvement of
MAP kinase (Erk) activation by ET-3 in the transcription of egr-1, and the molecular determinants by
which Egr-1 transactivates bFGF were determined. Transfection of astrocytes with a mitogen-activated protein (MAP)
kinase (MAPK) expression vector increased the transcription of a cotransfected egr-chloramphenicol
acetyltransferase (CAT) construct 3-fold. This induction is totally abolished by a dominant negative
MAPK mutant. A 3-fold induction of egr-CAT expression by ET-3 is significantly reduced by
treatment with ANP, or a cotransfected dominant negative MAPK plasmid. Using mobility shift
assays, it has been shown that ET-3 induces the expression of Egr-1 protein that binds specifically to
several early growth-related protein (Egr-1) binding sites on the bFGF promoter, and that this effect
is significantly reversed by treatment with ANP. The Sp1 transcriptional factor
is bound at these same sites, but is not stimulated by ET-3. Deletion experiments indicate that
only the site at -160 bp of the bFGF promoter is significant for bFGF transactivation by Egr-1. It is
concluded that the astrocyte mitogen, ET-3, stimulates egr-1 transcription through a MAP kinase (Erk)
related mechanism, and that Egr-1 transactivates bFGF through a specific, noncanonical, Egr-1 site on
the promoter. ANP inhibits each of these steps, providing a pathway for its anti-proliferative action (Biesiada, 1997).
The early growth response-1 gene (Erg-1) is rapidly upregulated after TCR stimulation.
Egr-1 is expressed by a subset of normal double positive thymocytes in the thymic cortex, as well by a
majority of medullary single positive thymocytes. Expression of Egr-1 is dramatically reduced in the
thymus of major histocompatibility complex knockout mice, but can be induced by anti-CD3 antibody
stimulation of isolated thymocytes from these animals. These and other data suggest that high level
expression of Egr-1 in the thymus is a consequence of selection. A similar pattern of expression is
found for family members Egr-2 and Egr-3. Expression of Egr-1, 2, and 3 is dependent upon ras activation, as is the initiation of differentiation to a
single positive cell. In contrast, the calcineurin inhibitor cyclosporin A, which inhibits DPK cell
differentiation as well as positive selection, inhibits expression of Egr-2 and Egr-3, but not Egr-1. The
identification of the Egr family in this context represents the first report of a link between the two
known signaling pathways involved in positive selection and downstream transcriptional regulators (Shao 1997).
Ligation of B cell receptor (BCR) on BKS-2, an immature B cell lymphoma by anti-IgM antibodies
(Ab) causes apoptosis. Signaling through the B cell receptor in wild type BKS-2 cells down-regulates the expression of Egr-1, a zinc finger-containing transcription factor. A reduction in the level of Egr-1 mRNA can be demonstrated as early as 30 min after the ligation of BCR on BKS-2 cells. The expression of EGR-1 protein is also inhibited by anti-IgM treatment. Antisense oligonucleotides to Egr-1 cause growth inhibition
and apoptosis in BKS-2 cells, suggesting that expression of Egr-1 is important for the survival of these B lymphoma cells. In contrast to wild type BKS-2 cells, the mutant 1.B5 cell line, which is refractory to B cell receptor-mediated growth-inhibitory signals, shows an increased expression of Egr-1 upon treatment with anti-IgM. These results implicate a role for Egr-1 in blocking B cell receptor-mediated apoptosis in immature B cells (Muthukkumar, 1997).
The interleukin-2 IL-2 receptor beta-chain (IL-2Rbeta) is an essential component of
the receptors for IL-2 and IL-15. Although IL-2Rbeta is constitutively expressed by
lymphocytes, its expression can be further induced by a number of stimuli, including
phorbol 12-myristate 13-acetate (PMA). Factors that bind
to an enhancer region located between nucleotides -170 and -139 of the human
IL-2Rbeta promoter have been characterized. Both Sp1 and Sp3 (Homologs of Drosophila Buttonhead) bind to the 5' portion of this region, whereas
a PMA-inducible factor (PIF) binds mainly to its 3' portion and to the Sp
binding motifs as well. In Jurkat T cells, induction of PIF DNA binding activity is
rapidly induced, required de novo protein synthesis, and is sustained at a high level
for at least 23 h. Interestingly, PIF is constitutively activated in human T-cell
leukemia virus type 1-transformed MT-2 cells. PIF
is Egr-1 based on its recognition by anti-Egr-1 antisera in gel mobility shift assays,
even though the IL-2Rbeta DNA binding motif differs substantially from the
canonical Egr-1 binding site. In addition, Egr-1 binds to the Sp binding site. In Jurkat
cells, both sites are required for maximal IL-2Rbeta promoter activity, and in
HeLaS3 cells, transfection of Egr-1 can drive activity of a reporter construct
containing both sites. Sp1 and Egr-1 can form a complex with kinetics
that correlate with the production of Egr-1 in Jurkat cells upon PMA stimulation.
Thus, Sp1 and Egr-1 physically and functionally cooperate to mediate maximal
IL-2Rbeta promoter activity (Lin, 1997).
Biosynthesis of tumor necrosis factor-alpha (TNF-alpha) is carried out predominantly by cells of the monocytic
lineage. This study examined the role of various cis-acting regulatory elements in the
lipopolysaccharide (LPS) induction of the human TNF-alpha promoter in cells of monocytic lineage.
In one region [-182 to -37 base pairs (bp)] the TNF-alpha promoter possesses enhancer elements that are
required for optimal transcription of the TNF-alpha gene in response to LPS. Two regions were
identified: region I (-182 to -162 bp) contains an overlapping Sp1/Egr-1 site, and region II (-119 to -88)
contains CRE and NF-kappaB (designated kappaB3) sites. The following were all found to bind to the CRE site: unstimulated THP-1, CRE-binding
protein and, to a lesser extent, c-Jun complexes. LPS stimulation
increases the binding of c-Jun-containing complexes. In addition, LPS stimulation induces the binding
of cognate nuclear factors to the Egr-1 and kappaB3 sites, which were identified as Egr-1 and p50/p65,
respectively. The CRE and kappaB3 sites in region II together confer strong LPS responsiveness to
a heterologous promoter, whereas individually they fail to provide transcriptional activation.
Increasing the spacing between the CRE and the kappaB3 sites completely abolishes
LPS induction, suggesting a cooperative interaction between c-Jun complexes and p50/p65. These
studies indicate that maximal LPS induction of the TNF-alpha promoter is mediated by concerted
participation of at least two separate cis-acting regulatory elements (Yao, 1997).
The transcription factor EGR-1 is a potential regulator of over 30 genes and plays a role in growth,
development, and differentiation; in addition, it is capable of significant transformation suppression activity.
The regulatory properties are reviewed and a hypothesis for the transformation suppression activity is proposed. EGR-1 contains three "zinc-finger" motifs in the C-terminal portion of the molecule that constitute the DNA-binding domain and interact with the promoters by virtue of two classes of GC-rich elements: single GC-elements (GCEs) with the consensus 5'-T-G-C-G-T/g-G/A-G-G-C/a/t-G-G/T-3' and overlapping sites consisting of an Sp-1 binding site and the GCE consensus or close homolog of these sequences. The Wilm's tumor suppressor gene product WT1 interacts with the same GCE. Owing in part to four alternate splice products, it also interacts with a broader range of GC-rich elements with the consensus 5'-GNGNGGGNG-3' and 5'-TCCTCCTCCTCCTC-3'. WT1 commonly but not invariably, acts as repressor of transcription, whereas EGR-1, in the absence of overlapping Sp-1 binding sequences, is often an activator. The well-known rapid response of the EGR-1 gene following mitogenic stimulation together with the occurrence of GCEs in the promoters of many growth factors and protooncogenes suggests a role of EGR-1 in growth. EGR-1 is constitutively expressed in several viral-transformed systems. In contrast, studies of model and human tumor lines reveal that EGR-1 has significant growth and transformation suppression roles. Recent studies show that this effect can be accounted for by the ability of EGR-1 to induce the expression and secretion of TGF-beta1, a potent growth suppressor for many cell types, by binding to a single GCE of the TGF-beta1 promoter. Although the effects of EGR- at overlapping Sp1/EGR-1 DNA binding sites are not predictable, known cases fall into two loose groups: Sp1 is usually activating; increasing the concentrations of EGR-1 leads to displacement that results in either inhibition of transactivation or EGR-1-dependent transactivation. Recent studies suggest that displaced Sp1 binds to and
activates the endogenous Egr-1 gene, thereby leading to "facilitated inhibition" of Sp1 function by the resulting increased EGR-1. This effect may augment the growth suppressive function of EGR-1 based on induction of TGF-beta1 (Liu, 1996).
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