The function and phenotype of vascular cells is controlled in part by diffusible, endothelial-derived mediators such as endothelin-1 (ET-1)()(1, 2, 3) . ET-1 is a 21-amino acid vasoconstrictor peptide that also regulates gene expression and growth of vascular and nonvascular cells in culture (4, 5, 6, 7, 8) . Accumulating evidence suggests that ET-1 contributes to growth and compensatory remodeling of the vasculature in vivo(9, 10, 11, 12) , and gene targeting studies demonstrate a critical role for ET-1 nuclear signaling in cell differentiation and development (13, 14, 15) . ET-1 binds to heterotrimeric G protein-coupled receptors and evokes a nuclear signaling cascade that activates immediate early gene transcription(16) . Transcription of immediate early genes is thought to convert ET-1-dependent nuclear signals into phenotypic changes in target cells. However, the molecular mechanisms linking ET-1 receptors to immediate early gene transcription remain unclear.

An ET-1 nuclear signaling cascade might involve nonreceptor protein-tyrosine kinases. ET-1 rapidly stimulates pp60 c-Src and pp125 focal adhesion kinase activity, resulting in tyrosine phosphorylation of specific cellular proteins(17, 18, 19, 20, 21) . A role for c-Src in ET-1 signaling is also supported by the observation that ET-1-stimulated phosphoinositide turnover is greatly amplified in v-src-transformed fibroblasts(22) . Protein tyrosine phosphorylation is required for induction by ET-1 of the c-fos immediate early gene(19) , which is one of the earliest genomic responses to ET-1(19, 23, 24) . These observations, and the finding that v-Src elevates c-fos transcription (i.e. see (25) ), suggest that the pathways that propagate ET-1 signals to the nucleus might involve c-Src.

In this study, we investigated whether c-Src or other Src family kinases participate in a nuclear signaling cascade linking G protein-coupled ET-1 receptors to the c-fos promoter in mesangial cells. We report here that ET-1-stimulated c-fos transcription is blocked by expression of a dominant negative c-Src mutant and by the COOH-terminal Src kinase (Csk), which both repress c-Src kinase activity. Moreover, full activation of the c-fos promoter by ET-1 requires c-Src-dependent pathways regulating the CArG box of the c-fos SRE and c-Src-independent pathways regulating the Ca/cAMP response element.

EXPERIMENTAL PROCEDURES

Reagents

Mesangial Cell Culture

Plasmids

Figure 1: Expression of the dominant negative SrcK- mutant blocks ET-1-stimulated c-fos transcription. A, schematic representation of the -356wt/fos luciferase (LUC) reporter and expression plasmids transfected into mesangial cells. Transcription of v-src and c-src inserts is driven by the M-murine leukemia virus long terminal repeat (LTR), whereas expression of the SrcK- insert is driven by the SV40 enhancer/promoter. B, left, mesangial cells transfected with the -356wt/fosLUC reporter (1 µg) with and without the -SrcK- expression plasmid (2 µg) were rendered quiescent in DMEM, 0.5% FBS. In all experiments promoter strength was held constant by inclusion of the appropriate amount of expression plasmid lacking a cDNA insert. As a negative control, cells were also transfected with 1 µg of the pGL3LUC parent vector lacking the c-fos promoter fragment. Cells were then left untreated (- - - ) or were treated with ET-1 (100 nM) or FBS (10%) for 16 h before cell lysis and measurement of luciferase activity. Data are normalized for -galactosidase activity and are expressed relative to untreated cells transfected with -356wt/fosLUC (- - - -). Mesangial cells were also transfected with a vector expressing Raf-1 (31) plus and minus the SrcK- plasmid. Right, mesangial cells transfected with -356wt/fosLUC (1 µg) and vectors expressing SrcK- (2 µg) or v-Src (2 µg) were treated as above with ET-1 (100 nM, 16 h). Typical relative light unit values ranged from 500 to 2000 in 20 µl of lysates from untreated cells transfected with -356wt/fosLUC.

Mesangial Cell Transfection and Reporter Gene Assays

For transient transfection with the wild-type and point mutant -356fosCAT reporters, cells in 100-mm Petri dishes (1.0 10 cells/plate) were transiently transfected as described above, but with 10 µg of the -356fosCAT reporters, 5 µg of pRSVGal, and pUC19 carrier DNA to a total of 30 µg of DNA/plate. Where indicated, cells were co-transfected with 10 µg of plasmids expressing either v-Src or c-Src (30) (see Fig. 1A) or treated with ET-1 or FBS as described above. CAT activity was quantified by liquid scintillation counting of thin layer chromatography C spots of the mono- and diacetylated forms of chloramphenicol and normalized for -galactosidase activity as described previously(37) .

Data Analysis

RESULTS

We used cultured rat mesangial cells in this study to investigate the potential role of c-Src in activation of the c-fos promoter by ET-1. Mesangial cells derive from the glomerular microvasculature of the kidney, and ET-1 apparently contributes to the compensatory growth of mesangial cells and remodeling of glomerular capillaries following renal injury(8, 9) . Previous experiments using cultured mesangial cells showed that receptors of the ET subtype stimulate c-Src activity and tyrosine phosphorylation of cellular proteins(19, 38) . Moreover, induction of c-fos mRNA by ET-1 is blocked by protein-tyrosine kinase inhibitors(19) . These results suggest that the signaling mechanisms that transduce the ET-1 signal from receptor to the nucleus are intact in mesangial cells and might involve c-Src protein-tyrosine kinases (17, 19, 20) .

To determine whether c-Src contributes to c-fos promoter activation by ET-1, we subcloned a genomic DNA fragment containing nucleotides -356 to +109 of the murine c-fos gene into a plasmid to drive transcription of a luciferase gene (Fig. 1A). When this reporter construct (-356wt/fos LUC) was transiently transfected into mesangial cells, ET-1 stimulated a 3.6-fold increase in luciferase activity (Fig. 1B). These results demonstrate that the -356wt/fos LUC reporter contains the necessary cis-elements to confer responsiveness to ET-1. Moreover, transfection with a luciferase vector without the c-fos promoter sequence (Fig. 1B, pGL3LUC) confirmed that the increase in transcription observed with ET-1 was not due to activation of spurious regulatory elements in the luciferase vector.

We next employed a dominant negative mutant strategy (39) to determine whether c-Src contributes to activation of c-fos transcription by ET-1. A kinase-inactivating mutation in c-Src (Lys Met, SrcK-) forms a dominant negative c-Src protein that blocks signaling by platelet-derived growth factor and epidermal growth factor in NIH 3T3 fibroblasts(27, 28) . Mesangial cells were co-transfected with the -356wt/fos LUC reporter and a vector expressing SrcK- under control of the SV40 promoter/enhancer (Fig. 1A) followed by stimulation with ET-1. The dominant negative SrcK- mutant prevented the increase in c-fos transcription in cells stimulated by ET-1 (Fig. 1B, 3.6-fold versus 1.2-fold with SrcK-). The wild-type SrcK+ construct (2 µg) (27) did not inhibit ET-1-stimulated c-fos transcription (data not shown). SrcK- failed to decrease transcription in cells transfected with the pGL3LUC control reporter (Fig. 1B), and SrcK- only partially inhibited c-fos transcription in cells stimulated by fetal bovine serum (Fig. 1B, 6.2-fold versus 4.4-fold with SrcK-). The ability of SrcK- to inhibit ET-1-stimulated c-fos transcription suggests a role for c-Src in ET-1 nuclear signaling.

Two additional experiments confirmed that SrcK- did not simply produce its blockade by a general inhibition of transcription. First, mesangial cells were co-transfected with the -356wt/fos LUC reporter and a vector expressing a constitutively activated c-Raf-1 mutant (Raf-1) that lacks the 303 NH-terminal amino acids(31) . c-Raf-1 acts downstream of c-Src in a signaling pathway that increases c-fos transcription (see (40, 41, 42) for review), and therefore SrcK- would not be predicted to inhibit c-Raf-1-induced transcription. Consistent with this prediction, Raf-1 stimulated a 3.0-fold increase in c-fos transcription that was not inhibited by SrcK- (Fig. 1B). Second, the actions of dominant negative mutants should be reversible(39) , and we demonstrated that expression of v-Src ( (30) and Fig. 1A) reversed inhibition of ET-1-stimulated c-fos transcription by SrcK- (Fig. 1B). Taken together, these results strongly suggest that the dominant negative actions of SrcK- are specific and that c-Src contributes to activation of c-fos transcription by ET-1.

To obtain independent evidence that c-Src propagates an ET-1 signal to the nucleus, we transfected cells with a vector expressing COOH-terminal Src kinase (Csk)(29) . Csk is a protein-tyrosine kinase containing SH2 and SH3 domains that phosphorylates the COOH-terminal tyrosine (i.e. Tyr) of c-Src and other Src family tyrosine kinases(43) . Phosphorylation of the COOH-terminal tyrosine suppresses Src kinase activity, and gene targeting and other studies demonstrate that Csk negatively regulates Src family tyrosine kinase activity in vivo(29, 44, 45, 46) . Csk expression blocked the increase in c-fos transcription in cells treated with ET-1 (Fig. 2, 4.1-fold versus 1.2-fold with Csk). Csk only partially inhibited FBS-stimulated c-fos transcription and had no effect on -Raf-1-stimulated transcription. These results support the hypothesis that c-Src or other Src family kinases contribute to an ET-1 signaling cascade that increases c-fos transcription.

Figure 2: Expression of the Src-inactivating COOH-terminal Src kinase (Csk) blocks ET-1-stimulated c-fos transcription. Mesangial cells were transfected with -356wt/fosLUC as described above plus or minus a plasmid expressing Csk (1 µg) under transcriptional control of the cytomegalovirus promoter/enhancer(29) . Cells were then treated with ET-1 (100 nM, 16 h) or FBS (10%, 16 h) before assay of luciferase activity. In some experiments cells were transfected with the vector expressing Raf-1 plus or minus Csk. Data are corrected for -galactosidase and normalized to control values with -356wt/fosLUC alone (- - - -).

We next asked which cis-elements of the c-fos promoter are activated by the ET-1/Src-based signaling cascade. Plasmids expressing either c-Src or v-Src (Fig. 1A) were co-transfected with a plasmid in which a genomic c-fos promoter sequence (bp -356 to +109) was subcloned upstream of a chloramphenicol acetyltransferase reporter gene (-356wt/fos CAT)(33) . Both c-Src and v-Src increased c-fos transcription (Fig. 3A, 2.4-fold versus 5.2-fold, respectively), demonstrating that this -356 to +109 c-fos promoter fragment contains Src-responsive cis-elements. We therefore transfected mesangial cells with a series of point mutant -356wt/fos CAT reporters(33, 34, 35, 36) . These extensively characterized point mutations prevent binding of cognate trans-acting factors to their respective cis-elements, thereby enabling analysis of the function of specific cis-elements in activation of the c-fos promoter by ET-1 and Src (see Table 1).

Figure 3: Src-based pathways propagate ET-1 signals to the CArG element of the c-fos SRE but not to the Ca/CRE. A, mesangial cells in 100-mm Petri dishes were transfected with the -356wt/fosCAT reporter plasmid and with plasmids expressing v-Src (10 µg, lane 2) or c-Src (10 µg, lane 3). After transfection, cells were held in DMEM, 0.5% FBS for 24 h and lysed for measurement of CAT activity (i.e. 48 h after DNA addition). Radioactive bands corresponding to acetylated and nonacetylated [H]chloramphenicol were excised from the thin layer plate and counted to calculate CAT activity. Activity was corrected for -galactosidase expression and expressed relative to values for null transfection (lane 1). Similar results were observed in three independent experiments. B, mesangial cells were transfected with point mutant c-fos promoter constructs linked to CAT (10 µg each, Table 1). As indicated in the legend, cells were also co-transfected with a plasmid expressing v-Src (10 µg, Fig. 1A) or treated with ET-1 (100 nM, 16 h) or FBS (10%, 16 h) as described in the legend to Fig. 1B. These point mutations are discussed in the text and have been extensively characterized and the sequences are published(33, 34, 35, 36) . Mutant cis-elements of the c-fos promoter are indicated schematically at the left, where a strike-through indicates that cognate trans-acting factors cannot bind to the point mutant cis-element. Transfection efficiencies were not always equivalent between sets transfected with different plasmids, thus the results were normalized to control values with the identical plasmid. Standard error bars were omitted for clarity but were never greater than 15% of the mean value. Abbreviations: SIE, sis-inducible element; Ets, E26 transformation-specific; CArG, CA-rich G; SRE, serum response element; FAP, AP-1/CRE-like element; Ca/CRE, Ca/cAMP response element.

Mutation of the CArG sequence of the c-fos SRE, which binds dimers of serum response factor, prevented transcriptional activation by ET-1 and v-Src (Fig. 3B, pm12). That FBS-stimulated transcription of the pm12fos CAT reporter plasmid demonstrated that the mutant construct was transcriptionally active. A promoter containing point mutations in the sis-inducible element, AP-1/CRE-like element, and Ca/CRE (Ca/CRE), but not in the SRE, were not responsive to ET-1 but were responsive to v-Src (Fig. 3B, pm3.6.9). Although promoters containing five tandem repeats of the SRE responded to v-Src, ET-1 failed to stimulate transcription of these constructs (Fig. 3B, 5SRE). Point mutation of the Ets DNA sequence of the c-fos SRE, which recognizes p62 ternary complex factors (i.e. Elk-1 or Sap-1), did not inhibit c-fos transcription stimulated by ET-1 or v-Src (Fig. 3B, pm18). In mesangial cells, the ability of v-Src to stimulate c-fos transcription in the absence of Ets-binding proteins is consistent with our previous observation that ET-1-stimulated c-fos transcription did not require Ets DNA-protein interactions (37) and substantiate the apparently cell type-specific requirement for p62 ternary complex factors in c-fos promoter regulation(25, 47, 48, 49) . Taken together, these results argue that c-fos transcription stimulated by ET-1 and v-Src requires the CArG DNA sequence of the SRE. Unlike v-Src, however, DNA sequences in addition to the CArG box are necessary for ET-1-stimulated c-fos transcription.

Point mutations in the c-fos Ca/CRE, which binds homo- or heterodimers of CREB and ATF, block c-fos transcription stimulated by cAMP and [Ca](36, 50, 51) . ET-1 does not increase intracellular cAMP in mesangial cells(52) , but elevation of [Ca] is an important effector in ET-1 signaling(16) . We therefore tested whether the Ca/CRE was required for ET-1 and Src nuclear signaling to the c-fos promoter. A c-fos promoter with Ca/CRE point mutations was not responsive to ET-1 but was stimulated by v-Src (Fig. 3B, pm3). Thus, ET-1 signaling to the c-fos promoter requires the Ca/CRE. Moreover, Src or effectors upstream of Src represent a point of divergence for nuclear signals stimulating c-fos transcription in cells treated with ET-1.

We previously demonstrated that a dominant negative Ras mutant (Asn-17-c-Ha-Ras(32) ) blocks activation of the c-fos SRE by ET-1(37) . Because Ras has been reported to be downstream of c-Src in NIH 3T3 cells(53, 54) , we asked whether Asn-17-c-Ha-Ras would block Src-stimulated transcription from the -356 to +109 c-fos promoter fragment in mesangial cells. As expected(37) , Asn-17-c-Ha-Ras inhibited c-fos transcription in cells treated with ET-1 (Fig. 4). Asn-17-c-Ha-Ras also inhibited c-fos transcription stimulated by c-Src (Fig. 4), thereby confirming that Ras lies downstream of Src in this pathway.

Figure 4: A dominant negative Ras mutant (Asn-17-c-Ha-Ras) blocks c-fos transcription stimulated by ET-1 and c-Src. Mesangial cells were transiently transfected with the -356wt/fosLUC reporter plus or minus a plasmid expressing a dominant negative Ras mutant under transcriptional control of the Moloney-murine leukemia virus terminal repeat. As indicated, cells were treated with ET-1 or co-transfected with a vector expressing c-Src as described in the legend to Fig. 1B. Promoter strength was held constant in all experiments by addition of expression plasmids without cDNA inserts.

DISCUSSION

ET-1 evokes nuclear signaling cascades leading to differential expression of genes that control cell growth and/or differentiation. Previous studies have shown that ET-1 receptors activate nonreceptor protein-tyrosine kinases such as c-Src and focal adhesion kinase, but it is not clear whether nonreceptor protein-tyrosine kinases contribute to nuclear signaling by ET-1. The goal of these studies was to determine whether c-Src or Src family kinases contribute to transcriptional activation of the c-fos immediate early gene by ET-1. Our results, based on inhibition with dominant negative SrcK- mutants and Csk, strongly suggest that c-Src contributes to a nuclear signaling pathway linking ET-1 receptors to c-fos transcription. c-Src appears to participate in a pathway specifically linking ET-1 receptors to the CArG cis-element of the c-fos SRE. Although stimulation of c-fos transcription by ET-1 signaling also requires the Ca/CRE, c-Src does not appear to participate in this limb of the pathway (Fig. 5).

Figure 5: Schematic representation of the nuclear signaling pathway linking ET-1 receptors to c-fos transcription in mesangial cells of the glomerular microvasculature. ET-1 binds to a G protein-coupled ET receptor subtype (19, 38) and a bifurcating pathway activates the CArG element of the SRE and the Ca/CRE. ET-1-activated c-Src (or a closely related Src family kinase) propagates the signal leading from the ET receptor to the CArG sequence, which binds SRF, but does not appear to regulate events occurring at the Ca/CRE. Ras apparently acts downstream of the ET receptor and c-Src in the pathway leading to CArG activation (see also (37) ).

c-Src or Src Family Protein-tyrosine Kinases Contribute to a Nuclear Signaling Cascade Linking ET-1 Receptors to the c-fos Promoter

As it is possible that both SrcK- and Csk inhibit other closely related members of the Src family of protein-tyrosine kinases such as Fyn and Lyk(27, 28, 44, 46) , we cannot formally rule out possible involvement of other Src-related kinases in ET-1 nuclear signaling. However, we have been unable to demonstrate stimulation of other Src-related kinases by ET-1 in mesangial cells. For example, mesangial cells contain abundant levels of p62 c-Yes, but ET-1 does not stimulate c-Yes protein-tyrosine kinase activity. ()We therefore think that it is likely that c-Src contributes to transduction of the ET-1 signal to the c-fos promoter in these cells.

Activation of the c-fos Promoter by ET-1 Requires Both the CArG Box of the SRE and the Ca/CRE

We demonstrated that full activation of the c-fos promoter by ET-1 also required the Ca/CRE, which binds homo- or heterodimers of CREB and ATF. Point mutations in the Ca/CRE that prevent binding of CREB/ATF (36) blocked ET-1-stimulated c-fos transcription. The dual requirement of the c-fos SRE and Ca/CRE for c-fos promoter activation by ET-1 is similar to nerve growth factor-induced c-fos transcription, which also requires the c-fos SRE and Ca/CRE(58) . Our data are also consistent with recent results by Robertson et al.(59) in transgenic mice, where regulation of c-fos transcription by external stimuli required multiple, interdependent cis-elements in the c-fos promoter.

Src Participates in the ET-1-Ras-c-fos CArG Box Signaling Cascade

Our experiments also provide additional support for the importance of ET-1-evoked signals in initiating immediate early gene transcription in vascular and nonvascular cells. The results do not exclude, however, the importance of other second messenger systems to regulate immediate early gene transcription and cell growth following exposure to ET-1. Indeed, we and others (19, 60) have found that protein kinase C is required for mitogenic signaling by ET-1 and for enhancement by ET-1 of EGF-induced transformation. Nonetheless, c-Src activation is an early step following ET-1 receptor activation and is temporally situated to transduce signals leading to long term changes in gene expression and vascular cell phenotype. Src kinases might also contribute to ET-1 nuclear signals that regulate determination of cell fate and development(13, 14, 15) . Finally, these results also point to a widening role for nonreceptor protein-tyrosine kinases in propagating signals from G protein-coupled receptors.

FOOTNOTES

*

This work was supported by a grant from the National Institutes of Health DK-46939 and by Grant-in-aid 93-1514 from the American Heart Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence and reprint requests should be addressed: Dept. of Medicine, Division of Nephrology, Biomedical Research Building, Rm. 427, Case Western Reserve University, 2065 Adelbert Rd., Cleveland, OH 44106. Tel.: 216-368-1251; Fax: 216-368-1249; mss5@po.cwru.edu.

()

The abbreviations used are: ET-1, endothelin-1; LUC, luciferase, SRE, serum response element; Ca/CRE, Ca/cAMP response element; SRF, serum response factor; TCF, ternary complex factor; CRE, cAMP response element; CREB, cAMP response element-binding; FBS, fetal binding serum; DMEM, Dulbecco's modified Eagle's medium; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine; ATF, activating transcription factor; CAT, chloramphenicol acetyltransferase.

()

W. H. Herman and M. S. Simonson, unpublished data.

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