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The Egr Family of Nuclear Signal Transducers
PROLIFERATION OF RENAL TUBULAR CELLS AND GROWTH FACTORS
The Egr Family of Nuclear Signal Transducers Vikas P. Sukhatme, MD, PhD • Extracellular ligands regulate the induction of several genes without the need for de novo protein synthesis. A subset of these so-called immedlate-early response genes (lEG) encode transcription factors. This report focuses on the Egr group of zinc finger transcription factors. Their characterization should provide important insights into how cells respond to diverse extracellular signals. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Signal transduction; gene expression; transcription factor.
T
HE PHENOTYPE of a cell changes in response to a variety of extracellular agents such as polypeptide growth factors, hormones, and neurotransmitters. In these processes, genes whose induction occurs in the presence of protein synthesis inhibitors are referred to as immediateearly response genes (lEG) (Fig 1) (for review, see Herschman l ). lEGs encode growth factors, growth factor receptors, cytoskeletal structures, and transcription factors. The importance of the latter group is that they serve as nuclear signal transducers by initiating a cascade of gene-protein interactions. Moreover, these immediate-early transcription factors are also induced during cellular differentiation, by signals that initiate a hypertrophic response, in response to ischemia, and by signals that cause neuronal excitation. I Immediateearly transcription factors comprise several "families": los (for review, see Curran2), jun,3.4 and Egr. 5.6 This report will focus on the Egr family. Egr-1: CDNA ISOLATION, SEQUENCE AND PROTEIN CHARACTERIZATION
The Egr-l cDNA5.6 (also known as Zif268,8 Krox-24,9 NGFI-A,IO and TIS8 11 ) was identified through a differential screening strategy aimed at isolating genes that were induced by serum addition to quiescent fibroblasts. In order to identify lEGs, serum induction was performed in the presence of cycloheximide. A critical second condition was used to enhance the probability of identifying transcription factors. We reasoned that these cDNAs might be universally conserved in diverse cell types. Only two cDNA clon~s were expressed in epithelial cells from liver and kidney and in lymphocytes following mitogenic stimulation. One was c-fos; the other clone was named Egr-l (early growth response gene-l). The Egr-l transcript had a message size of 3.4 kb and was induced rapidly
(>20-fold), but transiently, with a peak value occurring between 30 minutes and 1 hour and a halflife of approximately 15 minutes. Sequencing of the Egr-l cDNA clone revealed an open-reading frame of 533 amino acids,6 including a series of three tandem repeats, each of which conformed to the canonical sequence for a zinc finger structure of the Cys2-His2 subclass (Fig 2) (see references in Sukhatme et al 6). Such structures had previously been described in Xenopus, yeast, and Drosophila. These structures function as DNA-binding proteins and activators of gene expression. The specificity of binding is determined by the sequence of amino acids in the finger. The remainder of the protein has domains responsible for activating transcription. Thus, the discovery of a zinc finger encoding lEG suggested that this product may play a role in transducing an initial extracellular mitogenic signal into a longterm phenotypic response. An Egr-l antiserum had identified an 80-kD short-lived nuclear phosphoprotein in serum stimulated fibroblasts.12 The sequence 5 '-CGCCCCCGC-3 ' present in a single copy in the Egr-l promoter is a high-affinity binding site for this protein. 13 Binding is dependent on zinc. 12 Studies in progress are aimed at defining the most "optimal" binding site, the effects of Egr-l on its own promoter and the identification of physiologically important genes for Egr-l action. From the Departments of Medicine (Nephrology) and Molecular Genetics and Cell Biology, Howard Hughes Medicallnstitute, Chicago, IL. Address reprint requests to Vikas P. Sukhatme, MD, PhD, Departments of Medicine (Nephrology) and Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, Chicago , IL 60637. © 1991 by the National Kidney Foundation, Inc. 0272-638619111706-0006$3.0010
American Journal of Kidney Diseases, Vol XVII, No 6 (June), 1991: pp 615-618
615
616
VIKAS P. SUKHATME
ligand receptor
/"',,;:;; PO
P04
h
~ili1
second messengers
4
j--------'.....---- pre-existing transcription factor
.... - - - + - - - - - - - - t - - ~
immediate early gene (lEG) induction
Fig 1. Schematic of signal transduction pathways in a cell. A ligand (growth factor, neurotransmitter, etc) binds to its cognate receptor, thereby initiating a cascade of second messenger events. One such event includes kinase activation, which phosphorylates a preexisting transcription factor, rendering it capable of binding to the promoter region of an lEG and activating its transcription. (Reprinted with permission. 20)
Egr-I AS A NUCLEAR SIGNAL TRANSDUCER
Since c-fos is induced in a large number of biological responses (for review, see Sukhatme et a}5), we asked whether Egr-l expression might follow a similar pattern. Indeed, Egr-l can be induced by nerve growth factor upon addition to PCl2 pheochromocytoma cells. 6 . 10 These cells change from a mitotic state to a postmitotic state upon addition of this differentiation agent. Furthermore, Egr-l induction is also induced by depolarization of these cells by potassium ions. 6 An in vivo model of the latter, seizure activity, also induced Egr-l expression. 6 There is also a rapid increase in Egr-IIZit268 mRNA in hippocampal neurons by synaptic NMDA receptor activation. 14 Egr-l expression is also modulated during the differentiation of embryonal carcinoma cells. 6 In particular, in Pl9 embryonal carcinoma cells (these
cells differentiate along a neuronal route with retinoic acid treatment and along a "cardiac myocyte" route with DMSO addition), Egr-l is expressed at high levels as terminal differentiation proceeds. 6 Similarly in HL60 cells, treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) elicits a burst of Egr-l message, which then decreases rapidly within a few hours of stimulation (D. Slamon and Y.P.S., unpublished data). However, as these cells differentiate into macrophages and granulocytes (days 3 through 6), there is reexpression of Egr-l. Induction has also been seen in the kidney following both ischemic injury, as well as compensatory renal hypertrophy.15 These data indicate that many ligand receptor systems induce expression ofthe Egr-l gene. If this is the case, how then are distinct biological responses subsequently generated? We will return to this important question at the end of this report. How-
THE Egr GENE FAMILY
617
Egr-l protein structure:
nnnI,---~
C2H zinc finger domain 2 i _proline/serine/threonine _______ __ rich I I --
N
I
/
F
C
L
finger tip contains basic amino acids
Fig 2. Structure of Egr-1 protein and zinc finger. (Reprinted with permission. 20)
ever, given that Egr-l is a transcription factor that activates transcription through a specific DNA sequence and that Egr-l is induced by a broad array of extracellular signals, it clearly functions as a nuclear signal transducer. Furthermore, Egr-l expression during development l6 is particularly striking in cartilage and bone in a pattern similar to that of c-fos. These data support the idea that Egr1 and c-fos may be coregulated in vivo and together may regulate normal development. That Egr expression is not occuring primarily in rapidly dividing cells signifies a role for Egr-l as a transcription factor that mediates the expres~ion of a variety of tissue-specific genes, a function separate from its role as a cellular lEG.
OTHER MEMBERS OF THE Egr FAMILY
Several cDNAs (Egr-2,-3,-4) have been identified that encode proteins with closely related zinc fingers to those of Egr-l, but differ in sequence outside the DNA-binding domain. 7.17 Of particular interest is that a distant relative of this Egr family appears to be the candidate gene responsible for the genesis of Wilms' tumor. IS . 19 This gene has about 65 % similarity to the zinc finger domains of Egr-l ,-2,-3, and -4 in three of its four zinc fingers. Three of the Egr genes (Egr-I,-2, and -3) are growth factor-inducible, whereas the fourth is not. These genes have different developmental profiles and probably serve different functions during de-
618
VIKAS P. SUKHATME
velopment and differentiation, in contrast to possibly similar roles as transducers of a mitogenic response.
FUTURE DIRECTIONS
An important challenge is to define mechanisms by which extracellular signals that appear to elicit in a relatively nonspecific way a variety of lEG such as ios, jun, and members of the Egr family can lead to cell type-specific biological responses. A number of such mechanisms have recently been summarized, 1 including the identification of ligand-specific early response genes , the existence of cooperating cell-specific proteins, quantitative differences in induction pattern, and posttranslational modifications . A phenotype has not yet been defined for the Egr family. Gene transfer methods aimed at overexpressing or limiting the activity of these genes
(dominant negative or antisense methods) in cell culture and transgenic animals will be used. Another area that merits exploration is to try to identify the role of the Egr family of zinc finger proteins in human cancer. The localization of the human Egr-l gene to chromosome 5q23-31,6 a region often deleted in patients with therapy-related acute myelocytic leukemia, raises the intriguing possibility that the Egr-l protein may function as a negative regulator of cell growth, in a manner similar to that postulated for the Wilms' tumor and retinoblastoma genes. In support of this hypothesis, Egr-l expression is diminished in a number of human tumor samples as compared with normal surrounding tissue from the same patient (D. Slamon and Y.P.S., unpublished observa~ions). In summary, the major challenge ahead will be to derme functional signal transducing roles for immediate-early transcription factors in the diverse biological processes in which their expression is modulated.
REFERENCES 1. Herschman HR: Extracellular signals, transcriptional responses and cellular specificity. Trends Biochem Sci 14:455458, 1989 2. Curran , Fos T: The Oncogene Handbook , in Reddy EP, Ska1ka AM, Curran T (eds): Amsterdam , The Netherlands, Elsevier, 1988, pp 307-325 3. Ryder K, Nathans D: Induction of proto-oncogene c-jun by serum growth factors . Proc Natl Acad Sci USA 85:84548467, 1988 4 . Ryseck R-P, Harai SI, Yaniv M, et al: Transcriptional activation of c-jun during the Go/G, transition in mouse fibroblasts. Nature 334:535-537, 1988 5. Sukhatme Vp, Kartha S, Toback FG, et al: A novel early growth gene rapidly induced in fibroblasts , epithelial, and lymphocytic mitogens . Oncogene Res 1:343-355 , 1987 6. Sukhatme Vp, Cao X, Chang LL , et al: A zinc-finger encoding gene coregulated with c-fos during growth and differentiation and after depolarization . Cell 53:37-43, 1988 7. Joseph U , Le Beau MM , Jamieson GA: Molecular cloning , sequencing and mapping of Egr-2 , a human early growth response gene encoding a protein with " zinc-binding" finger structure. Proc Nat! Acad Sci USA 85:7164-7168, 1988 8. Christy BA, Lau LF, Nathans D: Agene activated in mouse 3T3 cells by serum growth factors encodes a protein with "zinc-finger" sequences. Proc Nat! Acad Sci USA 85 :7857-7861, 1988 9. Lemaire P, Revelant 0 , Bravo R, et al : Two mouse genes encoding potential transcriptional factors with identical DNAbinding domains are activated by growth factors in cultured cells. Proc Natl Acad Sci USA 85 :4691-4695 , 1988 10. Milbrandt J: A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science 238:797-799, 1987
11. Lim RW, Varnum BC, Herschman HR: Cloning of tetradecanoyl phorbol ester-induced "primary response" sequences and their expression in density-arrested Swiss 3T3 cells and a TPA non-proliferative variant. Oncogene 1:263-270, 1987 12 . Cao X , Koski RA , Gashler A :Identification and characterization of the Egr-I gene product, a DNA binding zinc finger protein induced by differentiation and growth signals. Mol Cell Bioi 10:1931-1939, 1990 13 . Christy BA, Nathans D: DNA binding site of the growth factor-inducible protein Zif268. Proc Nat! Acad Sci 86:87378741, 1989a 14. Cole AJ, Saffen DW, Baraban JM , et al: Rapid increase of an immediate-early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340:474-476, 1989 15 . Ouellette AJ , Malt RA , Sukhatme VP, et al: Expression of two " immediate early " genes, Egr-1 and c-fos , in response to renal ischemia and during compensatory renal hypertrophy in mice. J Clin Invest 85:766-771 , 1990 16. McMahon Ap, Champion JE, McMahon JA, et al: Developmental expression of the putative transcription factor Egr1 suggests that Egr-1 and c-fos are coregulated in some tissues. Development 108:281-287, 1990 17. Chavrier P, Zerial M, Lemaire P, et al: A gene encoding a protein with zinc fingers is activated during GO/G 1 transition in cultured cells. EMBO J 7:29-35 , 1988 18. Clark KM, Glaser TM , Ito CY, et al : Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms ' tumor locus. Cell 60:509-520, 1990 19. Gessler M, Poustka A, Cave nee W, et al : Homozygous deletion in Wilms' tumors of a zinc-finger gene identified by chromosome jumping. Nature 343 :774-778, 1990 20. Sukhatme VP: Early transcriptional events in cell growth: The Egr family. J Am Soc Nephrol 1:859-866, 1990
The Egr Family of Nuclear Signal Transducers Vikas P. Sukhatme, MD, PhD • Extracellular ligands regulate the induction of several genes without the need for de novo protein synthesis. A subset of these so-called immedlate-early response genes (lEG) encode transcription factors. This report focuses on the Egr group of zinc finger transcription factors. Their characterization should provide important insights into how cells respond to diverse extracellular signals. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Signal transduction; gene expression; transcription factor.
T
HE PHENOTYPE of a cell changes in response to a variety of extracellular agents such as polypeptide growth factors, hormones, and neurotransmitters. In these processes, genes whose induction occurs in the presence of protein synthesis inhibitors are referred to as immediateearly response genes (lEG) (Fig 1) (for review, see Herschman l ). lEGs encode growth factors, growth factor receptors, cytoskeletal structures, and transcription factors. The importance of the latter group is that they serve as nuclear signal transducers by initiating a cascade of gene-protein interactions. Moreover, these immediate-early transcription factors are also induced during cellular differentiation, by signals that initiate a hypertrophic response, in response to ischemia, and by signals that cause neuronal excitation. I Immediateearly transcription factors comprise several "families": los (for review, see Curran2), jun,3.4 and Egr. 5.6 This report will focus on the Egr family. Egr-1: CDNA ISOLATION, SEQUENCE AND PROTEIN CHARACTERIZATION
The Egr-l cDNA5.6 (also known as Zif268,8 Krox-24,9 NGFI-A,IO and TIS8 11 ) was identified through a differential screening strategy aimed at isolating genes that were induced by serum addition to quiescent fibroblasts. In order to identify lEGs, serum induction was performed in the presence of cycloheximide. A critical second condition was used to enhance the probability of identifying transcription factors. We reasoned that these cDNAs might be universally conserved in diverse cell types. Only two cDNA clon~s were expressed in epithelial cells from liver and kidney and in lymphocytes following mitogenic stimulation. One was c-fos; the other clone was named Egr-l (early growth response gene-l). The Egr-l transcript had a message size of 3.4 kb and was induced rapidly
(>20-fold), but transiently, with a peak value occurring between 30 minutes and 1 hour and a halflife of approximately 15 minutes. Sequencing of the Egr-l cDNA clone revealed an open-reading frame of 533 amino acids,6 including a series of three tandem repeats, each of which conformed to the canonical sequence for a zinc finger structure of the Cys2-His2 subclass (Fig 2) (see references in Sukhatme et al 6). Such structures had previously been described in Xenopus, yeast, and Drosophila. These structures function as DNA-binding proteins and activators of gene expression. The specificity of binding is determined by the sequence of amino acids in the finger. The remainder of the protein has domains responsible for activating transcription. Thus, the discovery of a zinc finger encoding lEG suggested that this product may play a role in transducing an initial extracellular mitogenic signal into a longterm phenotypic response. An Egr-l antiserum had identified an 80-kD short-lived nuclear phosphoprotein in serum stimulated fibroblasts.12 The sequence 5 '-CGCCCCCGC-3 ' present in a single copy in the Egr-l promoter is a high-affinity binding site for this protein. 13 Binding is dependent on zinc. 12 Studies in progress are aimed at defining the most "optimal" binding site, the effects of Egr-l on its own promoter and the identification of physiologically important genes for Egr-l action. From the Departments of Medicine (Nephrology) and Molecular Genetics and Cell Biology, Howard Hughes Medicallnstitute, Chicago, IL. Address reprint requests to Vikas P. Sukhatme, MD, PhD, Departments of Medicine (Nephrology) and Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, Chicago , IL 60637. © 1991 by the National Kidney Foundation, Inc. 0272-638619111706-0006$3.0010
American Journal of Kidney Diseases, Vol XVII, No 6 (June), 1991: pp 615-618
615
616
VIKAS P. SUKHATME
ligand receptor
/"',,;:;; PO
P04
h
~ili1
second messengers
4
j--------'.....---- pre-existing transcription factor
.... - - - + - - - - - - - - t - - ~
immediate early gene (lEG) induction
Fig 1. Schematic of signal transduction pathways in a cell. A ligand (growth factor, neurotransmitter, etc) binds to its cognate receptor, thereby initiating a cascade of second messenger events. One such event includes kinase activation, which phosphorylates a preexisting transcription factor, rendering it capable of binding to the promoter region of an lEG and activating its transcription. (Reprinted with permission. 20)
Egr-I AS A NUCLEAR SIGNAL TRANSDUCER
Since c-fos is induced in a large number of biological responses (for review, see Sukhatme et a}5), we asked whether Egr-l expression might follow a similar pattern. Indeed, Egr-l can be induced by nerve growth factor upon addition to PCl2 pheochromocytoma cells. 6 . 10 These cells change from a mitotic state to a postmitotic state upon addition of this differentiation agent. Furthermore, Egr-l induction is also induced by depolarization of these cells by potassium ions. 6 An in vivo model of the latter, seizure activity, also induced Egr-l expression. 6 There is also a rapid increase in Egr-IIZit268 mRNA in hippocampal neurons by synaptic NMDA receptor activation. 14 Egr-l expression is also modulated during the differentiation of embryonal carcinoma cells. 6 In particular, in Pl9 embryonal carcinoma cells (these
cells differentiate along a neuronal route with retinoic acid treatment and along a "cardiac myocyte" route with DMSO addition), Egr-l is expressed at high levels as terminal differentiation proceeds. 6 Similarly in HL60 cells, treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) elicits a burst of Egr-l message, which then decreases rapidly within a few hours of stimulation (D. Slamon and Y.P.S., unpublished data). However, as these cells differentiate into macrophages and granulocytes (days 3 through 6), there is reexpression of Egr-l. Induction has also been seen in the kidney following both ischemic injury, as well as compensatory renal hypertrophy.15 These data indicate that many ligand receptor systems induce expression ofthe Egr-l gene. If this is the case, how then are distinct biological responses subsequently generated? We will return to this important question at the end of this report. How-
THE Egr GENE FAMILY
617
Egr-l protein structure:
nnnI,---~
C2H zinc finger domain 2 i _proline/serine/threonine _______ __ rich I I --
N
I
/
F
C
L
finger tip contains basic amino acids
Fig 2. Structure of Egr-1 protein and zinc finger. (Reprinted with permission. 20)
ever, given that Egr-l is a transcription factor that activates transcription through a specific DNA sequence and that Egr-l is induced by a broad array of extracellular signals, it clearly functions as a nuclear signal transducer. Furthermore, Egr-l expression during development l6 is particularly striking in cartilage and bone in a pattern similar to that of c-fos. These data support the idea that Egr1 and c-fos may be coregulated in vivo and together may regulate normal development. That Egr expression is not occuring primarily in rapidly dividing cells signifies a role for Egr-l as a transcription factor that mediates the expres~ion of a variety of tissue-specific genes, a function separate from its role as a cellular lEG.
OTHER MEMBERS OF THE Egr FAMILY
Several cDNAs (Egr-2,-3,-4) have been identified that encode proteins with closely related zinc fingers to those of Egr-l, but differ in sequence outside the DNA-binding domain. 7.17 Of particular interest is that a distant relative of this Egr family appears to be the candidate gene responsible for the genesis of Wilms' tumor. IS . 19 This gene has about 65 % similarity to the zinc finger domains of Egr-l ,-2,-3, and -4 in three of its four zinc fingers. Three of the Egr genes (Egr-I,-2, and -3) are growth factor-inducible, whereas the fourth is not. These genes have different developmental profiles and probably serve different functions during de-
618
VIKAS P. SUKHATME
velopment and differentiation, in contrast to possibly similar roles as transducers of a mitogenic response.
FUTURE DIRECTIONS
An important challenge is to define mechanisms by which extracellular signals that appear to elicit in a relatively nonspecific way a variety of lEG such as ios, jun, and members of the Egr family can lead to cell type-specific biological responses. A number of such mechanisms have recently been summarized, 1 including the identification of ligand-specific early response genes , the existence of cooperating cell-specific proteins, quantitative differences in induction pattern, and posttranslational modifications . A phenotype has not yet been defined for the Egr family. Gene transfer methods aimed at overexpressing or limiting the activity of these genes
(dominant negative or antisense methods) in cell culture and transgenic animals will be used. Another area that merits exploration is to try to identify the role of the Egr family of zinc finger proteins in human cancer. The localization of the human Egr-l gene to chromosome 5q23-31,6 a region often deleted in patients with therapy-related acute myelocytic leukemia, raises the intriguing possibility that the Egr-l protein may function as a negative regulator of cell growth, in a manner similar to that postulated for the Wilms' tumor and retinoblastoma genes. In support of this hypothesis, Egr-l expression is diminished in a number of human tumor samples as compared with normal surrounding tissue from the same patient (D. Slamon and Y.P.S., unpublished observa~ions). In summary, the major challenge ahead will be to derme functional signal transducing roles for immediate-early transcription factors in the diverse biological processes in which their expression is modulated.
REFERENCES 1. Herschman HR: Extracellular signals, transcriptional responses and cellular specificity. Trends Biochem Sci 14:455458, 1989 2. Curran , Fos T: The Oncogene Handbook , in Reddy EP, Ska1ka AM, Curran T (eds): Amsterdam , The Netherlands, Elsevier, 1988, pp 307-325 3. Ryder K, Nathans D: Induction of proto-oncogene c-jun by serum growth factors . Proc Natl Acad Sci USA 85:84548467, 1988 4 . Ryseck R-P, Harai SI, Yaniv M, et al: Transcriptional activation of c-jun during the Go/G, transition in mouse fibroblasts. Nature 334:535-537, 1988 5. Sukhatme Vp, Kartha S, Toback FG, et al: A novel early growth gene rapidly induced in fibroblasts , epithelial, and lymphocytic mitogens . Oncogene Res 1:343-355 , 1987 6. Sukhatme Vp, Cao X, Chang LL , et al: A zinc-finger encoding gene coregulated with c-fos during growth and differentiation and after depolarization . Cell 53:37-43, 1988 7. Joseph U , Le Beau MM , Jamieson GA: Molecular cloning , sequencing and mapping of Egr-2 , a human early growth response gene encoding a protein with " zinc-binding" finger structure. Proc Nat! Acad Sci USA 85:7164-7168, 1988 8. Christy BA, Lau LF, Nathans D: Agene activated in mouse 3T3 cells by serum growth factors encodes a protein with "zinc-finger" sequences. Proc Nat! Acad Sci USA 85 :7857-7861, 1988 9. Lemaire P, Revelant 0 , Bravo R, et al : Two mouse genes encoding potential transcriptional factors with identical DNAbinding domains are activated by growth factors in cultured cells. Proc Natl Acad Sci USA 85 :4691-4695 , 1988 10. Milbrandt J: A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science 238:797-799, 1987
11. Lim RW, Varnum BC, Herschman HR: Cloning of tetradecanoyl phorbol ester-induced "primary response" sequences and their expression in density-arrested Swiss 3T3 cells and a TPA non-proliferative variant. Oncogene 1:263-270, 1987 12 . Cao X , Koski RA , Gashler A :Identification and characterization of the Egr-I gene product, a DNA binding zinc finger protein induced by differentiation and growth signals. Mol Cell Bioi 10:1931-1939, 1990 13 . Christy BA, Nathans D: DNA binding site of the growth factor-inducible protein Zif268. Proc Nat! Acad Sci 86:87378741, 1989a 14. Cole AJ, Saffen DW, Baraban JM , et al: Rapid increase of an immediate-early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340:474-476, 1989 15 . Ouellette AJ , Malt RA , Sukhatme VP, et al: Expression of two " immediate early " genes, Egr-1 and c-fos , in response to renal ischemia and during compensatory renal hypertrophy in mice. J Clin Invest 85:766-771 , 1990 16. McMahon Ap, Champion JE, McMahon JA, et al: Developmental expression of the putative transcription factor Egr1 suggests that Egr-1 and c-fos are coregulated in some tissues. Development 108:281-287, 1990 17. Chavrier P, Zerial M, Lemaire P, et al: A gene encoding a protein with zinc fingers is activated during GO/G 1 transition in cultured cells. EMBO J 7:29-35 , 1988 18. Clark KM, Glaser TM , Ito CY, et al : Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms ' tumor locus. Cell 60:509-520, 1990 19. Gessler M, Poustka A, Cave nee W, et al : Homozygous deletion in Wilms' tumors of a zinc-finger gene identified by chromosome jumping. Nature 343 :774-778, 1990 20. Sukhatme VP: Early transcriptional events in cell growth: The Egr family. J Am Soc Nephrol 1:859-866, 1990