Great strides have been made in the last year toward understanding the mechanisms of cytokine and growth factor signal transduction. These extracellular signaling proteins include growth hormone (GH), ()prolactin, interleukins (IL), interferons, granulocyte-macrophage colony stimulating factor, and colony stimulating factor 1. The binding of these polypeptides to their specific surface receptors in target cells is followed by a cascade of events activating the Jak-STAT pathway. In this pathway, the Janus kinase (Jak) family of tyrosine kinases, known to be associated with these receptors, are activated and tyrosine-phosphorylated. These kinases, in turn, presumably activate a family of latent cytoplasmic proteins known as signal transducers and activators of transcription (STAT), through phosphorylation of tyrosine residues. The activated STAT proteins are then translocated to the nucleus where they, by themselves or in combination with otherwise weak DNA-binding proteins, bind to specific response elements on responsive genes and activate transcription(1) . Six of these STAT proteins have been identified to date. Some of the STAT proteins are highly specific in their response to individual cytokines (e.g. Stat2 for interferon-), while others appear to be involved in multiple pathways(2) . The STAT proteins recognize response elements that share homology with the -interferon activation site (GAS) recognized by Stat1(1) .

The involvement of Jak-STAT pathways in GH signal transduction has been evidenced recently. Jak2 has been shown to be associated with GH receptors following GH binding with phosphorylation of both Jak2 and the GH receptor and subsequent activation of signal transduction(3) . Further, it has been observed that GH treatment appears to activate several STAT proteins resulting in their phosphorylation. This has been noted both in cultured cell systems (4, 5, 6, 7) and in liver(8, 9) , a known target organ for GH action. The association of these STAT protein activations with altered GH-responsive gene transcription is, however, less certain.

Our own investigations into the mechanism of GH-responsive gene expression in the rat liver have centered on the serine protease inhibitor (Spi) 2.1 gene. It is, to date, the best characterized physiological system for studying GH action. Spi 2.1 expression is greatly reduced by hypophysectomy and can be restored to 40% of its normal level by the administration of GH alone. Full restoration requires the synergistic action of GH, thyroxine, corticosterone, and dihydrotestosterone(10) . Its rapid induction by GH is direct and not mediated by insulin-like growth factor I, ()another GH early response gene(11) . We have previously characterized a GH response element, GHRE, extending from -147 to -103 in the 5`-flanking region of the Spi 2.1 gene that is responsible for its induction by GH and detected an inducible nuclear factor(s) in rat liver, designated as GHINF, which binds to the GHRE in a state-specific manner(12) . Appearance of this binding activity following GH treatment of hypophysectomized rats requires no new protein synthesis (12) suggesting that post-translational modification of an extant factor is required. We recently demonstrated that the critical modification of GHINF is that of tyrosine phosphorylation, which is required for its binding to the GHRE(13) . Within the GHRE, we and others have noted the presence of two GAS elements(11, 14) . To examine the function of these GAS elements and to further characterize GHINF, we undertook purification of GHINF from rat liver. These studies indicate that GHINF interacts synergistically with two GAS elements in the Spi 2.1 promoter for stimulating transcription and that GHINF has antigenic similarity to Stat5.

EXPERIMENTAL PROCEDURES

GHINF Purification

Salmon sperm DNA (Pharmacia) was sonicated and phenol-extracted according to standard protocols, then ethanol-precipitated twice, washed, and dissolved in coupling buffer(15) . An insert containing eight tandem copies of GHRE (12) was gel-purified from a pGem3Z plasmid and subjected to the same treatment as the sonicated salmon sperm DNA. Cyanogen bromide-activated Sepharose 4B (Pharmacia) was prepared according to the manufacturer's protocol. Coupling of either salmon sperm DNA or GHRE to activated Sepharose was then carried out(15) .

The following buffer was used in all chromatography and dialysis steps: 25 mM HEPES, pH 7.6, 0.1 M KCl, 0.1 mM EDTA, 0.5 mM dithiothreitol, 0.2 mM phenylmethylsulfonyl fluoride, 3 mM MgCl, 5 mM CaCl, and 20% glycerol. Subsequent to heparin-Sepharose chromatography, Nonidet P-40 was added to the above buffer at a final concentration of 0.05% for salmon sperm DNA-Sepharose, 0.1% for GHRE-Sepharose, and 1% for agarose-conjugated anti-phosphotyrosine columns. For the first three columns, the following protocol was followed. Crude extracts or fractions containing GHINF activity were pooled, dialyzed, and loaded onto the column. Fractions were eluted in a stepwise KCl gradient of 0.2 M to 1 M. Fractions containing GHINF activity, as monitored by electromobility shift assays (EMSA) (13) with GHRE (Table 1, probe A), were pooled, dialyzed, and then loaded onto the next column. After loading onto the final agarose-conjugated anti-phosphotyrosine column, GHINF was eluted with 2 mMo-phospho-L-tyrosine (Boehringer Mannheim) according to the manufacturer's protocol. Following dialysis, pooled fractions were stored at -80 °C.

DNA Binding Studies

Antibodies

Oligonucleotides

The sequences of several other oligonucleotides tested for GHINF binding are shown in Table 2. These include: the high affinity sis-inducible element (SIE) from c-fos(8) , -interferon response region (GRR) from the high affinity Fc receptor for IgG (FcRI)(4) , GAS-like element (SPI-GLE-1) from Spi 2.1(14) , and the prolactin response element (PRE) of the -casein gene(20) . Two sequences are shown for GRR: the full-length GRR and a 3` fragment. Two are also shown from the -casein promoter: the PRE and a longer fragment with an additional 5` sequence containing a second GAS-like element. Appropriate primers were also synthesized for duplex formation and extension reactions.

Plasmid Constructions

For each GHRE mutation, two PCRs were performed with appropriate primers to generate a fragment extending from the HindIII site at -275 to the mutation/restriction site and a second fragment extending from the mutation/restriction site to PstI site at +85 of the template Spi-A-CAT plasmid. The resultant PCR products were purified with the Qiaquick PCR product purification kit (Qiagen Inc., Chatsworth, CA), restriction-digested with appropriate enzymes, purified again, and quantitated. The template plasmid was digested with HindIII/PstI to remove the -275/+85 fragment, treated with calf intestinal phosphatase, and gel-purified with Prep-A-Gene (Bio-Rad). A triple ligation incorporating the two PCR products and the template vector was performed. The complete plasmid containing each mutation was transformed into Escherichia coli RR1 cells. With the exception of the mutation/restriction site, the resultant clones were identical with the original template plasmid. Mutations were confirmed by sequencing according to the manufacturer's protocol (Sequenase Version 2.0, United States Biochemical Corp.). The plasmids generated in this manner were designated Spi-B-CAT, Spi-C-CAT, Spi-D-CAT, Spi-E-CAT, and Spi-F-CAT to reflect, respectively, mutations B, C, D, E, and F as listed in Table 1.

Functional Assays

RESULTS

Purified GHINF Interacts with the Spi 2.1 GHRE

Figure 1: Purification and characterization of GHINF. A, GHINF binding activity at successive stages of purification. EMSA was performed as described previously(13) . Decreasing amounts of poly(dIdC) were added to fractions from successive stages of purification. No poly(dIdC) was added in the affinity- or immunopurified fractions. The following amounts of protein were added in each reaction: crude extract (Cr), 6 µg; heparin-Sepharose fraction (He), 6 µg; salmon sperm DNA-Sepharose fraction (sD), 3 µg; affinity-purified fraction (Af), 2 ng; immunopurified fraction (Im), 1 ng. B, SDS-PAGE of affinity- and immunopurified GHINF. SDS-PAGE (10%) was performed according to standard protocols(36) . Silver staining was performed as described previously(37) . Low molecular size SDS-PAGE standards (Bio-Rad Laboratories) were used in estimating the sizes. The heavy arrow indicates the position of the dominant band seen at 93 kDa. The minor band at 70 kDa is indicated by the light arrow. Shown are the affinity- (Af) and immunopurified (Im) fractions. C, UV-cross-linking of affinity-purified GHINF. GHRE was labeled with deoxy-GTP as the radioactive nucleotide to a specific activity of 1 10 cpm/µg. Prestained low molecular size SDS-PAGE standards (Bio-Rad Laboratories) were used in estimating sizes. Two bands, corresponding to 93 kDa and 70 kDa, were cross-linked to the GHRE.

To delineate the boundaries of the Spi 2.1 gene sequences bound by GHINF, DNase I footprinting was performed using affinity-purified GHINF and various crude liver nuclear extracts. With affinity-purified GHINF, only one domain of protection is seen on examination of the fragment from -192 to +85 of the Spi 2.1 gene (Fig. 2, lane 5). This protected region extends from -149 to -115. The same footprint, with somewhat less protection from -149 to -138, is apparent in extracts of normal rats (lane 3), normal rats treated with GH (lane 4), or hypophysectomized rats treated with GH (lane 2). It is absent in extracts from untreated hypophysectomized rats (lane 1). This binding activity is therefore GH state-specific.

Figure 2: DNase I footprinting of affinity-purified GHINF and extracts from normal and hypophysectomized rats treated with GH. The fragment -192/+85 from the 5`-flanking region of Spi 2.1 gene was end-labeled and employed as probe. Lane 1 represents labeled DNA species from reactions containing 10 µg of crude hepatic nuclear extract from hypophysectomized rats; lane 2, 10 µg of extract from hypophysectomized rats treated with GH; lane 3, 8 µg of extract from normal rats; lane 4, 36 µg of extract from normal rats treated with GH; lane 5, 7 ng of affinity-purified GHINF; lane 6, labeled -192/+85 fragment alone; lane 7, Maxam-Gilbert sequencing of the -192/+85 fragment. The region protected from DNase I digestion, -149 to -115, is marked.

Mutational Analysis of GHRE Binding

Figure 3: GHINF binds synergistically to two GAS elements in the GHRE. A, EMSA reactions were performed with affinity-purified GHINF and the GHRE mutations listed in Table 1. The lanes are labeled to reflect the mutated GHRE probes under investigation. B, competition assays of GHINF binding with mutations C, D, and E. Duplexes of mutations C, D, and E were extended with cold nucleotides and Klenow fragment of E. coli polymerase I. 20-fold molar excess of these duplexes (lane 2, +C; lane 3, +D; lane 4, +E) were then preincubated with GHINF for 30 min at 4 °C before addition of radiolabeled wild type GHRE. Lane 1 represents GHINF binding to GHRE (A) alone.

Functional Assays of GHRE Mutations

Figure 4: Both GAS elements of the GHRE are necessary for the functional response of primary hepatocytes to GH. Primary hepatocytes were transfected with either wild type Spi-A-CAT, or Spi-B-CAT, Spi-C-CAT, Spi-D-CAT, Spi-E-CAT, and Spi-F-CAT containing, respectively, mutations B, C, D, E, and F as listed in Table 1and then tested for their responses to GH. CAT activities were calculated as percentage conversion of chloramphenicol to its acetylated forms. The values shown are representative of three separate experiments.

While GHINF binding as shown on EMSA does not require the sequence upstream of the 5` GAS element, mutation of that sequence (Spi-B-CAT) led to a dramatic reduction of CAT activity in response to GH. This result suggests that another factor binding 5` to GHINF may be important for the GH response. However, mutation downstream of the 3` GAS element did not lead to any diminution of the GH response (Spi-F-CAT). This indicates that only the region delineated by DNase I footprinting is involved in GH activation of Spi 2.1 transcription.

GHINF Is Distinct from Stat1 and Stat3

Figure 5: GHINF is distinct from Stat1 and Stat3. The following buffer was used for all EMSA reactions in this figure: 20 mM HEPES, pH 7.6, 1 mM MgCl, 0.1 mM EDTA, 0.5 mM dithiothreitol, 0.2 mM phenylmethylsulfonyl fluoride, 4% Ficoll, 40 mM KCl, and 2 µg/20 µl poly(dIdC). Six µg of liver extracts from hypophysectomized rats(-) and those treated with GH (+) and 2 ng of affinity-purified GHINF (Af) were incubated with preimmune serum (lanes 1-3) or antiserum to Stat3, AbN (lanes 4-6), and then probed with the high affinity SIE from the promoter of c-fos. In addition, affinity-purified GHINF, preincubated with either the preimmune serum or AbN, was also probed with the GHRE (lanes 7 and 8). The positions of GHINF, Stat1, Stat3, and Stat1/3 heterodimers are indicated by the arrows.

Figure 6: GHINF is immunologically related to Stat5, but not to Stat1 or Stat3. Immunoblots of GH-treated rat liver extract (Cr), affinity-purified GHINF (Af), and positive control lysates (Ctl) (human A431 cell lysate for Stat1 antibody and mouse RSV3T3 cell lysate for Stat3 and Stat5 antibodies were obtained from Transduction Laboratories) were probed with C-terminal Stat1 antibody (Stat-1 (C)) (A), N-terminal Stat3 antibody, AbN (Stat-3(N)) (B), and C-terminal Stat5 antibody (Stat-5 (C)) (C). The migration distances of prestained molecular mass markers are shown to the right (in kilodaltons).

GHINF and Stat5

To further explore the relationship between GHINF and Stat5, we examined GHINF binding to a known Stat5 binding element. EMSA was performed with two probes from the PRE region of the rat -casein promoter. The PRE formed a band with purified GHINF; however, this band migrated with a faster mobility than the complex formed with the GHRE (Fig. 7, lane 4). Examination of the -casein promoter in the region of the PRE revealed a second GAS-like element located 7 bases upstream. This element is conserved at the same position in the promoters of the rat, mouse, rabbit, and cow -casein genes. We therefore probed with an oligonucleotide corresponding to this ``long'' -casein sequence. In this case, a diffuse complex with mobility between that of the PRE and that of the GHRE complex was seen (lane 3).

Figure 7: GHINF binds to both one or two GAS elements from -casein and FcRI genes. Standard EMSA conditions were used (see ``Experimental Procedures''). Affinity-purified GHINF was used in binding assays with labeled full-length GRR (lane 1) and its 3` fragment (lane 2), the -casein PRE (lane 4), and a longer fragment from the -casein promoter including a second GAS-like element 5` of the PRE (lane 3); lane 5 shows GHINF binding to the full-length GHRE. Lane 6 shows failure of binding of a GHRE fragment that contains only the 3` GAS element, SPI-GLE-1.

To examine another element which has similar architecture and which has known GH-state specific binding, we examined GHINF binding to the GRR of FcRI(4) . GHINF also binds to both the short (lane 2) and long (lane 1) forms of GRR from FcRI. As with the -casein probes, the complexes formed are qualitatively different from that of GHRE. The 3` fragment of the GRR forms a faster moving complex, and the full-length GRR appears to form a diffuse complex. In contrast to binding observed seen with both the PRE and the short GRR, an oligonucleotide corresponding to only the 3` GAS site of GHRE (SPI-GLE-1) did not lead to the formation of a DNA-protein complex with purified GHINF under our conditions (lane 6), suggesting that sequences flanking the PRE influenced binding. Together, these results suggest that the GHINF is a Stat5-like protein that interacts synergistically with two GAS elements for binding and function.

DISCUSSION

We have purified GHINF, a DNA binding activity of rat liver that recognizes the GHRE of the Spi 2.1 gene, to near homogeneity. SDS-PAGE of the immunopurified fraction revealed a dominant band of 93 kDa and a minor band at 70 kDa. Both 93-kDa and 70-kDa polypeptides cross-linked to the GHRE. Both bands also cross-react with both an anti-phosphotyrosine antibody (13) and a Stat5 antibody. The relationship of these two polypeptides to each other is uncertain. Since they do not purify in stoichiometric amounts, it is unlikely that they form an obligate heterodimer. More likely, the 70-kDa band represents an alternatively spliced or proteolytically cleaved form of the 93-kDa band.

The DNase I footprint observed using purified GHINF extends from -149 to -115 of the Spi 2.1 gene promoter and lies within the region that we previously defined as the GHRE. A similar footprint is noted in liver extracts from hypophysectomized rats that have been treated with GH. Within this region we now demonstrate that two GAS sites are necessary for the assembly of the intact GHREGHINF complex. Of the two GAS sites, the 3` site appears to have the stronger affinity for binding GHINF and is essential for GH action. Oligonucleotides with an intact 3` GAS site, but a mutated 5` GAS site, bind weakly to GHINF. However, mutations at the 3` site completely block binding to the 5` GAS site. This relative preference is also supported by competition studies, which showed that only an oligonucleotide with an intact 3` site was able to compete for binding. The 5` site contains one functional mismatch when compared to the 3` site (TTCNNNTAA instead of TTCNNNGAA), which may account for its lower affinity for GHINF. With the exception of the 5` A in the 3` GAS element, which is critical for GHINF binding, the relative importance of the remaining nucleotides in these palindromic half-sites and the significance of the spacing between them remains to be determined. However, it is clear from these binding studies that both sites are necessary for efficient formation of the GHINFGHRE complex.

These observations correlate well with functional assays in primary hepatocytes. Mutations of the TTC or GAA of the 3` GAS site that led to ablation of GHINF binding on EMSA led to a total loss of GH-induced CAT activity upon transfection. Transfection of constructs with the mutated 5` site that showed weak GHINF binding on EMSA led to reduced GH-induced CAT activity. Thus, the two GAS sites appear to function synergistically to support the GH response.

While mutation of the sequence upstream of the 5` GAS element led to no change in GHINF binding on EMSA, transfection of the construct with this mutation led to a greatly diminished GH response. This observation suggests that interaction with an accessory protein(s) binding to this region is required for normal GH response. We have observed that a Spi -147/+85-CAT construct did not support a GH response, consistent with a role for a factor binding upstream of -147 (data not shown). In contrast, transfection of a mutation downstream of the 3` GAS site that did not affect GHINF binding on EMSA led to a GH response that is comparable to that of the wild type. These functional data also correlate well with DNase I footprinting results: almost the entire region protected from DNase I is necessary for normal GH response. The stronger protection of the 3` site evident in the crude extract footprint supports the suggestion that the 3` site is the pivotal GHINF binding site.

Interestingly, Sliva et al.(14) reported a GH-responsive factor in crude rat liver extracts that requires only the 3` GAS element in the GHRE (SPI-GLE-1) for binding. We did not observe any binding using the same oligonucleotide element and purified GHINF in EMSA. In their functional assays performed in CHO cells stably transfected with GH receptor, a construct containing 3 copies of the 3` GAS element was shown to be sufficient to confer a 5- to 6-fold GH response to a heterologous promoter. Thus, the DNA binding activity these authors detected may reflect weak binding of GHINF to the 3` GAS element. We show here that in primary hepatocytes, one copy of the 3` GAS element in its native promoter (Spi-C-CAT) was sufficient to confer partial GH responsiveness. However, two copies are required for maximal GH induction. In addition, we show that the combined presence of Matrigel and high glucose concentration in the culture medium dramatically enhanced the ability of the cultured hepatocytes to respond to GH. This strategy facilitated evaluation of more subtle differences in promoter structure. The 20-fold GH induction observed with Spi-A-CAT compares favorably with the induction of Spi 2.1 mRNA in GH-deficient rats treated with GH.

The organization of the GHRE of the Spi 2.1 gene appears to parallel that of the GRR of the FcRI gene(24) . GRR contains a 3` GAS palindromic sequence, TTCNNNGAA, and, although not noted by the authors, a 5` GAS-like element that contains one mismatch (TTCNNNGAT). In functional assays, the ability of the 3` fragment alone to respond to interferon- was only 25% of that of the intact GRR. The 5` fragment alone was essentially inactive. In EMSA, only the 3` fragment was able to assemble complexes, while no complexes were observed with the 5` fragment. Thus, it appears that synergism between two GAS elements may also be important for interferon- induction from the GRR.

The GRR has also been shown to bind to a GH-stimulated factor in extracts of IM-9 lymphocytes(4) . Given the similarities of the architecture of GRR to that of GHRE, GHINF might be expected to bind to it and it does. As with interferon--induced activities, GHINF also binds to the 3` fragment of GRR, forming a complex with a faster mobility. Both GHINF and the IM-9 factor migrate to 93 kDa on SDS-PAGE. While the IM-9 factor has been reported to cross-react with a C-terminal Stat1 antibody, GHINF does not. In spite of this difference, they are likely to be similar proteins.

We have shown that while GHINF is neither Stat1 nor Stat3, it is capable of binding to the PRE that is recognized by Stat5. Its possible relationship with Stat5 is further demonstrated by its cross-reactivity to a C-terminal Stat5 monoclonal antibody on an immunoblot. However, it shows no cross-reactivity with AbN, either on an immunoblot or in EMSA when GHRE is used as a probe, although this antibody does cross-react with Stat5 in some studies(19, 23) . Nor does it cross-react with AbN in EMSA when PRE is used as a probe (data not shown). Thus, while GHINF shares antigenic determinants with the C-terminal sequence of Stat5, its N-terminal sequence is sufficiently different from those of Stat1, -3, and -5 such that AbN does not recognize it.

GH and prolactin both belong to the GH/prolactin/placental lactogen gene family. Both GH and prolactin receptors are characterized by similar structural features as members of the cytokine receptor superfamily. Both receptors are known to have associated Jak2 activities upon ligand binding(3, 25) . Recent reports indicate that other ligands binding to receptors of this cytokine receptor superfamily transduce signals through Stat5 isoforms or homologs: IL-3 and colony stimulating factor 1 in myeloid cells(26, 27) , IL-3, IL-5, and granulocyte-macrophage colony stimulating factor in mouse mast cells(28) .

The involvement of Stat5 in transducing GH signals, however, is less clear. Prolactin was not able to stimulate expression of Spi 2.1 and/or insulin-like growth factor I mRNA under conditions that produced a GH response(29, 30) . Although GH can activate Stat5(7) , it does not induce transcription of a -casein construct in transfection assays even if Stat5 is co-transfected along with GH receptor(23) . Thus, Stat5 alone is not sufficient to confer GH responsiveness to the -casein gene(23) . Wood et al.(7) reported that a rat liver SPI-GLE-I binding complex could be supershifted by polyclonal Stat5 antiserum. They were, however, unable to supershift this complex in its entirety even after increasing the ratio of antiserum to nuclear proteins. They suggested that in addition to Stat5, other, as yet uncharacterized, transcription factors are activated by GH in rat liver.

Using Stat5 cDNA as a probe, Stat5 mRNA has been found in several tissues in sheep, but not in liver(20) . An examination of cellular distribution of Stat5A and Stat5B, by nuclease protection assay, did not reveal their presence in liver(28) . However, using a PCR product generated from a murine thymocyte library as probe, Stat5 mRNA was demonstrated in several murine tissues, including liver (26) .

Stat5 shares DNA binding and transactivation potential with Stat3(31) . In luteinized granulosa cells, prolactin, but not GH, regulates the transcription of the acute phase response gene, -macroglobulin(32) . While GH does activate Stat3 in the rat liver, it does not induce the transcription of Spi 2.2, an acute phase-responsive gene and a homolog of Spi 2.1(33) . It is interesting to note that in the Spi 2.2 promoter, the region corresponding to the 5` GAS element in Spi 2.1 is disrupted twice with additional sequences(34) . This may explain why Spi 2.2 does not respond to GH.

Purified GHINF protects a region on the Spi 2.1 promoter encompassing two GAS elements. EMSA studies demonstrate that GHINF is capable of binding two GAS elements from either the Spi 2.1, -casein, or FcRI promoters. The occurrence of serial repeats of STAT binding elements and their relevance to the mechanism of enhancement of transcription by STAT proteins has been noted by others(14, 35) . We present evidence here that GHINF, in binding synergistically to two GAS elements on Spi 2.1, together with an accessory protein(s) binding to their flanking sequences, initiates GH-responsive transcription. The exact relationship of GHINF to Stat5 must await amino acid sequence information from a larger scale purification.

FOOTNOTES

*

This work was performed with the support of the Viking Children's Fund, the Graduate School (University of Minnesota), the Genentech Foundation for Growth and Development, and National Institutes of Health Grant DK32817. 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 Pediatrics, University of Minnesota, 420 Delaware St. S.E., Box 75 UMHC, Minneapolis, MN 55455. Tel.: 612-624-7144; Fax: 612-624-2682.

()

The abbreviations used are: GH, growth hormone; IL, interleukin; STAT, signal transducers and activators of transcription; GAS, -interferon-activated site; Spi 2.1, serine protease inhibitor 2.1; GHRE, GH response element from Spi 2.1; GHINF, GH-inducible nuclear factor; EMSA, electrophoretic mobility shift assay; SIE, sis-inducible element from c-fos; GRR, -response region from Fc receptor factor I (FcRI); SPI-GLE-1, GAS-like element from Spi 2.1; PRE, prolactin response element; PCR, polymerase chain reaction; CAT, chloramphenicol acetyltransferase; PAGE, polyacrylamide gel electrophoresis.

()

J.-B. Yoon, S. A. Berry, and H. C. Towle, unpublished results.

ACKNOWLEDGEMENTS

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