Laminins are glycoproteins which are constituents of a particular type of extracellular matrix called the basement membrane; basement membranes are synthesized by epithelial, endothelial, nerve, muscle, and other cell types. Laminins have a number of functions in the processes of cell adhesion, cell migration, proliferation, differentiation, neurite outgrowth, and tumor metastasis (for review, see (2) ). Much information concerning the structure and functions of laminins has come from the mouse Engelbreth-Holm Swarm (EHS) tumor(3) . Three protein chains are constituents of EHS laminin, Ae (M = 400,000), B1e (M = 215,000), and B2e (M = 205,000). These three polypeptide chains are assembled into a cross-like structure with a molecular weight of approximately 950,000(4, 5) . Recently, additional laminin chains related to Ae (Am; (6) and (7) ) or B1e (B1s; (8) ) have been reported. The human A chain homolog Am has also been named merosin (6) and is the same as the chain found in heart(7) . A specific deficiency in the laminin Am chain has been associated with the dystrophic dy mutation in mice(9, 10) . The dy mutation represents a severe neuromuscular disease resembling human muscular dystrophy. Furthermore, other laminin-related proteins have been reported(11, 12, 13) . A human variant B2 chain named laminin B2t has been described(14) . An epithelial specific laminin chain called laminin B1k has also been reported(15) . Various heterotrimers can be assembled from the different laminin subunits(16) . The nomenclature used is that of Engel et al.(17) . Another nomenclature for the protein chains has also been proposed recently; in this nomenclature, the laminin B1 protein is called 1 and the gene is LAMB1(18) .

From sequencing clones from an EHS expression library, the cDNA sequences of the murine laminin B1e chain(19) , the B2e chain(20) , and the Ae chain (21) have been determined. The sequences of human laminin B1(22, 23) , B2 chain(14, 24) , and the A chain (25, 26) have also been determined.

During early mouse embryogenesis, mRNAs for the B1 and B2 chains of laminin were detected from the 4-cell stage, while the A chain appeared at the 16-cell stage(27, 28) . During the period of mouse development in which major organs are forming, laminin was detected in the basement membranes of epithelial cells(29) , during intestinal development(30) , and in ureteric buds and nephrogenic vesicles during early prenatal kidney development(31) . The conversion of mesenchyme to epithelium in kidney is accompanied first by an increase in laminin B1 and B2 transcripts (31, 32) and is followed by an increase in A chain expression(32) . The 1/1 and 6/1 integrin heterodimers have been shown to mediate cell attachment to distinct sites on laminin (33) . The 6/1 laminin receptor is also regulated during development both by its level of expression and via phosphorylation (34, 35, 36) .

The expression of laminin has been studied in a number of model cell culture systems. In cultured neuroepithelial cells, basic fibroblast growth factor enhances the amount of laminin expressed at the protein level(37) . During myogenic differentiation, the expression of several different laminin chains is increased(38) . Retinoic acid, a member of the vitamin A family of signaling molecules called retinoids, induces laminin expression in cultured murine embryonic teratocarcinoma stem cells such as the F9 cell line which is induced to differentiate into parietal endoderm cells(39) . The levels of transcripts encoding the laminin A, B1, and B2 polypeptide chains are increased in F9 cells treated with RA ()as compared to undifferentiated stem cells(40, 41, 42, 43, 44, 45) . The laminin B1 chain produced by RA-treated F9 cells appears to be identical with the murine B1e chain as determined by DNA sequencing of partial cDNA clones. ()

Further studies by this laboratory demonstrated that the RA-mediated regulation of the expression of the LAMB1 gene occurred primarily at the transcriptional level(46, 47) . Cyclic AMP analogs were shown to augment the transcriptional response of the cells to retinoic acid, but cyclic AMP analogs alone did not enhance the rate of transcription of this gene(44, 46, 47) . An RARE (retinoic acid response element) was identified at position -477 to -432 in the promoter region of the murine LAMB1 gene, and this response element is recognized by retinoic acid receptors (RARs)(48, 49) . Furthermore, the targeted disruption of both copies of the RAR gene in F9 cells led to a defect in the RA-associated activation of the LAMB1 gene(1) . This suggested that the LAMB1 gene was a target gene regulated by the RAR. However, the late induction of the LAMB1 gene and the observation that the RA-mediated induction was prevented by the protein synthesis inhibitor cycloheximide (50) indicated that other RA-inducible transcription factors were involved in the regulation of the expression of the LAMB1 gene. In this manuscript, we present a more detailed analysis of the regulation of the LAMB1 gene in response to retinoic acid.

EXPERIMENTAL PROCEDURES

Cell Culture

Isolation of the Murine LAMB1 Genomic Clones

Plasmids

Nuclear Protein Preparations, DNase I Footprinting Assays, and Electrophoretic Mobility Shift Assays (EMSA)

Figure 6: EMSAs using mutant oligonucleotides. A, radiolabeled wild type probe P2860 (lanes 1 and 2) and the radiolabeled mutant probe P2860M1 (lanes 3-7). 3 µg of extract from PYS-2 cells was used in lane 2. Nuclear extracts (5 µg) from F9 cells: stem cells (lane 3), RA for 24 h (lane 4), RACT for 24 h (lane 5), RA for 72 h (lane 6), and RACT for 72 h (lanes 1 and 7). B, wild type radiolabeled probe P2860 (lanes 1-5) and the radiolabeled mutant probe P2860M2 (lanes 6-10). Nuclear extracts from F9 cells: stem cells (lanes 1 and 6), RA for 24 h (lanes 2 and 7), RACT for 24 h (lanes 3 and 8), RA for 72 h (lanes 4 and 9), and RACT for 72 h (lanes 5 and 10). C, wild type radiolabeled probe P2821 (lanes 1-5) and the mutant probe radiolabeled P2821M1 (lanes 6-10). Nuclear extracts from F9 cells: stem cells (lanes 1 and 6), RA for 24 h (lanes 2 and 7); RACT for 24 h (lanes 3 and 8), RA for 72 h (lanes 4 and 9), and RACT for 72 h (lanes 5 and 10). D, the sequences of wild type and mutant oligonucleotides with the mutations underlined and a summary of binding sites for C1, C2 (solid box), and C3 (dotted box), respectively (sequences are written 5` to 3`). A + indicates the presence of a complex by EMSA; a - indicates the absence of a complex.

Other Procedures

RESULTS

Mapping of DNase I Hypersensitive Sites

()

Figure 1: Mapping DHSS of the LAMB1 gene in F9 cells. A, the line diagram shows the LAMB1 gene with the positions of the ApaI (a), BamHI (b), HindIII (h), and PstI (p) sites in the genomic DNA relative to the transcription initiation site and the regions to which the DHSS maps marked. Probe SA is a 466-bp SacII/ApaI fragment covering from -353 to +113 bp of murine LAMB1 gene (hatched box). Probe HS is a 538-bp HindIII/SpeI fragment covering from -3961 to -3423 bp of murine LAMB1 gene (open box). B, mapping of distal DHSS 5` to the LAMB1 gene. Nuclei from F9 cells were treated with DNase I (1, 3, and 10 units). DNA from DNase I-treated nuclei was digested with ApaI, and the Southern blot was hybridized with the probe SA as described in A. The positions of DHSS are given. The RA concentration was 1 10M. This experiment was performed three times, and similar results were obtained in all three experiments.

To identify any DHSS closer to the initiation of transcription of the LAMB1 gene, DNA from DNase I-treated nuclei was digested with HindIII, analyzed by gel electrophoresis, and the resulting Southern blot was hybridized to a 538-bp HindIII/SpeI fragment containing -3961 to -3423 bp of mouse LAMB1 gene (Fig. 1A). Digestion of DNA in nuclei from untreated F9 stem cells resulted in a band of 3.7 kb (DHSS1) that maps to about -260 bp from the transcription initiation site. While this site, DHSS1, is located relatively close to the LAMB1 RARE(48) , this site was observed only in nuclei from stem cells and was not observed in DNA from nuclei of 24-h and 72-h RA-treated F9 cells (data not shown).

Overall, we have examined a total of 18 kb of genomic DNA at the 5` end of the murine LAMB1 gene. Three RA-sensitive DHSS were observed. DHSS1 is detected in F9 stem cells but is not observed after 24 h or 72 h of RA treatment. DHSS2 is observed only after 72 h of culture in the presence of RA, while DHSS3 is observed after both 24 h and 72 h of RA treatment. Because the DHSS2 was observed only at later times after RA addition (72 h), we concentrated on the further delineation of this site since its properties reflected the pattern of expression of the endogenous LAMB1 gene.

Isolation of the Murine LAMB1 Genomic Clones and Analysis of the DHSS2 Region of the Murine LAMB1 Gene

In order to define the regulatory elements in the DHSS 2 region of the murine LAMB1 gene in greater detail, the series of LAMB1 promoter/CAT constructs indicated in Fig. 2A were transfected into F9 cells, and this transfection was followed by treatment of the cells with RA for 24 h. For the 72-h time point, the cells were cultured in the presence of RA for 48 h, and then the cells were transiently transfected. This transfection was followed by further culture in the presence of RA for an additional 24 h. The results of these transient transfection assays indicated that all of the LAMB1 promoter/CAT constructs except the p0.13LAMCAT construct exhibited an increase in activity after 24 h of RA treatment (Fig. 2B). These results confirmed previous work by Vasios et al.(48, 49) which demonstrated that the p0.49LAMCAT construct which contains the RARE was RA-responsive by 24 h after RA addition.

Figure 2: CAT activities of the reporter plasmid containing the LAMB1 inserts. A, schematic representation of the CAT reporter constructs. Numbering is relative to the initiation site of transcription. The 3` end of LAMB1 insert is +113 bp. a, ApaI; b, BamHI; h, HindIII; and p, PstI. B, LAMCAT plasmids (10 µg) were co-transfected with a murine RAR expression plasmid (1 µg), pAclacZ (5 µg), and pUC9 DNA to 20 µg total. (Co-transfections with RAR or RAR gave similar results; data not shown.) Transfections were normalized by assaying for -galactosidase activity from the co-transfected pAclacZ construct. CAT activities of the constructs were measured and are expressed relative to the F9 stem cell control (without RA addition). The results shown are the averages of three independent transfection experiments (mean ± S.D.).

Further increases in CAT activity were observed after 72 h of RA treatment for most of the LAMB1/CAT constructs (Fig. 2B). Deletion of a 569-bp fragment containing the DHSS2 from the 5` end of p3.4LAMCAT resulted in much less additional CAT activity at 72 h versus 24 h (Fig. 2B). Taken together, the DNase I hypersensitivity data indicating the location of DHSS2 at about -2.9 kb, and the results of these transient transfection assays are consistent with the hypothesis that the region of the LAMB1 promoter between -2.8 kb and -3.4 kb contains a DNA regulatory site which is more active at later times (72 h) after RA treatment than at 24 h.

Footprinting Studies

Figure 3: DNase I footprinting assays. A, DNase I footprinting analysis with the nuclear extract from F9 cells cultured in the presence of 1 10M RA for 72 h. A probe spanning nucleotides -3136 to -2735 (DraI/MseI fragment) was used. This probe was prepared as described under ``Experimental Procedures.'' Increasing amounts of protein extract were used, from 1 µg to 40 µg. The lines indicate the footprints observed. The positions of the footprints are also marked. This assay was performed four times with different extracts; similar results were obtained. B, the sequence of the LAMB1 gene from -2898 to -2787 is shown. The footprinted sequences of individual binding elements are indicated by the underlining. The footprinted sequence is written 5` to 3`, with the nucleotide numbers shown on the left.

Characterization of Nuclear Protein Binding by EMSA

Figure 4: EMSA analysis of the nuclear protein-binding sites in F9 cells. EMSAs were performed with the radiolabeled P2860, P2821 oligonucleotides (10 cpm/0.5 ng). Lane 1, radiolabeled probe alone. Lane 2, 5 µg of the extract from F9 untreated stem cells. 5 µg of extract from F9 cells treated with RA for 24 h (lane 3), RACT for 24 h (lane 4), RA for 72 h (lane 5), and RACT for 72 h (lane 6) was used. The arrows indicate bands of altered mobility representing specific protein-DNA complexes. A, probe P2860; B, probe P2821. The sequences of probes P2860 and P2821 are shown in Fig. 6D. RA, 1 10M; RACT is RA at 1 10M plus dibutyryl cyclic AMP at 250 µM and theophylline at 500 µM. This experiment was performed three times with different extracts; one experiment is shown, but similar results were obtained in all three experiments.

Analysis using the probe P2821 identified a single major retarded complex, C3 (Fig. 4B). The C3 complex is slightly more abundant in extracts from cells treated with RA for 24 h and in extracts treated with RACT for 24 h (Fig. 4B). Thus, while this C3 complex is present in nuclei from RA-treated cells, it is also present at significant levels in extracts from untreated F9 stem cells. From mutation studies described later in the manuscript (Fig. 6), the C3 complex observed with probe P2821 appears to be identical with the C3 complex observed with probe P2860.

Analysis with probe P2892 resulted in some very weak retarded complexes which appeared to be different from the complexes described above (data not shown). Analysis of these complexes was not pursued further.

The Specificity of the Retarded Complexes

Figure 5: EMSA analysis of protein-binding sites with corresponding unlabeled competitors. Labeled oligonucleotides P2860 (A) and P2821 (B) with 4 µg of the nuclear extract from F9 cells (1 10M RA, 72-h treated) in the absence (lane 1) or in the presence (lanes 2-5) of the indicated (-fold) molar excess of various unlabeled competitors: P2860 (lanes 2 and 3) and P2821 (lanes 4 and 5).

The C3 complex formed with the P2860 probe was inhibited by a 100-fold molar excess of unlabeled P2821, whereas the C2 complex was not affected by a similar excess of P2821 (Fig. 5A). Reciprocal experiments showed that the C3 complex formed with the P2821 radiolabeled probe was inhibited by a 100-fold molar excess of unlabeled P2860 (Fig. 5B). These data suggest that the same protein is present in the complex C3 detected by both probes P2860 and P2821.

The Retarded Complexes in Murine PYS-2 Cells

The Effect of Mutations in P2860 and P2821 on Protein Binding by EMSA

Mutation M1 in probe P2821 abolished C3 complex formation (Fig. 6C; Fig. 6D for the sequence of the radiolabeled P2821M1). From these data, we conclude that a TAAT sequence (complementary strand (ATTA)) in both P2860 and P2821 is involved in C3 complex formation.

The Effect of Targeted Disruptions of the RAR and RAR Genes

In F9 wild type cells, the expression of the parent plasmid pLBCAT2 was not RA-inducible, while pL -3136/-2736TKCAT expression was RA-inducible (Fig. 7). In addition, the level of CAT activity of pL -3136/-2736TKCAT could be enhanced by RACT as compared to RA treatment (Fig. 7). The targeted disruption of the RAR gene did not inhibit the RA-induced pL -3136/-2736TKCAT expression (not shown). In contrast, the targeted disruption of the RAR gene abolished the RA-inducible pL -3136/-2736TKCAT expression (Fig. 7). These data show that the functional enhancer requires RAR nuclear signaling. This signaling is likely to be indirect since the DHSS2 region between -3136 and -2736 does not appear to contain an RARE to which RAR could bind directly. Furthermore, in this experiment, the pL -3136/-2736TKCAT construct displayed activity in the absence of co-transfected RARs.

Figure 7: The effects of the targeted disruption of the RAR or RAR gene on the expression of the pL -3136/-2736TKCAT. The CAT constructs (10 µg) were co-transfected with pAclacZ (5 µg) and pUC9 DNA (to 20 µg total) into F9 wild type, F9 RAR, or F9 RAR cells. No RAR expression vector was co-transfected. Cells were then cultured in the presence of no addition, RA, CT, or RACT for 24 h, followed by cell harvesting (RA, 1 10M; C, 250 µM dibutyryl cyclic AMP; T, 500 µM theophylline). The experiments were performed with 24-h drug treatment since a longer RACT treatment will severely reduce the transfection efficiency. As a control, 4.4 ± 1.1 (mean ± S.D.; n = 4)-fold of induction was observed when the pRARRARETKCAT was tested with 24-h RA treatment (not shown). Transfections were normalized by assaying for -galactosidase activity from the co-transfected pAclacZ construct. CAT activities of the constructs were measured and are expressed relative to those of the corresponding plasmid without drug addition. This experiment was performed twice with similar results; one representative experiment is shown.

Extracts from these two cell lines were then tested by EMSA to determine the effects of the loss of RAR versus RAR on the protein binding to regulatory elements in this 400-bp DHSS2 region of DNA. The targeted disruption of the RAR gene had no effect on the behavior of the retarded complexes (Fig. 8, compare lanes 2 and 3 with 4 and 5). In contrast, the targeted disruption of the RAR gene abolished the RA-associated C2 complex formation, but had no effect on the behavior of the C1 or C3 complexes (Fig. 8, A and B). These data strongly suggest that the C2 proteinDNA complex is of functional significance in the positive regulation of the LAMB1 gene in response to RA since this C2 complex does not form in extracts from RAR cells in which the LAMB1 gene is not activated by RA.

Figure 8: EMSA analysis of the nuclear protein-binding sites in RAR mutant cells. EMSA was performed with the radiolabeled probe P2860 (A) and the radiolabeled probe P2821 (B). Lane 1, probe alone. Four µg of the nuclear extracts were used from lanes 2-7: F9 wild type (lane 2), F9 wild type treated with RA for 72 h (lane 3), F9 RAR (lane 4), F9 RAR treated with RA for 72 h (lane 5); F9 RAR (lane 6), and F9 RAR treated with RA for 72 h (lane 7).

DISCUSSION

The Molecular Basis of the Delayed Murine LAMB1 Gene Expression during the Differentiation Process of F9 Teratocarcinoma Cells

In order to study the regulation of the LAMB1 gene, we searched for changes in chromatin structure that occur when the gene is activated. Our studies reveal that one of the DNase I hypersensitive sites, DHSS2, was observed only at late times (72 h) after RA addition (Fig. 1B). Further, functional transient transfection experiments have demonstrated that the DHSS2 region functions as an enhancer ( Fig. 2and Fig. 7). Detailed analysis of this enhancer by EMSA has led to the identification of several proteinDNA complexes in this enhancer (Fig. 4, A and B). Among them, the protein complex C2 is most intriguing because it is (a) found only in nuclear extracts of RA-treated F9 cells and is more abundant at late times (72 h) than at early times (24 h) (Fig. 4), (b) detected in extracts from RA-treated F9 wild type cells and F9 RAR cells, but not in RA-treated RAR cells (Fig. 8), and (c) detected at earlier times and in greater abundance in extracts from RACT-treated cells versus RA-treated cells (Fig. 4A). Thus, our data are consistent with the interpretation that the proteinDNA complex C2 contributes to the activation of the LAMB1 gene during the differentiation process. Our data also explain how a ``late'' cycloheximide-dependent RA-inducible gene such as LAMB1 can be positively regulated in a delayed fashion in this differentiation model (Fig. 9).

Figure 9: Model of LAMB1 gene regulation in response to RA.(1, RA binds to RXRRAR complex. (2), RARXRRAR complex binds directly to LAMB1 RARE. (3), transcriptional activation of a member of a homeodomain gene family () and homeodomain transcription factor produced (requires approximately 24 h of RA treatment). (4), cyclic AMP-dependent phosphorylation leads to greater transcription or higher affinity binding of homeodomain protein to elements at the DHSS2 region. (5), transcriptional activation of LAMB1 gene.

The Role of Cyclic AMP in the RA-induced LAMB1 Gene Expression

The Role of TAAT Core Recognition Sequence in LAMB1 Gene Expression

Retinoic Acid Receptors and LAMB1 Gene Expression

Further Analysis of the ``Late-acting RA-inducible Enhancer''

FOOTNOTES

*

This work was supported by Grant R01 HD24319 (to L. J. G.) and in part by a fellowship from the National Kidney Foundation (to C. L.). 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank(TM)/EMBL Data Bank with accession number(s) U43597[GenBank].

§

To whom correspondence should be addressed: Dept. of Pharmacology, Cornell University Medical College, 1300 York Ave., New York, NY 10021. Tel.: 212-746-6250; Fax: 212-746-8858.

()

The abbreviations used are: RA, all-trans-retinoic acid; RARE, retinoic acid response element; EMSA, electrophoretic mobility shift assays; RACT, retinoic acid, dibutyryl cyclic AMP, and theophylline; LAMB1, laminin B1 gene; DHSS, DNase I hypersensitive site(s); bp, base pair(s); kb, kilobase(s); CAT, chloramphenicol acetyltransferase; CRE, cAMP response element.

()

C. Stoner, J. Gold, and L. Gudas, unpublished observations.

()

C. Li and L. J. Gudas, unpublished data.

ACKNOWLEDGEMENTS

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