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[Cancer Research 59, 2068-2071, May 1, 1999]
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[Cancer Research 59, 2068-2071, May 1, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Mouse p73 Gene Maps to the Distal Part of Chromosome 4 and Might Be Involved in the Progression of {gamma}-Radiation-induced T-cell Lymphomas1

Michel Herranz, Javier Santos, Eduardo Salido, José Ferná ndez-Piqueras2 and Manuel Serrano

Departamento de Biologia, Laboratorio de Genética Molecular Humana, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049-Madrid, Spain [M. H., J. S., J. F-P.]; Unidad de Investigación, Hospital Universitario, Universidad de La Laguna, 38071-Tenerife, Spain [E. S.]; and Departamento de Inmunologia y Oncologia, Centro Nacional de Biotecnologia, 28049-Madrid, Spain [M. S.]


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
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We have isolated and sequenced a DNA fragment of about 12 kb that comprises exons 5–14 of the mouse p73 gene. We have identified four polymorphic markers, and one of them has been used to genetically map p73 to the distal part of chromosome 4. Previously, we have reported that {gamma}-radiation-induced T-cell lymphomas undergo frequent loss of heterozygosity around marker D4Mit205b at the distal part of chromosome 4. Based on this, we have performed loss of heterozygosity analysis in a set of T-cell lymphomas, and we have found allelic losses of p73 in 32.6% (16 of 49) of the tumors analyzed. Interestingly, allelic losses occur concurrently at both p73 and D4Mit205b, thus suggesting that p73 could be specifically inactivated in radiation-induced T-cell lymphomas.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
p53 is the most frequently mutated tumor suppressor gene in human and murine cancers to date (1) . A novel gene termed p73 encodes a protein with significant homology to the DNA binding (63%), transactivation (29%), and oligomerization (38%) domains of p53 (2) . Protein p73 has the potential to transcriptionally activate p53 target genes and to induce apoptosis (2 , 3) . However, in contrast to p53, p73 does not respond to DNA-damaging events (2) , and it is not affected by viral oncoproteins that inactivate p53 (4) .

Allelic losses at the p73 locus have been demonstrated in different types of human tumors, including neuroblastoma, lung cancers, and prostatic and colorectal carcinomas, but no mutations in coding sequences have been reported yet (2 , 5, 6, 7, 8) . Monoallelic expression of p73 has been reported in the peripheral blood cells, kidney, pancreas, thymus, lung, and colon (2 , 9 , 10) , and, in a few cases that have been analyzed, the expressed allele has been found to be of either maternal (2) or paternal origin (6) . However, other investigators have found biallelic expression of p73 in normal lung (6) ; more unexpectedly, several groups have reported the activation of the silent p73 allele in prostatic, colorectal, lung, and kidney tumors (7, 8, 9, 10) .

Recently, another member of the p53 gene family, termed variously as p63, KET, and p51, has been identified (11, 12, 13, 14) . This gene is expressed during embryonic development, and it seems to be involved in tissue-specific differentiation processes (11) . Interestingly, mutated p63 has been found in some human epidermal tumors (13) .

Previously, we have reported the existence of a putative tumor suppressor gene on the distal part of mouse chromosome 4 around microsatellite marker D4Mit205b, which is specifically lost in {gamma}-radiation-induced T-cell lymphomas (15) . The human p73 gene spans about 65 kb, with 14 exons and a large first intron (5) , and was mapped to an interval of the chromosome band 1p36 defined by markers TNFR2 (tumor necrosis factor receptor 2) and CDC2L1 (cell division cycle 2-like 1; Ref. 2 ). Interestingly, D4Mit205b has been mapped between the mouse orthologues Tnfr2 (75.5 cM) and Cdcl1 (79.4 cM; Mouse Genome Database).

Here, we characterize a genomic DNA fragment of about 12 kb corresponding to murine p73 gene, and we report evidence suggesting that p73 could be the tumor suppressor gene targeted by deletions on the distal part of chromosome 4 in T-cell lymphomas.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Genomic Library Screening and Sequencing.
A mouse genomic DNA library derived from the embryonic stem cell line D3 (from 129Sv mice) and prepared in phage vector Lambda-EMBL3 (Stratagene) was screened under high stringency conditions with the entire coding sequence of the simian p73 cDNA (obtained from W. Kaelin, Dana-Farber Cancer Institute, Boston, MA). After screening, five different overlapping clones were identified. For sequencing, one of these positive clones (clone {lambda}II) was digested with BamHI and EcoRI, and the derived fragments were subcloned into a pBluescript SK- plasmid (Stratagene). DNA sequencing was carried out using a 373 DNA Automatic Sequencer (Applied Biosystems; Perkin Elmer).

PCR Analysis of Polymorphic Markers.
Genomic DNAs from the strains BALB/cJ, C57BL/6J, RF/J, 129Sv, and SPRET/Ei were analyzed for intronic simple sequence length polymorphisms by PCR amplification of the microsatellites mMp73I4a, mMp73I4b, and mMp73I12, respectively. Primers for the analysis of the microsatellites were designed according to the Primer3 program.3 Primers used are as follows: mMp73I4, (forward) 5'-TGAGATCTGGTGCCCTCTCT-3' and (reverse) 5'-GCCTGATCTAGGCTGGAAAA-3'; mMp73I4b, (forward) 5'-GGCACACCCCTTTAATACCA-3' and (reverse) 5'-ACCTCTTGACCTCTGAGCCA-3'; and mMp73I12, (forward) 5'-GGTGGGTAATGATTGGACT-3' and (reverse) 5'-TGACGTGGAGGGAACTGCC-3'. PCR was performed in a Perkin Elmer 9600 DNA thermal cycler. Amplifications were carried out in a 25-µl volume containing 200 µM each of dATP, dCTP, dGTP, and dTTP; 0.2 µM each of forward and reverse primers; 10 mM Tris (pH 8.4); 50 mM KCl; 1.5 mM MgCl2; and 0.5 unit of Taq polymerase (Finnzymes Inc.). Cycling consisted of one cycle of 10 min at 95° C; 30 cycles of 30 s at 95°C, 30 s at 57°C, and 1 min at 72°C; and a final step at 72°C for 10 min. PCR products were separated in 12% nondenaturing acrylamide-Tris-HCl (pH 8.8)-buffered gels. After electrophoresis, DNA fragments were detected by silver staining.

In addition, we describe an EcoRI restriction length polymorphism by PCR amplification of complete exon 7, using the intronic primers mRLp73E7 forward (5' -ATAAGTGGCGAGATGGATGG-3') and reverse (5' -GAGACCACTCTTGACCCTGC-3') in the same conditions mentioned above. Both nondigested (458 bp) and digested PCR products (212 and 246 bp) were characterized in 1.5% agarose gels and detected with ethidium bromide.

Genetic Mapping.
The mouse chromosomal location of the mMp73I12 microsatellite was determined by interspecific backcross analysis with a subset of 94 informative progeny from the cross (C57BL/6J x SPRET/Ei)F1 x C57BL/6J of The Jackson Laboratory DNA Panel Mapping Resource (BSB4 interspecific backcross panel; Ref. 16 ). The Map Manager v.2.6.5 program (17) was used to estimate the map location and the distances between loci.

Allelotyping.
T-cell lymphomas were induced by whole-body {gamma}-irradiation, as described previously (18) . A set of 49 {gamma}-radiation-induced T-cell lymphomas from (C57BL/6J x RF/J)F1 hybrid mice was analyzed for LOH with the microsatellite marker mMp73I12 and with microsatellites D4Mit68 and D4Mit203. Scoring of LOH and the significance of allelic losses were performed as described previously (18) .


   Results
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 ABSTRACT
 Introduction
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 Results
Discussion
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We have identified a recombinant lambda phage clone (clone {lambda}II) that hybridized with a simian cDNA p73 probe. We have determined the complete sequence of the 12-kb fragment derived from the above-mentioned recombinant lambda phage (Fig. 1Citation ; complete sequence deposited in GenBank, accession number AF138873). This sequence showed segments of homology with human p73 exons 5–14, and the deduced amino acid sequence of these segments showed an overall identity of 74.6% with human p73 protein. In addition, we identified three microsatellite sequences located on intron 4 (mMp73I4a and mMp73I4b) and intron 12 (mMp73I12). The variability of these microsatellites was determined by simple sequence length polymorphism in a group of five mouse strains including BALB/cJ, C57BL/6J, RF/J, 129Sv, and SPRET/Ei (Fig. 2)Citation . Sequence analysis of the polymorphic variants is summarized in Fig. 3Citation . We also found a polymorphism at exon 7 that was silent for the amino acid sequence of p73 but resulted in the presence or absence of an EcoRI restriction site (see Fig. 2Citation ). It is important to note that this polymorphism is exonic; therefore, it will be useful for future studies on genomic imprinting of the murine p73 gene.



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  		Fig. 1. Genomic structure of murine p73 from exons 5–14. The complete sequence of the 12-kb fragment represented in the figure is available at GenBank (accession number AF138873). Exons are indicated ({blacksquare}) and numbered according to their human counterparts (6 , 7) . Arrows indicate the position of the polymorphic markers: three of the markers are microsatellites; and one of them (R) is a restriction enzyme polymorphism in exon 7 (see the text for details). Restriction sites for BamHI (B1) and EcoRI (R1) are indicated.

 


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  		Fig. 2. Analysis of polymorphism of markers located in the murine p73 gene. Genomic DNAs from five different inbred mouse strains were used to PCR-amplify regions mMp73I4a, mMp73I4b, or mMp73I12, which contain repetitive microsatellites, or region mRLp73E7, which contains a polymorphic EcoRI site. Strains are abbreviated as follows: C57BL/6J, B6; BALB/cJ, BA; RF/J, RF; 129Sv, SV; and SPRET/Ei, SPR.

 


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  		Fig. 3. Sequence of p73 polymorphic microsatellites in different mouse strains. The reference sequence D3 corresponds to the genomic DNA sequence obtained from the embryonic stem cell line D3-derived mouse strain 129Sv. Other abbreviations are as defined in the legend to Fig. 2Citation . Bold nucleotides in the reference sequence indicate the position of the primers used to amplify the corresponding microsatellite regions; the total length of the PCR products is indicated at the end of each sequence. Dots indicate sequence identity. Hyphens indicate deletions.

 
To establish the genetic map localization of the murine p73 gene, we characterized microsatellite mMp73I12 in a 94-individual N2 progeny of the Jackson Laboratory BSB interspecific backcross panel. A linkage analysis was performed with markers located on mouse chromosome 4, which contains the homologous region to human 1p36 where the human p73 gene was mapped (2) . No recombination in 91 meioses was found between this marker and the cosegregating Rnr4, Dv1, and D4Smh6b loci, suggesting that these loci are closely linked on the distal part of chromosome 4. Three of 94 N2 progeny displayed recombination between the above-mentioned four loci and Hes2, a more proximal marker, indicating a separation of about 3.2 cM (Fig. 4)Citation . Marker D4Mit205b, which is located on this region (19) , was not informative. In addition, we have ruled out linkage with marker D16Mit3 that is located between Smst and Apod on chromosome 16, a region where mouse p63 gene has been recently mapped (12) .



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  		Fig. 4. Genetic mapping of murine p73. Schematic representation of the distal region of mouse chromosome 4 indicating the location of the markers used in this study. The leftmost numbers correspond to the genetic distances obtained in the present study using a panel of 94 informative backcrosses (C57BL/6J x SPRET/Ei)F1 x C57BL/6J. The numbers in parentheses are the same distances for all the markers, except for the p73 marker (mMp73I12), according to the Mouse Chromosome 4 Committee (19) . {blacksquare}, SPRET/Ei alleles; {square}, C57BL/6J alleles. The number of progeny exhibiting each type of chromosome is listed at the bottom.

 
DNAs from 49 {gamma}-radiation-induced primary T-cell lymphomas of (C57BL/6J x RF/J)F1 hybrid mice were screened to detect allelic losses of the polymorphic microsatellite mMp73I12. Overall, 32.6% (16 of 49) of tumors showed LOH with this marker. Representative examples of tumors with allelic losses for mMp73-I12 are shown in Fig. 5Citation (top). In all cases, LOH at p73 was accompanied by losses of the marker D4Mit205b, which was previously characterized to define the minimal region of loss at chromosome 4 named TLSR2 (Ref. 15 ; see also Fig. 5Citation , bottom). Interestingly, 94% (15 of 16) T-cell lymphomas with LOH for mMp73I12 lost the paternally derived RF/J allele. Altogether, these results suggest that p73 could be the tumor suppressor gene targeted in TLSR2 by {gamma}-radiation-induced T-cell lymphomas.



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  		Fig. 5. Analysis of LOH in murine p73 gene in {gamma} -radiation-induced lymphomas. Tumors were induced in F1 hybrids between RF/J and C57BL/6J. Top, example of LOH analysis with a set of 13 lymphomas. Top panel, LOH analysis with marker mMp73I12; bottom panel, LOH analysis with control marker Tnf{alpha} located in chromosome 17. Control PCR reactions correspond to genomic DNAs from parental RF/J (RF) and C57BL/6J (B6) or from a F1 hybrid (F1). All the other lanes correspond to genomic DNA extracted from lymphomas induced in F1 hybrids. Bottom, summary of LOH results with different markers located in the distal region of chromosome 4. {blacksquare}, LOH; {square}, retention of heterozygosity. The data corresponding to markers with an asterisk were reported previously (18) . Distances are indicated in cM according to the Mouse Chromosome 4 Committee (19) .

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
We have characterized a genomic fragment of about 12 kb that shows considerable similarity to the human p73 gene. This genomic DNA shows segments of homology with the human p73 gene and a perfect conservation of the exon-intron boundaries. In addition, there is a remarkable conservation in the corresponding amino acid sequences (76.4% identity). This high degree of conservation with human p73 is in contrast to the low conservation with human p53 or human p63 (<50%). The characterization of the above-mentioned genomic DNA sequence also served to identify three polymorphic microsatellites and one polymorphic restriction site (Fig. 2)Citation . The microsatellite located at the intron 12 (mMp73I12), which showed allelic differences between C57BL/6J and SPRET/Ei (derived from Mus spretus), was used for the genetic mapping of a BSB interspecific backcross panel. This analysis indicates that mouse p73 maps to the distal part of mouse chromosome 4, linked to the D4Smh6b, Dv1, and Rnr4 loci (Fig. 4)Citation . It should be noted that the mouse orthologue of the human p63 gene has been recently mapped to chromosome 16 (12) , and we have excluded linkage of mMp73I12 with a genetic marker closely linked to the p63 locus. Data derived from the comparison of the predicted amino acid sequences, together with evidence obtained from the genetic map, unequivocally indicate that the mouse p53-related nucleotide sequence that we have characterized represents the murine orthologue of the human p73 gene.

Recent studies from our laboratory have reported a high frequency of allelic losses on the distal part of mouse chromosome 4 in {gamma} -radiation-induced T-cell lymphomas (15 , 18) . This region has also been implicated by its frequent allelic losses in chemically induced primary lymphomas (20) . The microsatellite marker mMp73I12 was used for a study of LOH in a panel of T-cell {gamma}-radiation-induced lymphomas. We found that 16 of 49 lymphomas (32.6%) showed LOH of p73 (Fig. 5)Citation . These allelic losses were always accompanied by losses of D4Mit205b, a marker that we had previously found to define the smallest region of allelic loss at the distal part of mouse chromosome 4 (15) . Therefore, we conclude that p73, together with D4Mit205b, is part of the minimal deletion region at the distal part of chromo-some 4.

Several investigators have found LOH of human p73 in neuroblastomas, prostate carcinomas, and lung cancer (2 , 6 , 7) , but no mutations have been reported yet in this gene. Similarly, we have failed to detect mutations in the analyzed coding sequences of murine p73 (data not shown). In some human tissues, including the thymus, p73 has been found to be expressed monoallelically (2 , 9 , 19) . This raises the possibility that in these particular tissues, preferential loss of the expressed p73 allele would result in a complete loss of p73 function. However, no support for this proposal has yet been found, although the number of studies and tumor types analyzed is still very limited. Here, we have analyzed {gamma}-radiation-induced T-cell lymphomas, which show frequent allelic loss of a distal region of chromosome 4 named TLSR2 (15) . We have found that allelic loss of p73 occurs concurrently with LOH at TLSR2 and that there is preferential loss of the RF/J-derived p73 allele. Altogether, our results suggest that p73 could be the tumor suppressor gene that is present in TLSR2 and specifically inactivated in {gamma} -radiation-induced T-cell lymphomas. In addition, we have developed molecular markers that will facilitate additional investigations to unequivocally assess the role of p73 as a tumor suppressor in different experimental systems of murine tumors.


   ACKNOWLEDGMENTS
 
We are indebted to William G. Kaelin (Dana-Farber Cancer Institute) for providing us with simian p73 cDNA.


   FOOTNOTES
 
1 Supported by Grants PB96/001 (Ministerio de Educación y Cultura, Spain), 08/0009/1997 (Comunidad Autónoma de Madrid), and Fundación Ramón Areces (Spain; to J. F-P.); PM95-0014 (Ministerio de Educación y Cultura, Spain) and 08.1/0043.2198 (Comunidad Autónoma de Madrid; to M. S.); FIS 96/0867 (to E. S.); and BIOMED 2 (BMH4-98-3426; to J. S.). The Department of Immunology and Oncology (Centro Nacional de Biotecnología) is supported by Pharmacia and Upjohn and by the Spanish Council for Scientific Research. M. H. was supported by a fellowship from the Fundación Ramón Areces (Madrid, Spain). Back

2 To whom requests for reprints should be addressed. Phone: 34913978203; Fax: 34913978202; Back

3 The Primer3 program is available at http://www-genome.wi.mit.edu/genome_software/other/primer3.html. Back

4 The abbreviations used are: B5B, (C57BL/6J x SPRET/Ei)F1 x C57BL/6J; LOH, loss of heterozygosity. Back

Received 2/ 1/99. Accepted 3/18/99.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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