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The Human Gene Encoding Phosphatidylinositol-3 Kinase Associated P85a Is at Chromosome Region 5Ql2-13'

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The Human Gene Encoding Phosphatidylinositol-3 Kinase Associated P85a Is at Chromosome Region 5Ql2-13' [CANCER RESEARCH 5l. .1818-.1820, July 15, 1991| Advances in Brief The Human Gene Encoding Phosphatidylinositol-3 Kinase Associated p85a Is at Chromosome Region 5ql2-13' L. A. Cannizzaro, E. Y. Skolnik, B. Margolis, C. M. Croce, J. Schlesinger, and K. Huebner2 Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 [L. A. C., C. M. C., K. H.J, and Department of Pharmacology, New York University Medical Center, New York, New York 10016 [E. Y. S., B. M., J. S.J Abstract scribed previously (10, 11). Hybrids 9142 (full name GM9142), 114 (GM100114), 115 (GM100115), 7297 (GM7297), 7300 (GM7300), I In' human chromosomal location of the gene encoding the phospha- 449 (GM10449), 10095 (GM10095), and 7301 (GM7301) were ob tidylinositol-3 kinase associated protein, p85a, has been determined by tained from the National Institute of General Medical Sciences Human analysis of its segregation in rodent-human hybrids and by chromosome Genetic Mutant Cell Repository (Corieli Institute for Medical Re in situ hybridization using a complementary DNA clone, GRB-1. search, Camden, NJ). Human chromosomes or chromosome regions The gene for p85<*is at chromosome region 5ql3, perhaps near the retained by individual hybrids in the panel are illustrated in Fig. 1. gene encoding another receptor associated signal transducing protein, the Hybrids retaining partial chromosome 5 have also been described GTPase activating protein. previously (12). Filter Hybridization. DNA from mouse, human, and hybrid cell lines Introduction was obtained by a standard phenol-chloroform extraction procedure (10). Approximately 10 Mgof DNA were digested to completion with Skolnik et al. (l ) have recently developed a novel method for an appropriate restriction endonuclease and size fractionated on 0.8% expression cloning of receptor tyrosine kinase target proteins agarose gels. The gels were denatured, neutralized, and blotted to and have illustrated the method by cloning of the GRB-1 Duralon membranes (Stratagene) according to manufacturer's recom cDNA,' representing the gene for the PI 3 kinase associated mendations. DNA was immobilized by UV cross-linking. Prehybridi- P85a(l,2). zation and washing were performed as described elsewhere (13). The hybridized filters were exposed to XAR-2 X-ray films (Kodak) with The gene for GRB-1 codes for a protein, p85«,previously intensifying screens for I to 3 days at -70°C. shown to associate with activated growth factor receptors. The Chromosomal in Situ Hybridization. Chromosomal in situ hybridi function of p85«is not known but it was previously assumed zation was performed as described (14). Slides containing metaphase to be PI3 kinase since PI3 kinase activity copurifies with a M, chromosomes from normal male (46,XY) peripheral blood lymphocytes 85,000 protein in platelet derived growth factor stimulated and were aged at 4°Cfor 7-10 days and pretreated with RNase A (Sigma) middle-T antigen transformed cells (3-5). The gene encoded by for l h at 37°C.The chromosomal DNA was denatured in a hybridi GRB-1 cDNA does not have an ATP binding site and is thus zation mixture containing 50% formamide, 2x SSC and 10% dextran probably not a phospholipid kinase (1, 2, 6). p85«is found sulfate (pH 7.0). Hybridization was carried out at 37°Covernight. After associated with a M, 110,000 tyrosine phosphorylated protein being rinsed at 39°Cin three changes of 50% formamide:2x SSC and which may be the catalytic subunit of the PI3 kinase (7, 8); five changes of 2x SSC, slides were dehydrated, air dried, subjected to p85n modulates the interaction between PI3 kinase and platelet autoradiography, and banded with Wright-Giemsa stain solution mixed derived growth factor receptor and could therefore be a regu with 1-3 parts of borate buffer, pH 9.2. latory subunit or a bridge between activated receptors and the PI3 kinase (6, 9). Results The chromosomal location of this gene has now been deter mined by analysis of its segregation pattern in rodent-human Hindlll digested DNAs from a rodent-human somatic cell hybrids and by chromosomal in situ hybridization using the hybrid panel were electrophoresed, transferred to nylon filters, GRB-1 cDNA clone. and hybridized to the radiolabeled GRB-1 cDNA probe. The presence of human specific GRB-1 Hindlll fragments in the Materials and Methods hybrid DNAs was correlated with the presence of specific human chromosome regions in the hybrids as summarized in Probe. The GRB-1 probe was an isolated cDNA insert corresponding Fig. 1 and illustrated in Fig. 2A. Hybrids which carried a to the 3' most 2460 nucleotides of the cDNA clone (1). The GRB-1 insert was radiolabeled with [«-32P]dCTPto a specific activity of 10a complete or partial chromosome 5 were positive for human GRB-1 Hindlll fragments (see Fig. 2A, Lanes 2 and 6, for cpm/0.1 ¿/gand10s cpm were used for each filter hybridization. For in situ hybridization the GRB-1 insert was nick-translated with 'H-labeled example); hybrids without chromosome 5 were negative for the deoxynucleotide triphosphates to a specific activity of ~4 x IO7cpm/ human GRB-1 locus (see Fig. JA, Lanes 3-5, for example). /<g. Screening of the entire panel of hybrid DNAs revealed segre Cells. The panel of rodent-human somatic cell hybrids used in gation of all GRB-1 specific human fragments with a portion chromosomal localization of the human GRB-1 locus has been de- of the long arm of chromosome 5 (5q); results are summarized in Fig. 1; hybrid 114 which retains human chromosome 5 as its Received 5/13/91; accepted 5/28/91. The costs of publication of this article were defrayed in part by the payment sole human chromosome, is positive for the GRB-1 locus as of page charges. This article must therefore be hereby marked advertisement in are two other hybrids which retain chromosome 5 or a portion accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This work was supported by NIH Grants CA21124 and CA39860. thereof. All hybrids which do not retain chromosome 5 do not 2To whom requests for reprints should be addressed, at Jefferson Cancer retain the GRB-1 locus. Chromosomes 2, 13, and 16 are not Center. Thomas Jefferson University. 233 S. 10'" St., Phila., PA 19107-5541. fully represented in the panel shown but since all human GRB- ' The abbreviations used are: cDNA, complementary DNA; P13 kinase, phos- phatidylinositol-3 kinase; SSC. standard saline-citrate, I x SSC. 0.15 M NaCI, 1 specific bands segregate with chromosome 5, these chromo 0.015 M sodium citrate. somes are also eliminated. 3818 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1991 American Association for Cancer Research. GENE ENCODING PI3 KINASE-ASSOCIATED p85« Human Chromosomes over 5q with 87% of 5q grains (119 of 137) over 5q 12-5q 13 as Hybrid illustrated to the right of chromosome 5 in Fig. 3. There were GB31 IM•p^i no background grain clusters at any other chromosome region. GL3K While testing human DNAs with abnormalities of 5q for 9142 integrity of the GRB-1 locus, a Hindlll restriction fragment 114 length polymorphism was noted and is illustrated in Fig. 2B. 7297 ¡!!7À 115 Of 18 human DNAs tested, 11 were homozygous for the 1.4- 7300 kilobase pair A1 alíele(see legend to Fig. 2Ä),1 was homozy G5N gous for the A2 alíele(Fig. IB, Lane 6, and see legend for 734 449 discussion of alíeles),and 6 were heterozygous for A1/A2 at 10095 this locus (see Fig. IB, Lanes 1, 4, 5). Several other restriction 7301 endonucleases (EcoRl, BamHl, Sst\, Pst\) did not detect J14-2123"I5!6! I89)1011)121314I1516171819I202122Xpolymorphism. Fig. 1. The GRB-1 probe detects a locus on chromosome region 5q. A panel of 13 hybrid DNAs was tested for the presence of GRB-I specific fragments by filter hybridization. Completely cross-hatched box, hybrid named on left contained Discussion the chromosome indicated above the box; lower right cross-hatching, presence of the long arm (or part of the long arm, indicated by a smaller fraction of cross- The long arm of human chromosome 5 is clinically interest hatching) of the chromosome; upper left cross-hatching, presence of the short arm (or partial short arm) of the chromosome; open box. absence of the chromosome. ing in several specific regions. A gene(s) for spinal muscular The column for chromosome 5 is boldly outlined and cross-hatched to highlight atrophy (SMA) has been mapped to 5ql2—»5ql3(individual correlation of the presence of this chromosome with the presence of the GRB-1 references cited in Ref. 15); large acquired interstitial deletions locus. The pattern of retention of the GRB-1 locus in the hybrids is shown on the right, where presence of the locus is indicated by a hatched box enclosing a plus of 5q, many of them including the region 5ql3, which is not (+) sign and absence of the locus is indicated by an open box enclosing a minus the critical region, are seen in refractory anemia and therapy (-) sign. related acute nonlymphocytic leukemias (cited in Ref. 16). Many sporadic colon carcinomas carry deletions of 5q centering In order to regionally localize the GRB-1 probe on 5q, DNAs on band 5q21 (cited in Ref. 17), which carries the locus for from a small panel of hybrids retaining all of chromosome 5 or familial adenomatous polyposis coli (the APC gene). portions thereof (12) were tested for the presence of the GRB- The GRB-1 locus is not deleted in any of the six colorectal 1 locus by filter hybridization.
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