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1.
Oncogene ; 27(29): 4122-7, 2008 Jul 03.
Article in English | MEDLINE | ID: mdl-18345035

ABSTRACT

Aurora A (also known as STK15/BTAK in humans), a putative oncoprotein naturally overexpressed in many human cancers, is a member of the conserved Aurora protein serine/threonine kinase family that is implicated in the regulation of G(2)-M phases of the cell cycle. In vitro studies utilizing antibody microinjection, siRNA silencing and small molecule inhibitors have indicated that Aurora A functions in early as well as late stages of mitosis. However, due to limitations in specificity of the techniques, exact functional roles of the kinase remain to be clearly elucidated. In order to identify the physiological functions in vivo, we have generated Aurora A null mouse embryos, which show severe defects at 3.5 d.p.c. (days post-coitus) morula/blastocyst stage and lethality before 8.5 d.p.c. Null embryos at 3.5 d.p.c. reveal growth retardation with cells in mitotic disarray manifesting disorganized spindle, misaligned and lagging chromosomes as well as micronucleated cells. These findings provide the first unequivocal genetic evidence for an essential physiological role of Aurora A in normal mitotic spindle assembly, chromosome alignment segregation and maintenance of viability in mammalian embryos.


Subject(s)
Chromosomes, Mammalian/metabolism , Embryo Loss/enzymology , Embryo, Mammalian/enzymology , Mitosis , Oncogene Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Spindle Apparatus/metabolism , Animals , Aurora Kinase A , Aurora Kinases , Chromosomes, Mammalian/genetics , Embryo Loss/genetics , G2 Phase/genetics , Humans , Mice , Mice, Knockout , Mitosis/genetics , Morula/enzymology , Morula/pathology , Oncogene Proteins/genetics , Protein Serine-Threonine Kinases/genetics , Spindle Apparatus/genetics
2.
Genes Chromosomes Cancer ; 30(3): 221-9, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11170278

ABSTRACT

Microcell-mediated chromosome transfer allows for the introduction of normal chromosomes into tumor cells in an effort to identify putative tumor suppressor genes. We have used this approach to introduce an intact copy of chromosome 18 into the prostate cancer cell line DU145, and independently to introduce human chromosomes 8 and 18 into the prostate cancer cell line TSU-PR1. Introduction of an extra copy of human chromosome 8 had no effect on the growth properties in vitro or the tumorigenicity in vivo of TSU-PR1 cells. However, microcell hybrids containing an introduced copy of human chromosome 18 exhibited a longer population doubling time, retarded growth in soft agar, and slowed tumor growth in athymic nude mice. These experiments provide functional evidence for the presence of one or more tumor suppressor genes on human chromosome 18 that are involved in prostate cancer.


Subject(s)
Cell Transformation, Neoplastic/genetics , Chromosomes, Human, Pair 18/genetics , Genes, Tumor Suppressor , Prostatic Neoplasms/genetics , Agar , Animals , Cell Culture Techniques/methods , Cell Division/genetics , Cell Transformation, Neoplastic/pathology , Gene Transfer Techniques , Humans , Hybrid Cells/transplantation , Male , Mice , Mice, Nude , Neoplasm Transplantation/methods , Prostatic Neoplasms/etiology , Prostatic Neoplasms/pathology , Tumor Cells, Cultured
3.
Oncogene ; 19(54): 6277-85, 2000 Dec 14.
Article in English | MEDLINE | ID: mdl-11175342

ABSTRACT

The identity of many tumor suppressor genes important in epithelial ovarian cancer tumorigenesis remains unknown. In an effort to localize a novel tumor suppressor on chromosome 22, a psv2neo tagged human chromosome 22 was transferred into the malignant epithelial ovarian cancer cell line, SKOv-3, by microcell-mediated chromosome transfer. Complete suppression of the transformed phenotype was observed in 16 of 18 individual microcell hybrid clones as evidenced by the complete abrogation of cell growth under anchorage-independent conditions. In vitro doubling times were also dramatically reduced, as was the ability to form subcutaneous tumors in CD1 nu/nu mice. Only one polymorphic marker, D22S429, segregated with decreased transformation and tumorigenic potential, suggesting that an unrecognized tumor suppressor may localize to chromosome 22q11-q12. These data provide functional support for the presence of a novel tumor suppressor locus (or loci) on chromosome 22 that is important in ovarian cancer tumorigenesis.


Subject(s)
Carcinoma/genetics , Chromosomes, Human, Pair 22 , Gene Transfer Techniques , Genes, Tumor Suppressor , Ovarian Neoplasms/genetics , Animals , Carcinoma/pathology , Cell Division , Cell Fusion , Female , Genetic Markers , Humans , Hybrid Cells , Mice , Mice, Nude , Microsatellite Repeats , Ovarian Neoplasms/pathology , Phenotype , Suppression, Genetic , Tumor Cells, Cultured
4.
Cancer Genet Cytogenet ; 113(1): 49-53, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10459346

ABSTRACT

Myoepithelioma, a rare benign salivary gland neoplasm, is a tumor composed entirely of myoepithelial cells. Unlike pleomorphic adenoma, these tumors lack any ductal epithelial differentiation, and manifest a minor stromal element. Previous cytogenetic and molecular genetic studies have mainly investigated pleomorphic adenomas and reported recurring specific chromosomal alterations at 8q12 and 12q13-q15 regions. The cell origin of these alterations, however, remains speculative. We report the cytogenetic analysis of a parotid myoepithelioma and discuss the putative origin for the cells with cytogenetic alterations. Our analysis shows 12q12 involved in a translocation with a previously unreported partner (1q), and nonrandom del(9)(q22.1q22.3) and del(13)(q12q22). Our results indicate that the myoepithelial cell is the source of those cells with chromosomal alterations, and that myoepithelioma shares 12q alterations reported in a subset of pleomorphic adenomas.


Subject(s)
Myoepithelioma/genetics , Salivary Gland Neoplasms/genetics , Translocation, Genetic , Actins/analysis , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 13 , Chromosomes, Human, Pair 9 , Desmin/analysis , Flow Cytometry , Humans , Immunohistochemistry , Karyotyping , Keratins/analysis , Male , Middle Aged , Myoepithelioma/pathology , Salivary Gland Neoplasms/pathology
5.
Cancer Res ; 59(9): 2182-9, 1999 May 01.
Article in English | MEDLINE | ID: mdl-10232606

ABSTRACT

Human chromosome 3p cytogenetic abnormalities and loss of heterozygosity have been observed at high frequency in the nonpapillary form of sporadic renal cell carcinoma (RCC). The von Hippel-Lindau (VHL) gene has been identified as a tumor suppressor gene for RCC at 3p25, and functional studies as well as molecular genetic and cytogenetic analyses have suggested as many as two or three additional regions of 3p that could harbor tumor suppressor genes for sporadic RCC. We have previously functionally defined a novel genetic locus nonpapillary renal carcinoma-1 (NRC-1) within chromosome 3p12, distinct from the VHL gene, that mediates tumor suppression and rapid cell death of RCC cells in vivo. We now report the suppression of tumorigenicity of RCC cells in vivo after the transfer of a defined centric 3p fragment into different histological types of RCC. Results document the functional involvement of NRC-1 in not only different cell types of RCC (i.e., clear cell, mixed granular cell/clear cell, and sarcomatoid types) but also in papillary RCC, a less frequent histological type of RCC for which chromosome 3p LOH and genetic aberrations have only rarely been observed. We also report that the tumor suppression observed in functional genetic screens was independent of the microenvironment of the tumor, further supporting a role for NRC-1 as a more general mediator of in vivo growth control. Furthermore, this report demonstrates the first functional evidence for a VHL-independent pathway to tumorigenesis in the kidney via the genetic locus NRC-1.


Subject(s)
Carcinoma, Renal Cell/genetics , Chromosomes, Human, Pair 3/genetics , Genes, Tumor Suppressor , Kidney Neoplasms/genetics , Ligases , Protein Kinases/physiology , Proteins/physiology , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , Animals , Carcinoma, Papillary/genetics , Carcinoma, Papillary/pathology , Carcinoma, Renal Cell/blood supply , Carcinoma, Renal Cell/pathology , Cell Transformation, Neoplastic/genetics , Female , Gene Deletion , Genetic Complementation Test , Humans , Hybrid Cells/transplantation , Kidney Neoplasms/blood supply , Kidney Neoplasms/pathology , Mice , Mice, Nude , Microsatellite Repeats , Middle Aged , Mitogen-Activated Protein Kinase Kinases , Neoplasm Transplantation , Neovascularization, Pathologic/genetics , Protein Kinases/genetics , Proteins/genetics , Tumor Cells, Cultured/transplantation , Von Hippel-Lindau Tumor Suppressor Protein
6.
Cancer Genet Cytogenet ; 109(1): 66-9, 1999 Feb.
Article in English | MEDLINE | ID: mdl-9973962

ABSTRACT

We present the cytogenetic, interphase fluorescence in-situ hybridization (FISH) and DNA content findings in a clinically aggressive adenoid cystic carcinoma (ADCC) of the parotid gland. The tumor manifested diploid chromosomal and DNA content by cytogenetic, interphase FISH and flow cytometry. G-banding analysis revealed inv(5)(p15.2q33) and t(6;15)(q25;q15) as the only structural alterations in all 30 metaphases examined. The limited structural abnormalities found in this recurrent lesion suggest that they may constitute a primary or early event in the development of this tumor. The involvement of 6q region in our tumor and in some of the previously reported ADCC supports the association between this region and the evolution of at least a subset of these tumors.


Subject(s)
Carcinoma, Adenoid Cystic/genetics , Chromosome Aberrations , Chromosome Mapping , Parotid Neoplasms/genetics , Adult , Carcinoma, Adenoid Cystic/pathology , Carcinoma, Adenoid Cystic/surgery , Chromosome Banding , Chromosome Inversion , Chromosomes, Human, Pair 15 , Chromosomes, Human, Pair 5 , Chromosomes, Human, Pair 6 , Humans , Karyotyping , Male , Parotid Neoplasms/pathology , Parotid Neoplasms/surgery , Recurrence , Translocation, Genetic
7.
Cancer Genet Cytogenet ; 107(2): 132-6, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9844608

ABSTRACT

We report the cytogenetic, fluorescence in situ hybridization (FISH), and DNA ploidy analyses of a high grade carcinoma ex-pleomorphic adenoma of the submandibular gland. Our overall combined analyses showed a marked DNA aneuploidy and numerical abnormalities involving all chromosomes. Cytogenetic analysis revealed a near tetraploid modal chromosomal number with tetraploid loss of chromosomes Y, 1, 6, 9, 11, 14, 15, 17, and 19-21 and hypertetraploid gain of chromosomes 7, 8, and 22. The structural abnormalities included der(1;14)(q10;q10), del(6)(q15q34), +del(6)(q15q34), +der(8) t(1;8)(q12;q12.2),der(9;19)(q10;q10),add(14)(p11.2),i(20)(q10),der(21) t(8;21)(q11.2;q22.3),+der(21)t(8;21) (q11.2;q22.3). Interphase FISH of the primary and short-term cultured cells using directly labeled pericentromeric probes for chromosomes 6-12, 17, 18, and Y resulted in alterations corresponding to the cytogenetic findings. DNA ploidy analysis of both the primary and cultured tumor cells showed a hyperdiploid stemline with DNA indices of 2.6. The results indicate that: (1) marked numerical, structural chromosomal, and DNA content abnormalities are present in this tumor; and (2) alteration at 8q and 6q regions, together with previous results, suggest an association between these events and the development and/or progression of this tumor.


Subject(s)
Adenocarcinoma/genetics , Adenoma, Pleomorphic/genetics , Parotid Neoplasms/genetics , Adenocarcinoma/pathology , Adenoma, Pleomorphic/pathology , Flow Cytometry , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Karyotyping , Male , Middle Aged , Parotid Neoplasms/pathology
8.
Cancer Res ; 58(16): 3533-7, 1998 Aug 15.
Article in English | MEDLINE | ID: mdl-9721855

ABSTRACT

Using a functional genetic approach, we previously identified a novel genetic locus, NRC-1 (Nonpapillary Renal Cell Carcinoma 1), that mediated tumor suppression and rapid cell death of renal cell carcinoma (RCC) cells in vivo. For these experiments, a defined subchromosomal fragment of human chromosome 3p was transferred into a sporadic RCC cell line via microcell fusion, and microcell hybrid clones were tested for tumorigenicity in vivo. The results indicated functional evidence for a novel tumor suppressor locus within the 3p14-p12 interval known to contain the most common fragile site of the human genome (FRA3B), the FHIT gene, and the breakpoint region associated with the familial form of RCC. We now report the physical mapping of the NRC-1 critical region by detailed microsatellite analyses of novel microcell hybrid clones containing transferred fragments of chromosome 3p in the RCC cell background that were phenotypically suppressed or unsuppressed for tumorigenicity in vivo. The results limit the region containing the tumor suppressor locus within chromosome 3p12. The FHIT gene, FRA3B, and the familial RCC breakpoint region were excluded from the NRC-1 critical region. Furthermore, the NRC-1 locus falls within a well-characterized homozygous deletion region of 5-7 Mb associated with a small cell lung carcinoma cell line, U2020, suggesting that a more general tumor suppressor gene may reside in this region.


Subject(s)
Acid Anhydride Hydrolases , Carcinoma, Renal Cell/genetics , Chromosome Mapping , Chromosomes, Human, Pair 3/genetics , Genes, Tumor Suppressor/genetics , Kidney Neoplasms/genetics , Humans , Microsatellite Repeats/genetics , Mitogen-Activated Protein Kinase Kinases , Neoplasm Proteins/genetics , Protein Kinases/genetics , Proteins/genetics , Translocation, Genetic
9.
Ann Surg ; 227(2): 229-35, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9488521

ABSTRACT

OBJECTIVE: We report a unique, previously undescribed multigeneration kindred with von Hippel-Lindau (VHL) disease in whom clinical or genetic screening led to the detection of surgically resectable neoplastic disease in several family members. SUMMARY BACKGROUND DATA: Patients with VHL disease have a propensity to develop neoplasms of several different organ sites. Retinal angiomas, cerebellar and spinal hemangioblastomas, solid organ cysts, and renal carcinoma are common lesions; pheochromocytomas and pancreatic islet cell tumors occur less frequently but are important causes of morbidity and mortality. METHODS: A detailed pedigree was constructed based on clinical screening and family history that describes the development of pancreatic islet cell tumors in four of five female siblings. VHL mutation analysis was performed in an attempt to determine if genotype-phenotype correlations could be made in this interesting family. RESULTS: The age of onset of VHL-associated neoplasms for three affected siblings was in the third decade of life and in the fourth decade for the fourth sibling. The mother of the four siblings affected with pancreatic tumors developed bilateral pheochromocytomas in the seventh decade of life; she has no pancreatic or kidney tumors. We identified maternal transmission of a missense mutation in codon 238 in exon 3 of the VHL gene in the four affected siblings with pancreatic islet cell tumors. Mutation screening on unaffected family members showed no abnormalities in the VHL gene. Interestingly, one of the four affected siblings had no evidence of VHL on her initial clinical screening evaluation; however, she was followed closely because of her mutated VHL gene. Four years after initial screening, she developed two pancreatic islet cell tumors and a premalignant renal cyst. CONCLUSIONS: Clinical and genetic screening for VHL in this family had a significant impact on surgical management by detecting early-stage islet cell tumors or pheochromocytomas. Furthermore, we conclude that the preponderance of pancreatic islet cell tumors in this family cannot be explained by a strict genotype-phenotype correlation. This suggests that additional genetic abnormalities, possibly on chromosome 3p where the VHL gene is located, may be responsible for the variety of VHL-associated neoplasms.


Subject(s)
Adenoma, Islet Cell/complications , Adenoma, Islet Cell/genetics , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/genetics , von Hippel-Lindau Disease/complications , von Hippel-Lindau Disease/genetics , Adenoma, Islet Cell/surgery , Adrenal Gland Neoplasms/complications , Adult , Decision Making , Female , Humans , Liver Neoplasms/secondary , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Pedigree , Pheochromocytoma/complications , Point Mutation , Polymorphism, Single-Stranded Conformational
10.
Cancer Genet Cytogenet ; 100(2): 155-8, 1998 Jan 15.
Article in English | MEDLINE | ID: mdl-9428361

ABSTRACT

We report the cytogenetic, fluorescence in-situ hybridization (FISH) and DNA flow cytometric analysis of a rare metastatic epimyoepithelial carcinoma of the parotid gland to the lung with a clinical course of 29 years. DNA content and FISH analyses of tumor and short-term culture cells showed diploid DNA content and lack of numerical chromosomal abnormalities. Immunohistochemical analysis of the short-term culture cells showed predominantly keratin positive and sparse desmin staining supporting an epithelial rather than myoepithelial origin. Cytogenetic analysis showed 46,XY karyotype with clonal translocations of t(3;22)(q13.2;q13.1), t(1;7)(q21;q22), t(8;9)(p10;p10), and t(5;6) (q35;q21). Our findings indicate that these alterations developed in a diploid stemline during tumor progression and in the epithelial component of this tumor.


Subject(s)
Carcinoma/genetics , Lymphatic Metastasis , Parotid Neoplasms/genetics , Translocation, Genetic , Adult , Carcinoma/pathology , Chromosome Banding , Humans , Karyotyping , Male , Parotid Neoplasms/pathology
11.
Genes Chromosomes Cancer ; 20(3): 260-7, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9365833

ABSTRACT

The development of primary human brain tumors, particularly glioblastoma multiforme (GBM), has been associated with a number of molecular and chromosomal abnormalities. In this study, a novel tumor suppressor locus was identified and localized after the transfer of a human chromosome 4 into U251 human GBM cells. Hybrid clones containing a transferred neomycin-resistance tagged chromosome 4 revealed an inability to form tumors in nude mice and a greatly decreased efficiency of soft agarose colony formation. As a control, clones containing a transferred chromosome 2 were generated, and these retained the tumorigenic phenotype of the parental U251 cells. The presence of the transferred chromosomes was demonstrated by gain of polymorphic loci and FISH analyses. Several suppressed hybrid clones were shown to contain spontaneously reduced versions of the transferred chromosome 4. A common region of the fragmented chromosome 4 was retained among these clones that included the epidermal growth factor locus at 4q24-26 and several adjacent markers. The identification of a common fragment in the suppressed clones suggests the presence of a tumor suppressor gene or genes in this region, involved in glioma oncogenesis.


Subject(s)
Chromosomes, Human, Pair 4/genetics , Genes, Tumor Suppressor/genetics , Glioma/genetics , Animals , Blotting, Southern , Chromosome Mapping , DNA/analysis , Epidermal Growth Factor/genetics , Glioma/pathology , Humans , Hybrid Cells , Mice , Microsatellite Repeats , Phenotype , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Transfection , Tumor Cells, Cultured , Tumor Stem Cell Assay
12.
Oncogene ; 13(11): 2387-96, 1996 Dec 05.
Article in English | MEDLINE | ID: mdl-8957080

ABSTRACT

High frequencies of allelic loss on the short arm of chromosome 3 in small cell lung cancer (SCLC) and a number of other tumors suggest the existence of a tumor suppressor gene(s) within the deleted regions. Two small cell lung cancer lines, NCI H740 and GLC20, have been described which have homozygous deletions in the region 3p21.3. The deleted region overlaps with a 2 Mb fragment of human DNA present in the interspecies hybrid HA(3)BB9F, that suppresses tumor formation by mouse A9 fibrosarcoma cells. Human sequences from this cell hybrid were isolated using inter Alu PCR. From this starting point, a P1 contig was developed for the region of 450 Kb that is common to the homozygous deletions seen in the SCLC lines NCI H740 and GLC20 and is also present in HA(3)BB9F, the suppressed A9 hybrid. Individual P1 clones were assayed for their ability to suppress the tumorigenicity of the mouse fibrosarcoma cell line A9 as assayed by injection of transfected A9 cells into athymic nude mice. The introduction of one of the P1 clones into A9 cells resulted in suppression of tumor growth whereas two other P1 clones from the contig failed to suppress tumor formation in athymic nude mice. These data functionally delimit a tumor suppressor locus to a region of 80 kb within a P1 clone at 3p21.3.


Subject(s)
Carcinoma, Small Cell/genetics , Chromosomes, Human, Pair 3/genetics , Genes, Tumor Suppressor/genetics , Lung Neoplasms/genetics , Sequence Deletion , Animals , Carcinoma, Small Cell/pathology , Fibrosarcoma/genetics , Genetic Markers , Humans , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Oligonucleotide Probes/genetics , Sequence Analysis, DNA/methods , Tumor Cells, Cultured
13.
Cancer Genet Cytogenet ; 89(1): 38-43, 1996 Jul 01.
Article in English | MEDLINE | ID: mdl-8689608

ABSTRACT

We present a case of mucoepidermoid carcinoma with t(3;12)(q24;p13) and polysomy X by cytogenetic and fluorescence in situ hybridization (FISH) techniques. Flow cytometric DNA analysis of the primary tumor showed DNA aneuploidy and analysis of cultured tumor cells showed DNA diploidy indicating restricted growth of the diploid tumor cells in short-term tissue culture. Interphase cytogenetic analysis of chromosomes 1, 3, 6-12, 16-18, and X in the primary tumor showed polysomy 1, 9, 18, and X, monosomy 8 and 17, and disomy 3, 6, 7, 10-12, and 16. Except for chromosome X, other numerical chromosomal abnormalities were not detected by conventional cytogenetic analysis. Our combined approach allowed for better characterization of the genotypic features of this neoplasm.


Subject(s)
Carcinoma, Mucoepidermoid/genetics , Chromosome Aberrations , DNA, Neoplasm/analysis , In Situ Hybridization, Fluorescence , Parotid Neoplasms/genetics , Ploidies , Aged , Carcinoma, Mucoepidermoid/pathology , Female , Flow Cytometry , Genotype , Humans , Parotid Neoplasms/pathology
14.
Cancer Genet Cytogenet ; 87(1): 29-33, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8646736

ABSTRACT

We present the cytogenetic analysis of a mucoepidermoid carcinoma of the minor salivary gland with t(11,19)(q21;p13.1) as the sole karyotypic abnormality. Our findings, along with those of previous reports, indicate that this translocation is an early and most likely a primary event in the development of a least a subset of these neoplasms.


Subject(s)
Carcinoma, Mucoepidermoid/genetics , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 19 , Salivary Gland Neoplasms/genetics , Translocation, Genetic , Adolescent , Female , Humans , Salivary Gland Neoplasms/pathology , Salivary Glands, Minor
15.
Proc Natl Acad Sci U S A ; 93(6): 2551-6, 1996 Mar 19.
Article in English | MEDLINE | ID: mdl-8637912

ABSTRACT

Prostate cancer is the second leading cause of male cancer deaths in the United States. Yet, despite a large international effort, little is known about the molecular mechanisms that underlie this devastating disease. Prostate secretory epithelial cells and androgen-dependent prostate carcinomas undergo apoptosis in response to androgen deprivation and, furthermore, most prostate carcinomas become androgen independent and refractory to further therapeutic manipulations during disease progression. Definition of the genetic events that trigger apoptosis in the prostate could provide important insights into critical pathways in normal development as well as elucidate the perturbations of those key pathways in neoplastic transformation. We report the functional definition of a novel genetic locus within human chromosome 10pter-q11 that mediates both in vivo tumor suppression and in vitro apoptosis of prostatic adenocarcinoma cells. A defined fragment of human chromosome 10 was transferred via microcell fusion into a prostate adenocarcinoma cell line. Microcell hybrids containing only the region 10pter-q11 were suppressed for tumorigenicity following injection of microcell hybrids into nude mice. Furthermore, the complemented hybrids undergo programmed cell death in vitro via a mechanism that does not require nuclear localization of p53. These data functionally define a novel genetic locus, designated PAC1, for prostate adenocarcinoma 1, involved in tumor suppression of human prostate carcinoma and furthermore strongly suggest that the cell death pathway can be functionally restored in prostatic adenocarcinoma.


Subject(s)
Adenocarcinoma/genetics , Apoptosis , Chromosomes, Human, Pair 10 , Prostatic Neoplasms/genetics , Animals , DNA Damage , Genes, Tumor Suppressor , Humans , Hybrid Cells , Male , Mice , Mice, Nude , Tumor Cells, Cultured
16.
Prostate Suppl ; 6: 31-5, 1996.
Article in English | MEDLINE | ID: mdl-8630227

ABSTRACT

To examine the role of human chromosomes in the development of metastatic prostate cancer, we introduced a copy of human chromosomes into highly metastatic Dunning R-3327 rat prostatic cancer cells by microcell-mediated chromosome transfer. Each microcell hybrid clones containing human chromosomes 8, 10, 11, and 17, respectively, showed decreased ability to metastasize to the lung, without any loss of tumorigenicity. This finding demonstrates that these human chromosomes contain metastasis suppressor genes for prostate cancer. Spontaneous deletion of portions of human chromosomes was observed in human chromosome 10, 11, and 17 studies. In the human chromosome 8 study, irradiated microcell-mediated chromosome transfer was performed to enrich chromosomal arm deletions of human chromosome 8. Relationships between the size of human chromosomes introduced into microcell hybrid clones and the number of lung metastases produced by the clones were analyzed to determine which part of human chromosomes contained metastasis suppressor gene(s) for prostate cancer. Molecular and cytogenetic analyses of microcell hybrid clones demonstrated that metastasis suppressor genes on human chromosomes 8, 10, and 11 were located on 8p23-q12, 10q, 11p13-11.2, respectively. Further analyses are proposed to confirm the potentially useful advantage of this assay system to identify metastasis suppressor gene(s) for prostate cancer.


Subject(s)
Genes, Tumor Suppressor , Neoplasm Metastasis/genetics , Prostatic Neoplasms/genetics , Animals , Chromosomes, Human, Pair 10 , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 17 , Chromosomes, Human, Pair 8 , Humans , Male , Rats
17.
Genes Chromosomes Cancer ; 14(2): 112-9, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8527392

ABSTRACT

To examine the role of human chromosome 10 in development of prostatic cancer, we introduced human chromosome 10 into highly metastatic rat prostatic cancer cells by microcell-mediated chromosome transfer. Microcell hybrid cells introduced with human chromosome 10 showed suppression of the metastatic ability to the lung to some extent without any suppression of tumorigenicity, although the tumor growth rate decreased slightly. To minimize the region that contains metastasis suppressive activity, the hybrid cells in metastasis foci of lung were established in culture and reanalyzed for portions of human chromosome 10 retained in the metastasis tissues. Cytogenetic and molecular analyses demonstrated that loss of the region between 10cen and D10S215 on human chromosome arm 10q was related to expression of the metastatic phenotype. These results demonstrate that the region between 10cen and D10S215 on human chromosome arm 10q contains at least one of the metastasis suppressor genes for rat prostatic cancer.


Subject(s)
Chromosomes, Human, Pair 10 , Genes, Tumor Suppressor , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Animals , Chromosome Banding , Chromosome Mapping , Clone Cells , Humans , Hybrid Cells , Karyotyping , Male , Neoplasm Metastasis/genetics , Polymerase Chain Reaction , Rats
18.
Somat Cell Mol Genet ; 21(5): 357-65, 1995 Sep.
Article in English | MEDLINE | ID: mdl-8619133

ABSTRACT

To access a wide a variety of expressed sequence from human chromosome 21 we have placed this chromosome into undifferentiated P19 mouse embryonic carcinoma cells. Cell lines resulting from these experiments have a range of morphologies and a wide variety of karyotypes. We have studied the retinoic acid response of five cell lines, compared to P19 cells, by observing three markers of retinoic acid induced P19 differentiation--cell morphology, RAR alpha and Wnt1 transcription. We see an 'early' retinoic acid response effect, however this response breaks down by the time the 'late' gene. Wnt1 would be transcribed in P19 cells. A highly responsive cell line will be useful for cloning expressed sequences from human chromosome 21 which are produced by early genes in retinoic acid inducible pathways, such as those involved in neurogenesis.


Subject(s)
Chromosomes, Human, Pair 17 , Gene Expression/drug effects , Tretinoin/pharmacology , Zebrafish Proteins , Animals , Base Sequence , Carcinoma, Embryonal , Cell Fusion , Cell Line , DNA Primers , Humans , Hybrid Cells , In Situ Hybridization, Fluorescence , Karyotyping , Mice , Molecular Sequence Data , Polymerase Chain Reaction , Protein-Tyrosine Kinases/biosynthesis , Proto-Oncogene Proteins/biosynthesis , Receptors, Retinoic Acid/biosynthesis , Recombinant Proteins/biosynthesis , Retinoic Acid Receptor alpha , Transcription, Genetic , Tumor Cells, Cultured , Wnt Proteins , Wnt1 Protein
19.
Cell ; 82(4): 611-20, 1995 Aug 25.
Article in English | MEDLINE | ID: mdl-7664340

ABSTRACT

Transfer of human chromosome 11, which contains the myoD locus, from primary fibroblasts into 10T1/2 cells results in activation of myoD. In contrast, hybrids that retain human chromosome 11 and additional human chromosomes fail to activate myoD. We show that human chromosome 4 inhibits myoD activation. myoD enhancer/promoter reporter constructs show that repression is at the transcriptional level. Chromosome fragment-containing hybrids localize the repressing activity to the region of 4p that contains the homeobox gene MSX1. MSX1 is expressed in primary human fibroblasts and in 10T1/2 cells containing human chromosome 4, while parental 10T1/2 cells do not express Msx1. Forced expression of Msx1 represses myoD enhancer activity. Msx1 protein binds to the myoD enhancer and likely represses myoD transcription directly. Antisense MSX1 relieves repression mediated by chromosome 4. We conclude that MSX1 inhibits transcription of myoD and that myoD is a target for homeobox gene regulation.


Subject(s)
Genes, Homeobox , MyoD Protein/genetics , Animals , Base Sequence , Cell Line , Chromosome Mapping , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 4 , DNA Primers/genetics , DNA, Antisense/genetics , Enhancer Elements, Genetic , Extremities/embryology , Fibroblasts , Gene Expression Regulation, Developmental , Humans , Hybrid Cells , Mice , Molecular Sequence Data
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