1: Genes Chromosomes Cancer. 2006 Jan;45(1):47-60. Combined genome-wide allelotyping and copy number analysis identify frequent genetic losses without copy number reduction in medulloblastoma. Langdon JA, Lamont JM, Scott DK, Dyer S, Prebble E, Bown N, Grundy RG, Ellison DW, Clifford SC. Northern Institute for Cancer Research, University of Newcastle, Newcastle-upon-Tyne, UK. Detailed analysis of mechanisms of genetic loss for specific tumor suppressor genes (TSGs; e.g., RB1, APC and NF1) indicates that TSG inactivation can occur by allelic loss of heterozygosity (LOH), without any alteration in DNA copy number. However, the role and prevalence of such events in the pathogenesis of specific malignancies remains to be established on a genome-wide basis. We undertook a detailed molecular assessment of chromosomal defects in a panel of nine cell lines derived from primary medulloblastomas, the most common malignant brain tumors of childhood, by parallel genome-wide assessment of LOH (allelotyping) and copy number aberrations (comparative genomic hybridization and fluorescence in situ hybridization). The majority of genetic losses observed were detected by both copy number and LOH methods, indicating they arise through the physical deletion of chromosomal material. However, a significant proportion of losses (17/42, 40%) represented regions of allelic LOH without any associated copy number reduction; these events involved both whole chromosomes (10/17) and sub-chromosomal regions (7/17). Using this approach, we identified medulloblastoma-characteristic alterations, e.g., isochromosome for 17q, MYC amplification and losses on chromosomes 10, 11, and 16, alongside novel regions of genetic loss (e.g., 10q21.1-26.3, 11q24.1-qter). This detailed genetic characterization of the majority of medulloblastoma cell lines provides important precedent for the widespread involvement of copy number-neutral genetic losses in medulloblastoma and demonstrates that combined assessment of copy number aberrations and LOH will be necessary to accurately determine the contribution of chromosomal defects to tumor development. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. (c) 2005 Wiley-Liss, Inc. PMID: 16149064 [PubMed - in process] --------------------------------------------------------------- 2: Am J Dermatopathol. 2003 Feb;25(1):21-7. Malignant blue nevus: a case report and molecular analysis. Ariyanayagam-Baksh SM, Baksh FK, Finkelstein SD, Swalsky PA, Abernethy J, Barnes EL. Department of Pathology, University of Pittsburgh Medical Center, Pennsylvania, USA. bakshfs@hotmail.com Malignant blue nevus is a rare melanocytic tumor that is described by some authors as a variant of malignant melanoma, whereas others regard it as a distinct entity. To our knowledge no molecular studies of this tumor have been performed, although the molecular pathogenesis of conventional melanomas has been extensively described. We present a case of malignant blue nevus that developed in a 15-cm congenital blue nevus on the back of a 41-year-old man. Subsequent regional lymph node and lung metastases developed within 1 and 29 months, respectively. We performed a molecular analysis for loss of heterozygosity on microdissected samples from the spectrum of benign to malignant blue nevus, using a panel of eight genes (MTS1, MXI1, CMM1, p53, NF1, L-myc hOGG1, and MCC), many of which are commonly associated with conventional melanomas. No loss of heterozygosity was detected, despite informativeness in seven genes. We suggest that malignant blue nevus may represent a distinct entity with a different molecular pathway to tumorigenesis than that of conventional melanomas. Publication Types: Case Reports PMID: 12544095 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Nucleic Acids Res. 2003 Jan 15;31(2):562-9. Basal transcriptional regulation of human damage-specific DNA-binding protein genes DDB1 and DDB2 by Sp1, E2F, N-myc and NF1 elements. Nichols AF, Itoh T, Zolezzi F, Hutsell S, Linn S. Department of Molecular and Cell Biology, Barker Hall, University of California, Berkeley, CA 94720-3202, USA. The human DDB1 and DDB2 genes encode the 127 and 48 kDa subunits, respectively, of the damage-specific DNA-binding protein (DDB). Mutations in the DDB2 gene have been correlated with the hereditary disease xeroderma pigmentosum group E. We have investigated the proximal promoters of the DDB genes, both of which are G/C-rich and do not contain a TATA box. Transient expression analysis in HeLa cells using a luciferase reporter system indicated the presence of core promoters located within 292 bp (DDB1) and 220 bp (DDB2) upstream of the putative transcription initiation sites. Both core promoters contain multiple active Sp1 sites, with those of DDB1 at -123 to -115 and of DDB2 at -29 to -22 being critical determinants of promoter activity. In addition, an N-myc site at -56 to -51 for DDB1 is an essential transcription element, and mutations in a DDB1 NF-1 site at -104 to -92, a DDB2 NF-1 site at -68 to -56 and a DDB2 E2F site at +36 to +43 also reduce promoter activity. Taken together, these results suggest a regulation of basal transcription typical of cell cycle-regulated genes, and therefore support conjectures that the DDB heterodimer and/or its subunits have functions other than direct involvement in DNA repair. PMID: 12527763 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 4: J Virol. 2002 Sep;76(18):9046-59. Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations. Jiang X, Hanna Z, Kaouass M, Girard L, Jolicoeur P. Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, H2W 1R7 Quebec, Canada. The Ahi-1 locus was initially identified as a common helper provirus integration site in Abelson pre-B-cell lymphomas and shown to be closely linked to the c-myb proto-oncogene. Since no significant alteration of c-myb expression was found in Abelson murine leukemia virus-induced pre-B-lymphomas harboring a provirus inserted within the Ahi-1 locus, this suggested that it harbors another gene whose dysregulation is involved in tumor formation. Here we report the identification of a novel gene (Ahi-1) targeted by these provirus insertional mutations and the cloning of its cDNA. The Ahi-1 proviral insertions were found at the 3' end of the gene, in an inverse transcriptional orientation, with most of them located around and downstream of the last exon, whereas another insertion was within intron 22. In addition, another previously identified provirus insertion site, Mis-2, was found to map within the 16th intron of the Ahi-1 gene. The Ahi-1 cDNA encodes a 1,047-amino-acid protein. The predicted Ahi-1 protein is a modular protein that contains one SH3 motif and seven WD40 repeats. The Ahi-1 gene is conserved in mammals and encodes two major RNA species of 5 and 4.2 kb and several other shorter splicing variants. The Ahi-1 gene is expressed in mouse embryos and in several organs of the mouse and rat, notably at high levels in the brain and testes. In tumor cells harboring insertional mutations in Ahi-1, truncated Ahi-1/viral fused transcripts were identified, including some splicing variants with deletion of the SH3 domain. Therefore, Ahi-1 is a novel gene targeted by provirus insertion and encoding a protein that exhibits several features of a signaling molecule. Thus, Ahi-1 may play an important role in signal transduction in normal cells and may be involved in tumor development, possibly in cooperation with other oncogenes (such as v-abl and c-myc) or with a tumor suppressor gene (Nf1), since Ahi-1 insertion sites were identified in tumors harboring v-abl defective retroviruses or a c-myc transgene or in tumors exhibiting deletion of Nf1. PMID: 12186888 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 5: Oncogene. 1998 Mar 26;16(12):1525-31. The OMgp gene, a second growth suppressor within the NF1 gene. Habib AA, Gulcher JR, Hognason T, Zheng L, Stefansson K. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. The Oligodendrocyte-Myelin glycoprotein gene (OMgp) is placed within an intron of the NF1 gene. Neurofibromin, the product of NF1, acts as a RasGAP and suppresses growth; inactivating mutations in NF1 lead to neurofibromatosis type 1. We report that OMgp also has growth suppressive effects and downregulates mitogenic signaling pathways closely related to those influenced by neurofibromin. Overexpression of OMgp alters mitogenic signaling in NIH3T3 fibroblasts. Cells overexpressing OMgp grow more slowly in serum compared to controls and show a partial G1 block upon cell cycle analysis. PDGF is the primary mitogen for fibroblasts in serum. Overexpression of OMgp alters PDGF signaling in fibroblasts which results in a block of mitogenic signaling. PDGF induced activation of c-Src is blocked, as is the induction of c-Myc and c-Fos, while tyrosine phosphorylation of the PDGFbeta receptor, PLCgamma1 and induction of c-Jun are intact. Although a number of genes embedded within other genes have been described, the biological significance of this arrangement remains unknown. We demonstrate here that structurally unrelated products of two such genes may exercise closely related functions. Our data also raise the possibility of a role for OMgp in disorders of cell proliferation such as NF1. PMID: 9569019 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 6: Mol Cell Biochem. 1998 Apr;181(1-2):137-42. Receptor-Ck-dependent regulation of genes involved in the cell cycle. Kaur M, Kaul D, Sobti RC. Department of Experimental Medicine and Biotechnology, Post graduate Institute of Medical Education and Research, Chandigarh, India. The present study was addressed to understand the interrelationship between Receptor-Ck activation, mevalonate pathway and primary response genes such as c-fos, c-myc and cyclin 'D' involved in the cell cycle. The results reported here unambiguously revealed that the phosphatidic acid (generated through the activation of Receptor-Ck by cholesterol) regulates mevalonate pathway, DNA synthesis as well as expression of genes coding for c-fos, c-myc and cyclin 'D'. By using the specific blockers of ras farnesylation as well as phospholipase D, it became apparent that phosphatidic acid regulates two processes: (a) activation of Gap-ras pathway leading to the expression of c-fos, c-myc proto-oncogenes probably through the activation of NF1 transcription factor; (b) cleavage of 125 kDa endoplasmic reticulum protein leading to the generation of 47 kDa protein factor which not only regulates mevalonate pathway but also has an ability to heterodimerize with Receptor-Ck protein and this heterodimer may be responsible for the regulation of cyclin 'D' expression probably by binding to the SRE like sequence present in the promoter region of this gene. On the basis of these findings, we propose a pathway through which Receptor-Ck upon endocytosis regulate these primary response genes (c-fos, c-myc, cyclin 'D') involved in the cell cycle. PMID: 9562250 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 7: Eur J Cancer. 1997 Oct;33(12):1953-6. Loss of heterozygosity for chromosome 1p in familial neuroblastoma. Tonini GP, Lo Cunsolo C, Cusano R, Iolascon A, Dagnino M, Conte M, Milanaccio C, De Bernardi B, Mazzocco K, Scaruffi P. Unit of Solid Tumour Biology, G. Gaslini Institute/Advanced Biotechnology Centre, Genoa, Italy. Loss of heterozygosity (LOH) and deletion of chromosome 1p are very often found in sporadic neuroblastoma. Nevertheless, very few data are available concerning 1p LOH in familial neuroblastoma. Families with recurrent neuroblastoma are rare and analysis of chromosome 1p in these families might give useful information for identifying the putative neuroblastoma suppressor gene. We used combined cytogenetic and molecular techniques to study 1p LOH in two neuroblastoma families. Family M has 2 out of 3 children with neuroblastoma and family C has 2 children, 1 of whom has neuroblastoma and type 1 neurofibromatosis (NF1). All patients of both families showed tumour cells with chromosome 1p deletion (1pdel), but only the patient from family C also had MYCN gene amplification. In all cases the deleted chromosome 1 was of maternal origin. Publication Types: Case Reports PMID: 9516831 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 8: EMBO J. 1997 Jun 2;16(11):2985-95. Targeted expression of MYCN causes neuroblastoma in transgenic mice. Weiss WA, Aldape K, Mohapatra G, Feuerstein BG, Bishop JM. G.W. Hooper Foundation, and Department of Neurology, University of California, San Francisco 94143-0552, USA. The proto-oncogene MYCN is often amplified in human neuroblastomas. The assumption that the amplification contributes to tumorigenesis has never been tested directly. We have created transgenic mice that overexpress MYCN in neuroectodermal cells and develop neuroblastoma. Analysis of tumors by comparative genomic hybridization revealed gains and losses of at least seven chromosomal regions, all of which are syntenic with comparable abnormalities detected in human neuroblastomas. In addition, we have shown that increases in MYCN dosage or deficiencies in either of the tumor suppressor genes NF1 or RB1 can augment tumorigenesis by the transgene. Our results provide direct evidence that MYCN can contribute to the genesis of neuroblastoma, suggest that the genetic events involved in the genesis of neuroblastoma can be tumorigenic in more than one chronological sequence, and offer a model for further study of the pathogenesis and therapy of neuroblastoma. PMID: 9214616 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 9: J Virol. 1996 Dec;70(12):8571-83. The HNF1/HNF4-dependent We2 element of woodchuck hepatitis virus controls viral replication and can activate the N-myc2 promoter. Fourel G, Ringeisen F, Flajolet M, Tronche F, Pontoglio M, Tiollais P, Buendia MA. Unite de Recombinaison et Expression Genetique, INSERM U163, Institut Pasteur, Paris, France. Transcriptional activation of myc family proto-oncogenes through the insertion of viral sequences is the predominant mechanism by which woodchuck hepatitis virus (WHV) induces liver tumors in chronically infected animals. The main target is N-myc2, a functional retroposon of the N-myc gene, but c-myc and N-myc are also marginally involved. Here we identify a major, liver-specific regulatory element in the WHV genome (We2) which efficiently activates the N-myc2 promoter in cultured hepatoma cells. In the context of the episomal viral genome, We2 governs the production of pregenomic RNA and thus plays a central role in the control of viral replication. We2 activity is primarily controlled by the liver-enriched HNF1 and HNF4 transcription factors, although NF1 and Oct proteins were also shown to bind in a central region. The expression of HNF1 and HNF4 appears to be maintained in woodchuck tumors. Thus, We2 is a prime candidate for controlling myc gene cis activation during WHV-induced hepatocarcinogenesis. PMID: 8970982 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 10: Genes Cells. 1996 Jan;1(1):125-37. Neurocristopathy resembling neurofibromatosis type 1 in an NGF-SV40 transgenic line. Mazarakis ND, Yannoutsos N, el-Jabbour JN, Hatton W, Fletcher R, Grosveld F. Norman and Sadie Lee Research Centre, Division of Neurobiology, National Institute for Medical Research, London, UK. BACKGROUND: Animal models of carcinogenesis have been produced in transgenic mice by directing the expression of oncogenes such as SV40 T antigen and myc to different tissues by creating fusions with promoter/enhancer elements of various mammalian or viral genes. RESULTS: A transgenic mouse line was created in which SV40 T antigen is under the control of the mouse nerve growth factor (NGF) promoter. While the oncogene is expressed in a wide range of NGF producing tissues, it specifically causes the development of either neurofibromas or neurofibrosarcomas similar to those found in the human disease neurofibromatosis type 1 (NF1). These tumours are completely penetrant and appear after a mean latency of about 8 months. In contrast to the previously reported neurofibromatosis mouse model HTLV-1 tax, the tumours in these transgenic mice arise in Schwann cells rather than perineural fibroblasts and have a very restricted tissue distribution. In a cell line cloned from a neurofibroma from these mice, NGF was detected in the culture medium at levels similar to those produced by cultured primary Schwann cells. CONCLUSION: As all animal model for a heritable neurocristopathy resembling NF1, this mouse should allow study of the pathology and treatment of this disease. PMID: 9078372 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 11: Nippon Rinsho. 1994 Dec;52(12):3319-29. [Tumor suppressor genes] [Article in Japanese] Kuchino Y. Cell fusion experiments performed by Harris et al. informed that tumor suppressor genes are inactivated in malignant cells. Inactivation of tumor suppressor genes induced by genetic alteration such as point mutation and deletion leads to disturbance in the control of cell proliferation resulting in deregulated growth of normal cells. Recently, many challenges of scientists including clinicians trying to direct the studies of tumor suppressors toward cancer therapy have been stimulated. For that purpose, it is important to understand the molecular mechanism in which change of normal phenotypes into tumor take place. In this review, recent topics on tumor suppressors such as Rb, p53, Wt1, APC, NF1, s-Myc and H19 are included to discuss their significance and function. Publication Types: Review Review, Tutorial PMID: 7853729 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 12: J Biol Chem. 1994 Sep 30;269(39):24321-7. Activation of nuclear factor kappa B and oncogene expression by 12(R)-hydroxyeicosatrienoic acid, an angiogenic factor in microvessel endothelial cells. Laniado-Schwartzman M, Lavrovsky Y, Stoltz RA, Conners MS, Falck JR, Chauhan K, Abraham NG. Department of Pharmacology, New York Medical College, Valhalla 10595. 12(R)-Hydroxy-5,8,14(Z,Z,Z)-eicosatrienoic acid (12(R)-HETrE) is an arachidonic acid metabolite formed by the corneal epithelium of several species, porcine leukocytes, and human and rat epidermal cells. It is a potent, stereospecific proinflammatory and angiogenic factor and its synthesis is increased manyfold in inflamed tissues, e.g. cornea and skin. It is possible that the angiogenic activity of 12(R)-HETrE is due to a direct mitogenic effect on microvessel endothelial cells via yet to be elucidated cellular and molecular mechanisms. In the present study, we demonstrated the ability of 12(R)-HETrE to stimulate the growth of quiescent endothelial cells in a time- and concentration-dependent manner with a maximal effect at 0.1 nM. This effect was highly stereospecific since its enantiomer, 12(S)-HETrE, had no effect within the same concentration range. Northern blot analysis and transient transfection experiments with chloramphenicol acetyltransferase constructs of oncogene promoter regions demonstrated significant increases over control (0.5% fetal calf serum) in c-myc-, c-jun, and c-fos mRNA levels and expression in cells treated with 0.1 nM 12(R)-HETrE. Electrophoretic mobility shift assay of nuclear protein extracts from cells treated with 12(R)-HETrE with specific radiolabeled oligonucleotides corresponding to known transcriptional binding sites, including AP-1, AP-2, SP1, TRE, NF kappa B, TFIID, OKT1, CREB, CTF/NF1, and GRE demonstrated a markedly rapid and specific increase in the binding activity of NF kappa B and to a lesser extent, AP-1. No significant increase was observed in the binding of other transcription factors assayed as compared to control (untreated) cells. Since the protooncogenes (c-fos, c-jun, and c-myc) are immediate early response genes that are implicated in the process of cell proliferation and differentiation, and activation of certain transcription factors, in particular NF kappa B, is associated with the immediate response of the cell to an injury, we propose that 12(R)HETrE's mitogenic and angiogenic activities are mediated, in part, via the activation of NF kappa B and expression of these protooncogenes. PMID: 7523372 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 13: Bioessays. 1994 Jul;16(7):489-96. Regulation of the Ras signalling network. Maruta H, Burgess AW. Ludwig Institute for Cancer Research, Melbourne, Australia. The mitogenic action of cytokines such as epidermal growth factor (EGF) or platelet derived growth factor (PDGF) involves the stimulation of a signal cascade controlled by a small G protein called Ras. Mutations of Ras can cause its constitutive activation and, as a consequence, bypass the regulation of cell growth by cytokines. Both growth factor-induced and oncogenic activation of Ras involve the conversion of Ras from the GDP-bound (D-Ras) to the GTP-bound (T-Ras) forms. T-Ras activates a network of protein kinases including c-Mos, c-Raf-1 and MAP kinase. Eventually the activation of MAP kinase leads to the activation of the elongation factor 4E and several transcription factors such as c-Jun, c-Myc and c-Fos. There are several modulators of Ras activity, such as the GTPase activating proteins (GAP1 and NF1), which stimulate the conversion of T-Ras to D-Ras. A series of small NF1 fragments, which bind T-Ras, as well as truncated forms of derivatives of c-Raf-1, c-Jun and c-Myc, are capable of blocking the T-Ras-activated mitogenesis in a competitive manner. These agents offer a unique opportunity to control the proliferation of T-Ras-associated tumors, which represent more than 30% of total human carcinomas. Publication Types: Review Review, Tutorial PMID: 7945277 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 14: Cancer Res. 1993 Sep 1;53(17):4053-8. Mutation of the p53 gene in neuroblastoma and its relationship with N-myc amplification. Imamura J, Bartram CR, Berthold F, Harms D, Nakamura H, Koeffler HP. University of California, School of Medicine, Los Angeles 90024. Mutation of the p53 tumor suppressor gene frequently occurs in a variety of tumors including lung, breast, gastrointestinal, and brain, as well as lymphomas-leukemias. Neuroblastoma, one of the most common solid tumors in childhood, often has amplification of the N-myc gene. We examined for mutations of the p53 tumor suppressor gene by single-strand conformational polymorphism using polymerase chain reaction products and direct sequencing method in neuroblastoma; in addition, we assessed the relationship between p53 mutation and N-myc gene amplification in the disease. Of 86 DNA samples from patients with neuroblastoma, two mutations (2%) were found in the coding region of the p53 gene. Each mutation caused a substitution of amino acid residues. One mutation was located in exon 5, and another was in exon 6. N-myc gene was amplified in 26% of the samples. No p53 mutations were found in neuroblastoma samples with N-myc amplification. In the two individuals, p53 mutations appeared as their disease became more progressive. The neurofibromatosis 1 (NF1) gene is frequently abnormal in another neural disorder, neurofibromatosis type 1; in addition, a potential mutational hot spot of NF1 at lysine at codon 1423 has been identified in several types of tumors. Using single-strand conformational polymorphism, we were unable to detect an abnormality in this region of NF1 in 50 samples of neuroblastoma. The data suggest that p53 mutations occasionally are associated with progression of neuroblastomas, and tumorigenetic influences of mutant p53 may differ from those of N-myc. PMID: 8358734 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 15: Oncogene. 1993 Jun;8(6):1567-74. The hepatitis B virus (HBV) pX transactivates the c-fos promoter through multiple cis-acting elements. Avantaggiati ML, Natoli G, Balsano C, Chirillo P, Artini M, De Marzio E, Collepardo D, Levrero M. I Clinica Medica, Policlinico Umberto I, Rome, Italy. The hepatitis B virus (HBV) X protein (pX) stimulates transcription regulated by cis-acting elements that control many viral and cellular genes, including the c-myc and the c-fos proto-oncogenes. Using several c-fos promoter deletion mutants, we found the serum-responsive element (SRE) located at -315, the modified TPA-responsive element located at -296 (fos-AP-1 binding site, FAP) and the region spanning from nucleotide -220 to -120, which contains an NF1-like site and several stretches of sequence homologous to the AP-2 consensus binding sites, to be responsive to pX. pX does not modify the pattern of the retarded complexes bound to the SRE/FAP region which, in our system, appears to be occupied by SRE-binding factors. The activation of the SRE does not involve complex formation between SRE-binding factors and pX, it is not associated with an increase in serum response factor binding to the SRE and it does not determine changes in SRE mobility-shift pattern. PMID: 8502480 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 16: Curr Opin Oncol. 1993 May;5(3):474-80. Epidemiology, cytogenetics, and molecular biology of brain tumors. Kyritsis AP, Saya H. Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston 77030. The incidence of primary brain tumors has increased dramatically among elderly North Americans during the past two decades. Numerous chromosomal abnormalities have been associated with these tumors; various subsets of these abnormalities are specific to certain types of brain tumors. Astrocytic gliomas may exhibit losses of genetic information from chromosomes 9p, 10q, 11p, 13q, 17p, or 22. Mutations of the p53 gene are found mostly in the malignant astrocytic forms and have been linked to malignant tumor transformation and progression. Functional and structural abnormalities of the neurofibromatosis 1 (NF1) gene and overexpression of the epidermal growth factor receptor have been associated with expression of the malignant glioma phenotype. Other less clearly defined abnormalities in astrocytomas include mutations of the retinoblastoma (RB) gene and overexpression of platelet-derived growth factor; transforming growth factor-alpha and -beta; the c-erb B-1, c-myc, ras, c-fos, and ros oncogenes; and insulin-like growth factor I and II. In other glioma tumors, p53 mutations are either infrequent, as in oligodendrogliomas, or absent, as in ependymomas. Occasionally, medulloblastomas exhibit p53 mutations and loss of genetic information from chromosomes 6q and 16q or expression of the c-erb B-2 oncogene. Loss of heterozygosity in chromosome 22 is the most frequent event in meningiomas, suggesting the presence of a tumor-suppressor gene in this chromosome. Publication Types: Review Review, Tutorial PMID: 8494908 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 17: Oncogene. 1991 Nov;6(11):2067-75. Regulatory domains within the P0 promoter of human c-myc. Lang JC, Wilkie NM, Clark AM, Chudleigh A, Talbot S, Whitelaw B, Frame MC. Beatson Institute for Cancer Research, Glasgow, UK. Expression of P0 RNA in some Burkitt lymphoma cell lines varies independently of levels of RNA derived from P1 and P2. These data suggest the possibility that expression of P0 RNA may be capable of independent regulation. In order to investigate this possibility we have isolated putative regulatory domains flanking P0 RNA starts within the human c-myc gene and analysed both their ability to direct expression of control reporter genes and their ability to interact with specific transcription factors. Regulatory regions necessary for expression of P0 RNA have been located within 131 bp 5' of the first major P0 RNA start. DNAase 1 footprint analysis and gel retardation assays demonstrate binding of transcription factors Sp1, NF1 and CBP to this region. NF1 binds specifically to two consensus sequences. The more distal site overlaps with the binding site for CBP, and it is likely that concomitant binding of NF1 and CBP within the distal region of the P0 promoter is not possible. Previous work from our laboratory has described a negative regulatory domain within the 5' flanking region of c-myc. The P0 promoter resides within this domain and therefore may contain a negative regulator of c-myc gene expression. PMID: 1945411 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------