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NCI CANCERLIT^® Search: Neurofibromatosis 1 and 2 - April 2002

Imprima English

National Cancer Institute^®
Ultima Vez Modificado: 1 de abril del 2002

NF1 tumor suppressor mRNA is targeted to the cell-cell contact zone in Ca(2+)-induced keratinocyte differentiation.

Aberrant splicing in several human tumors in the tumor suppressor genes neurofibromatosis type 1, neurofibromatosis type 2, and tuberous

Genetic aspects of pheochromocytoma.

p21-activated kinase links Rac/Cdc42 signaling to merlin.

Presymptomatic diagnosis for children of sporadic neurofibromatosis 2 patients: a method based on tumor analysis.

Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain.

Familial neurogenic tumor syndromes.

Table of Contents

1
UI - 11896214
AU - Yla-Outinen H; Koivunen J; Nissinen M; Bjorkstrand AS; Paloniemi M;
TI - Korkiamaki T; Peltonen S; Karvonen SL; Peltonen J NF1 tumor suppressor mRNA is targeted to the cell-cell contact zone in Ca(2+)-induced keratinocyte differentiation.
SO - Lab Invest 2002 Mar;82(3):353-61
AD - Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland.
SUMMARY: We have previously shown that NF1 (type 1 neurofibromatosis) p21ras GTPase-activating tumor suppressor protein undergoes major relocalization during the formation of cell-cell junctions in differentiating keratinocytes in vitro. This prompted us to study the distribution of NF1 mRNA under the same conditions by in situ hybridization. In differentiating keratinocytes, the NF1 mRNA signal intensified within the cell cytoplasm within the first 0.5 to 2 hours after induction of cellular differentiation. First, the hybridization signal was evenly distributed throughout the cytoplasm. Subsequently, NF1 mRNA was gradually polarized to the cellular periphery at the side of cell-cell junctions and finally disappeared. Reappearance of NF1 mRNA was found in migrating keratinocytes forming a bilayered culture. Disruption of microfibrillar cytoskeleton, but not microtubules, caused a marked change in the subcellular distribution of NF1 mRNA. This data may suggest that intact actin microfilaments are essential for transport of NF1 mRNA to the cell periphery. This is the first study demonstrating that NF1, or any tumor suppressor mRNA, belongs to a rare group of mRNAs not targeted to free polysomes or ribosomes of the rough endoplasmic reticulum. This finding recognizes a potential way for post-transcriptional modification of NF1 expression.

2
UI - 11888927
AU - Kaufmann D; Leistner W; Kruse P; Kenner O; Hoffmeyer S; Hein C; Vogel W;
TI - Messiaen L; Bartelt B Aberrant splicing in several human tumors in the tumor suppressor genes neurofibromatosis type 1, neurofibromatosis type 2, and tuberous sclerosis 2.
SO - Cancer Res 2002 Mar 1;62(5):1503-9
AD - Universitatsklinikum Ulm, Abteilung Humangenetik, D-89070 Ulm, Germany. dieter.kaufmann@medizin.uni-ulm.de
Mutations at splice sites or surrounding sequences have been reported to cause aberrant splicing. However, splicing errors can also occur without sequence alterations. We investigated three tumor suppressor genes for aberrant splicing in tumors. At a low frequency per exon it was found in five of seven of the investigated in-frame exons of the neurofibromatosis type 1 (NF1) gene, in two of three exons of the neurofibromatosis type 2 (NF2) gene, and in one of three exons of the tuberous sclerosis 2 gene. It was detectable in all of the human tumor tissues tested (NF1 neurofibroma, sporadic intramedullar neurinoma, sporadic meningiomas, NF2 schwannoma, NF2 meningioma, basalioma, and naevus) as well as in cultured tumor cell lines and cultured primary cells. Hence, our data show that aberrant splicing is a very common process. According to simulations of the secondary structures of the pre-mRNA, we suggest that aberrant splicing is attributable to the rare occurrence of alternative structures at the splice donor site, which are not recognized by the splice machinery. In HeLa cells, aberrant splicing is found to be increased at elevated temperatures and low pH in vitro, conditions often found in tumor tissues. In three tumor tissues tested for one NF1 exon, we found approximately twice the amount of aberrant transcript as in normal tissues. Therefore, we suggest that the increase in aberrant splicing caused by environmental factors represents an additional mechanism for the reduction of the amount of tumor suppressor mRNA in the absence of relevant mutations in the tumor.

3
UI - 11308996
AU - Koch CA; Vortmeyer AO; Huang SC; Alesci S; Zhuang Z; Pacak K
TI - Genetic aspects of pheochromocytoma.
SO - Endocr Regul 2001 Mar;35(1):43-52
AD - National Institutes of Health, SNB, Bethesda, Maryland 20892, U.S.A. Kochc@exchange.nih.gov
We here review the literature on genetics related to pheochromocytoma. About 10 percent of these neuroendocrine tumors are hereditary and are most often associated with multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease, and neurofibromatosis type 1 (NF 1). Hereditary tumor syndromes such as the aforementioned ones, are ideal to study the molecular pathogenesis of tumorigenesis as opposed to sporadic tumors in which genetic alterations often merely represent epigenetic tumor progression phenomena. Recent advances in molecular genetics, especially of RET, VHL, NF1, and SDHD, helped better understand the pathogenesis of pheochromocytoma. In this paper, we not only summarize key points of genetic discoveries related to pheochromocytoma, but also report in table format all known RET germline mutations related to pheochromocytoma.

4
UI - 11719502
AU - Xiao GH; Beeser A; Chernoff J; Testa JR
TI - p21-activated kinase links Rac/Cdc42 signaling to merlin.
SO - J Biol Chem 2002 Jan 11;277(2):883-6
AD - Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
The neurofibromatosis type 2 tumor suppressor gene, NF2, is mutated in the germ line of NF2 patients and predisposes affected individuals to intracranial and spinal tumors. Moreover, somatic mutations of NF2 can occur in the sporadic counterparts of these neurological tumor types as well as in certain neoplasms of non-neuroectodermal origin, such as malignant mesothelioma and melanoma. NF2 encodes a 595-amino acid protein, merlin, which exhibits significant homology to the ezrin-radixin-moesin family of proteins. However, the mechanism by which merlin exerts its tumor suppressor activity is not well understood. In this investigation, we show that merlin is phosphorylated in response to expression of activated Rac and activated Cdc42 in mammalian cells. Furthermore, we demonstrate that merlin phosphorylation is mediated by p21-activated kinase (Pak), a common downstream target of both Rac and Cdc42. Both in vivo and in vitro kinase assays demonstrated that Pak can directly phosphorylate merlin at serine 518, a site that affects merlin activity and localization. These biochemical investigations provide insights into the regulation of merlin function and establish a framework for elucidating tumorigenic mechanisms involved in neoplasms associated with merlin inactivation.

5
UI - 11839955
AU - Kluwe L; Friedrich RE; Tatagiba M; Mautner VF
TI - Presymptomatic diagnosis for children of sporadic neurofibromatosis 2 patients: a method based on tumor analysis.
SO - Genet Med 2002 Jan-Feb;4(1):27-30
AD - Laboratory of Brain Tumor Biology, Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany.
PURPOSE: To provide presymptomatic diagnosis for children of sporadic neurofibromatosis 2 patients in whom no NF2-mutations were found by screening their blood-DNA. METHODS: Tumors of four patients were analyzed for NF2 allele losses and mutations. RESULTS: Nonsense NF2 mutations and NF2 allele losses were found in all tumors. None of these alterations was found in any of eight children examined, suggesting that these children did not inherit the disease. CONCLUSIONS: Finding two genetic alterations of a tumor suppressor gene in associated tumors is useful for presymptomatic diagnosis. Identification of the lost allele in tumors alone also enables exclusion of disease transmission in 50% of cases.

6
UI - 11756419
AU - Shimizu T; Seto A; Maita N; Hamada K; Tsukita S; Tsukita S; Hakoshima T
TI - Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain.
SO - J Biol Chem 2002 Mar 22;277(12):10332-6
AD - Structural Biology Laboratory, Nara Institute of Science and Technology and CREST, Japan.
Neurofibromatosis type 2 (NF2) is a dominantly inherited disease associated with the central nervous system. The NF2 gene product merlin is a tumor suppressor, and its mutation or inactivation causes this disease. We report here the crystal structure of the merlin FERM domain containing a 22-residue alpha-helical segment. The structure reveals that the merlin FERM domain consists of three subdomains displaying notable features of the electrostatic surface potentials, although the overall surface potentials similar to those of ezrin/radixin/moesin (ERM) proteins indicate electrostatic membrane association. The structure also is consistent with inactivation mechanisms caused by the pathogenic mutations associated with NF2.

7
UI - 11770299
AU - Kimmelman A; Liang BC
TI - Familial neurogenic tumor syndromes.
SO - Hematol Oncol Clin North Am 2001 Dec;15(6):1073-84
AD - Mount Sinai-NYU Medical Center and Health Systems, Derald H. Ruttenberg Cancer Center, New York, New York, USA.
Cancer caused more than 0.5 million deaths in the United States in 2000. This estimate includes patients who have a genetic predisposition to neoplastic disease, including brain neoplasms. Familial tumor syndromes are important to identify clinically because family members require high degrees of monitoring and genetic counseling. Study of these individuals and families has led to the discovery of genes that are an intrinsic aspect of cell regulation and will continue to be relevant in defining mechanisms of neoplastic development in brain and other tissues.

The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.

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