UI - 11896214
AU - Yla-Outinen H; Koivunen J; Nissinen M; Bjorkstrand AS; Paloniemi M;
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,
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.
UI - 11888927
AU - Kaufmann D; Leistner W; Kruse P; Kenner O; Hoffmeyer S; Hein C; Vogel W;
Messiaen L; Bartelt B
Aberrant splicing in several human tumors in the tumor suppressor genes
neurofibromatosis type 1, neurofibromatosis type 2, and tuberous
SO - Cancer Res 2002 Mar 1;62(5):1503-9
AD - Universitatsklinikum Ulm, Abteilung Humangenetik, D-89070 Ulm, Germany.
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.
UI - 11308996
AU - Koch CA; Vortmeyer AO; Huang SC; Alesci S; Zhuang Z; Pacak K
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.
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
UI - 11719502
AU - Xiao GH; Beeser A; Chernoff J; Testa JR
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.
UI - 11839955
AU - Kluwe L; Friedrich RE; Tatagiba M; Mautner VF
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
UI - 11756419
AU - Shimizu T; Seto A; Maita N; Hamada K; Tsukita S; Tsukita S; Hakoshima T
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.
UI - 11770299
AU - Kimmelman A; Liang BC
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.
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