Overgrowth syndromes: is dysfunctional PI3-kinase signalling a unifying mechanism?
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Studies in drosophila and animal models have shown that the phosphoinositide-3-kinase (PI3-kinase) axis plays a central role in normal development, defining the number and size of cells in tissues. Dysfunction of this pathway leads to growth anomalies and has been established to play a key role in the pathogenesis of Cowden syndrome and tuberous sclerosis. It is probable that dysfunction of this pathway is the basis of other disorders especially those typified by asymmetric overgrowth. (+info)
Tuberous sclerosis-associated neoplasms express activated p42/44 mitogen-activated protein (MAP) kinase, and inhibition of MAP kinase signaling results in decreased in vivo tumor growth.
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PURPOSE: Tuberous sclerosis (TS) is a common autosomal disorder attributable to inactivation of the tumor suppressor genes tuberin and hamartin. To determine whether mitogen-activated protein (MAP) kinase signaling plays a role in the pathogenesis of TS, we stained human TS-associated neoplasms with antibodies directed against activated MAP kinase, and observed high-level expression. EXPERIMENTAL DESIGN: To determine whether MAP kinase is functionally important for the development of neoplasia in TS, we established a murine model of TS-associated neoplasia (Tsc2Ang1 cells) from a tumor arising in a mouse heterozygous for tuberin. Tsc2Ang1 cells demonstrate tumorigenesis in vivo and high-level expression of activated MAP kinase in vitro. The functionality of MAP kinase signaling was assessed by inactivating MAP kinase using a dominant-negative MAP kinase kinase in tsc2ang1 cells and assessing the effect of this intervention on in vivo tumorigenicity and production of the potent angiogenic factor vascular endothelial growth factor (VEGF). RESULTS: Human TS-related neoplasms demonstrate high-level expression of activated MAP kinase, as does a tumor arising in a mouse heterozygous for tuberin. The inhibition of MAP kinase signaling by the introduction of a dominant-negative MAP kinase kinase leads to the inhibition of tumor growth in vivo and decreased production of VEGF. CONCLUSIONS: MAP kinase is activated in TS-related neoplasia in mice and humans. Inhibition of MAP kinase leads to decreased tumor growth in vivo. Pharmacological inhibition of MAP kinase may be a therapeutic target in the prevention and treatment of TS-related tumors. (+info)
Quantitative RT-PCR reveals tuberous sclerosis gene, TSC2, mRNA degradation following cryopreservation in the human preimplantation embryo.
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The use of cryopreserved human embryos in gene expression studies provides an additional source to the scarce embryos available for research. To validate their use we have implemented a quantitative RT-PCR to characterize the levels of the tuberous sclerosis, TSC2 gene in fresh and frozen-thawed human embryos. Frozen embryos were thawed using two different clinical protocols. In fresh embryos 9.95 fg of TSC2 cDNA was present in the unfertilized oocyte, which was comparable to the level on day 2 of preimplantation development. On day 3 there was a significant drop (P<0.001) to 6.8 fg, followed by an increase in cDNA levels to 10.8 fg (P<0.01) on day 6 at the expanded blastocyst stage. Day 2 frozen embryos possessed 50% less (P<0.001) TSC2 mRNA in comparison to the fresh embryos using thawing protocol one (from frozen to 37 degrees C) and 25% less TSC2 mRNA (P<0.01) with thawing protocol 2 (from frozen to room temperature). After culturing day 2 frozen embryos for an additional day they showed mRNA levels comparable with fresh day 3 embryos. There was no significant difference in the levels of TSC2 mRNA between fresh and frozen day 3 human embryos with either thawing protocol. This study demonstrates that cryopreservation does affect the normal pattern of gene expression during human preimplantation development, and that intact frozen-thawed embryos are not equivalent to their non-frozen counterparts. Furthermore human embryos frozen on day 2 appear to be more susceptible to temperature change than embryos frozen on day 3. (+info)
The cystic growth of a subependymal giant-cell astrocytoma with tuberous sclerosis.
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A case of a 7 year-old boy with subependymal giant-cell astrocytoma is reported. CT scanning of this patient for 6 years showed the cystic growth of the astrocytoma. The surgical indication and importance of periodic CT studies for subependymal giant-cell astrocytomas associated with tuberous sclerosis are discussed. (+info)
Evidence for genetic heterogeneity in tuberous sclerosis: one locus on chromosome 9 and at least one locus elsewhere.
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Linkage of tuberous sclerosis complex (TSC), an autosomal dominant disorder, to markers on chromosome 9 was reported first in 1987. This assignment was confirmed by an international collaborative study that suggested more than one locus may be responsible for the phenotype. We studied 14 multigenerational TSC families (13 previously unreported) with markers for nine loci in the linked region of chromosome 9q32-q34. Our results confirm the previous reports that the genetic locus in one-third to one-half of families maps to chromosome 9. Comparison of clinical findings in the chromosome 9-linked families with those in the chromosome 9-unlinked families reveals only a higher incidence of ungual fibromata in the chromosome 9-linked families. (+info)
Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B.
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Tuberous sclerosis complex is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, and benign tumors of the brain, skin, heart, and kidneys. Hamartin and tuberin, the products of the TSC1 and TSC2 genes, respectively, form a complex and inhibit signaling by the mammalian target of rapamycin. Here, we demonstrate that endogenous hamartin is threonine-phosphorylated during nocodazole-induced G2/M arrest and during the G2/M phase of a normal cell cycle. In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (Thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70S6 kinase by the hamartin-tuberin complex. These findings support a model in which phosphorylation of hamartin regulates the function of the hamartin-tuberin complex during the G2/M phase of the cell cycle. (+info)
Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis.
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Tuberous sclerosis is an autosomal dominant human genetic disorder in which distinctive tumors called hamartomas develop. Germline mutations in either TSC1 or TSC2 cause this syndrome, and hamartomas typically display second hit events with loss of the remaining normal allele. Studies initiated in Drosophila have identified a role for the Tsc1 and Tsc2 genes in the regulation of cell and organ size, and genetic interaction studies have placed them in the PI3K-Akt-mTOR-S6K pathway. Biochemical studies have shown that activated Akt phosphorylates TSC2 in the TSC1/TSC2 protein complex, inactivating it; while TSC1/TSC2 has GAP activity for the Rheb GTPase (a member of the ras family), and activated Rheb-GTP activates mTOR. Thus, in cells lacking TSC1 or TSC2 there are increased levels of Rheb-GTP which leads to activation of mTOR, leading to cell size increase and growth. These developments provide enhanced understanding of this signaling pathway and fundamental insights into the pathogenesis of tuberous sclerosis, and open the possibility of treatment for hamartomas by several pharmacologic approaches. (+info)
Indocyanine green angiography of retinal astrocytomas associated with tuberous sclerosis.
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As small astrocytic hamartomas can sometimes be missed during routine ophthalmoscopy in patients with tuberous sclerosis, fluorescein and/-or indocyanine green angiography maybe more helpful in identifying such small astrocytomas. In fluorescein angiography, astrocytomas show gradually increasing hyperfluorescence due to the vascular permeability of astrocytomas. In indocyanine green angiography, astrocytomas appear hypocyanescent, most prominently during the late phases. We report the indocyanine green angiographic findings of retinal astrocytomas in a patient with tuberous sclerosis. (+info)