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Biomedical subjects

Tyler Jacks

Publications and source records attributed to Tyler Jacks.

62 records · Page 4Linked to original sources
PubMed2002

Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.

Animals↗
PubMed2002

Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization.

The Nf2 tumor suppressor gene product merlin is related to the membrane-cytoskeleton linker proteins of the band 4.1 superfamily, including ezrin, radixin, and moesin (ERMs). Merlin is regulated by phosphorylation in a Rac/cdc42-dependent fashion. We report that the phosphorylation of merlin at serine 518 is induced by the p21-activated kinase PAK2. This is demonstrated by biochemical fractionation, use of active and dominant-negative mutants of PAK2, and immunodepletion. By using wild-type and mutated forms of merlin and phospho-directed antibodies, we show that phosphorylation of merlin at serine 518 leads to dramatic protein relocalization.

3T3 Cells↗
PubMed2002

Defective proliferative responses in B lymphocytes and thymocytes that lack neurofibromin.

Nf1(-/-) fetal liver cells were used to reconstitute B and T cells in Rag-1(-/-) mice. Lymphocyte development was largely unimpaired in the absence of neurofibromin. However antigen-receptor induced proliferation was defective in neurofibromin deficient peripheral B cells and CD4(+) single positive thymocytes. In contrast to its role as a negative regulator of proliferation in many other cell types, neurofibromin may be a positive regulator of lymphocyte proliferation. Peripheral B cells exhibited circumscribed defects in anti-IgM induced protein tyrosine phosphorylation, which may contribute to the unexpected proliferative defect seen in these cells.

Animals↗
PubMed2002

Technologically advanced cancer modeling in mice.

Multiple approaches now exist for the generation of genetically engineered murine cancer models. These new models utilize latent, conditional and inducible alleles to better mimic the in vivo setting in which sporadic human cancers occur. The murine tumor models are beginning to reveal mysteries of tumorigenesis, such as the role of the tumor microenvironment and the dependence of tumors on continuous oncogenic stimulation.

Animals↗
PubMed2002

Tumor suppression by a severely truncated species of retinoblastoma protein.

Rb(+/+):Rb(-/-) chimeric mice are healthy until early in adulthood when they develop lethal pituitary tumors composed solely of Rb(-/-) cells. In an effort to delineate the minimal structures of the retinoblastoma protein necessary for RB tumor suppression function, chimeric animals derived from stably transfected RB(-/-) embryonic stem (ES) cells were generated. One such ES cell transfectant expressed a human RB allele encoding a stable, truncated nuclear derivative lacking residues 1 to 378 (Delta 1-378). Others encoded either wild-type human RB or an internally deleted derivative of the Delta 1-378 mutant. All gave rise to viable chimeric animals with comparable degrees of chimerism. However, unlike control mice derived, in part, from naive Rb(-/-) ES cells or from ES cells transformed by the double RB mutant, Delta 1-378/Delta exon22, animals derived from either wild-type RB- or Delta 1-378 RB-producing ES cells failed to develop pituitary tumors. Thus, in this setting, a substantial fraction of the RB sequence is unnecessary for RB-mediated tumor suppression.

Animals↗
PubMed2002

Inhibition of oncogenic K-ras signaling by aerosolized gene delivery in a mouse model of human lung cancer.

PURPOSE: Transfer of growth-suppressive genes to lung tumors has therapeutic potential, but effective delivery techniques have not been developed. Here, we investigated gene delivery to lung tumors by aerosolization of adenoviral vectors incorporated into calcium phosphate precipitates. EXPERIMENTAL DESIGN: To investigate the efficacy of this delivery method in normal and neoplastic lung, an adenoviral vector expressing beta-galactosidase was administered by jet nebulization to K-ras(LA1) mice, which develop lung adenocarcinomas through activation of a latent allele carrying mutant K-ras(G12D). Furthermore, we investigated whether aerosolized delivery of Ad-MKK4 (KR), an adenoviral vector expressing dominant-negative mutant mitogen-activated protein kinase kinase 4(MKK4), can block Ras-dependent signaling in K-ras(LA1) mice. RESULTS: After a single administration, beta-galactosidase was detected in lung tissue for up to 21 days, and expression was much greater in tumors than in normal lung tissue. MKK4 was activated in the lungs of K-ras(LA1) mice, and aerosolized treatment with Ad-MKK4 (KR) decreased c-Jun-NH(2)-terminal kinase but not extracellular signal- regulated kinase activity, providing evidence that MKK4 was selectively inhibited. CONCLUSIONS: These findings demonstrate a novel approach to targeting oncogenic pathways in lung tumors by aerosolized gene delivery.

Adenocarcinoma↗
PubMed1995

Characterization of Pheochromocytomas in a Mouse Strain with a Targeted Disruptive Mutation of the Neurofibromatosis Gene Nf1.

Patients with neurofibromatosis type 1 (NF1) show an increased frequency of pheochromocytomas. The NF1 gene encodes a GTPase-activating protein that controls the activity of ras proteins in intracellular signaling. A mouse strain with a knockout mutation of Nf1, the murine counterpart of NF1, has recently been constructed. This mutation, designated Nf1(n31), has been shown to be associated with the frequent development of pheochromocytomas in heterozygous animals. Pheochromocytomas are extremely rare in wild-type mice. We have characterized the tumors to assess their relevance as a model for human pheochromocytomas. The frequency of pheochromocytomas was determined in inbred compared to outbred mice carrying the Nf1(31) mutation. Paraffin sections of pheochromocytomas from seven mice were stained immunohistochemically for the catecholamine biosynthetic enzymes, tyrosine hydroxylase (TH), and phenylethanolamine-N-methyltransferase (PNMT) to infer their profiles of catecholamine synthesis, and for chromogranin A (CGA) to infer their content of secretory granules. Cultured cells from a representative tumor were studied in vitro to assess proliferation and neuronal differentiation. Pheochromocytomas arose in approx 15% of Nf1(n31) mice with a mixed genetic background, but were absent in inbred mice. Approximately one-fourth of the tumors were bilateral. The tumors exhibited variable morphology. All included cells that appeared well differentiated and resembled normal chromaffin cells in that they expressed TH, PNMT, and CGA. Focal neuronal differentiation was also observed. In cell culture, the tumor cells ceased to proliferate and the majority underwent terminal differentiation into TH-positive cells with neuronal morphology. The phenotype of pheochromocytomas in mice with the Nf1(31) mutation resembles that of human pheochromocytomas, particularly with respect to their ability to produce epinephrine, as inferred from positive staining for PNMT. The tumors also resemble both normal and neoplastic human adrenal medulla with respect to their extensive differentiation into neuron-like cells in vitro. This change in phenotype may be related to ras activation. These neoplasms may be valuable both as models for the pathobiology of adrenal medullary neoplasia, and as a source of epinephrine-producing pheochromocytoma cell lines, for which adequate models currently do not exist.

Journal Article↗