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Tan D Nguyen,
Jason M Gow,
Leslie W Chinn,
Libusha Kelly,
Hotcherl Jeong,
Conrad C Huang,
Doug Stryke,
Michiko Kawamoto,
Susan J Johns, Elaine Carlson,
Travis Taylor,
Thomas E Ferrin,
Andrej Sali,
Kathleen M Giacomini,
Deanna L Kroetz
Pharmacological Reviews 04/2006; 58(1):1-2. · 20.23 Impact Factor
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Yan Shu,
Maya K Leabman,
Bo Feng,
Lara M Mangravite,
Conrad C Huang,
Doug Stryke,
Michiko Kawamoto,
Susan J Johns,
Joseph DeYoung, Elaine Carlson,
Thomas E Ferrin,
Ira Herskowitz,
Kathleen M Giacomini
Pharmacological Reviews 07/2004; 56(2):161. · 20.23 Impact Factor
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Mignon L Loh,
Shashaank Vattikuti,
Suzanne Schubbert,
Melissa G Reynolds, Elaine Carlson,
Kenneth H Lieuw,
Jennifer W Cheng,
Connie M Lee,
David Stokoe,
Jeannette M Bonifas,
Nicole P Curtiss,
Jason Gotlib,
Soheil Meshinchi,
Michelle M Le Beau,
Peter D Emanuel,
Kevin M Shannon
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ABSTRACT: The PTPN11 gene encodes SHP-2 (Src homology 2 domain-containing protein tyrosine Phosphatase), a nonreceptor tyrosine protein tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21Ras (Ras) and other signaling molecules. Mutations in PTPN11 cause Noonan syndrome (NS), a developmental disorder characterized by cardiac and skeletal defects. NS is also associated with a spectrum of hematologic disorders, including juvenile myelomonocytic leukemia (JMML). To test the hypothesis that PTPN11 mutations might contribute to myeloid leukemogenesis, we screened the entire coding region for mutations in 51 JMML specimens and in selected exons from 60 patients with other myeloid malignancies. Missense mutations in PTPN11 were detected in 16 of 49 JMML specimens from patients without NS, but they were less common in other myeloid malignancies. RAS, NF1, and PTPN11 mutations are largely mutually exclusive in JMML, which suggests that mutant SHP-2 proteins deregulate myeloid growth through Ras. However, although Ba/F3 cells engineered to express leukemia-associated SHP-2 proteins cells showed enhanced growth factor-independent survival, biochemical analysis failed to demonstrate hyperactivation of the Ras effectors extracellular-regulated kinase (ERK) or Akt. We conclude that SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies. Further investigation is required to clarify how these mutant proteins interact with Ras and other effectors to deregulate myeloid growth.
Blood 04/2004; 103(6):2325-31. · 9.90 Impact Factor
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Yan Shu,
Maya K Leabman,
Bo Feng,
Lara M Mangravite,
Conrad C Huang,
Doug Stryke,
Michiko Kawamoto,
Susan J Johns,
Joseph DeYoung, Elaine Carlson,
Thomas E Ferrin,
Ira Herskowitz,
Kathleen M Giacomini
[show abstract]
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ABSTRACT: The organic cation transporter, OCT1, is a major hepatic transporter that mediates the uptake of many organic cations from the blood into the liver where the compounds may be metabolized or secreted into the bile. Because OCT1 interacts with a variety of structurally diverse organic cations, including clinically used drugs as well as toxic substances (e.g., N-methylpyridinium, MPP(+)), it is an important determinant of systemic exposure to many xenobiotics. To understand the genetic basis of extensive interindividual differences in xenobiotic disposition, we functionally characterized 15 protein-altering variants of the human liver organic cation transporter, OCT1, in Xenopus oocytes. All variants that reduced or eliminated function (OCT1-R61C, OCT1-P341L, OCT1-G220V, OCT1-G401S, and OCT1-G465R) altered evolutionarily conserved amino acid residues. In general, variants with decreased function had amino acid substitutions that resulted in more radical chemical changes (higher Grantham values) and were less evolutionarily favorable (lower blosum62 values) than variants that maintained function. A variant with increased function (OCT1-S14F) changed an amino acid residue such that the human protein matched the consensus of the OCT1 mammalian orthologs. Our results indicate that changes at evolutionarily conserved positions of OCT1 are strong predictors of decreased function and suggest that a combination of evolutionary conservation and chemical change might be a stronger predictor of function.
Proceedings of the National Academy of Sciences 06/2003; 100(10):5902-7. · 9.68 Impact Factor
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Samuel Hawgood,
Matthias Ochs,
Anja Jung,
Jennifer Akiyama,
Lennell Allen,
Cindy Brown,
Jess Edmondson,
Stacey Levitt, Elaine Carlson,
Anne Marie Gillespie,
Angela Villar,
Charles J Epstein,
Francis R Poulain
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ABSTRACT: Surfactant proteins-A and -D (SP-A and SP-D) are members of the collectin protein family. Mice singly deficient in SP-A and SP-D have distinct phenotypes. Both have altered inflammatory responses to microbial challenges. To further investigate the functions of SP-A and SP-D in vivo, we developed mice deficient in both proteins by sequentially targeting the closely linked genes in embryonic stem cells using graded resistance to G-418. There is a progressive increase in bronchoalveolar lavage phospholipid, protein, and macrophage content through 24 wk of age. The macrophages from doubly deficient mice express high levels of the matrix metalloproteinase MMP-12 and develop intense but patchy lung inflammation. Stereological analysis demonstrates significant air space enlargement and reduction in alveolar septal tissue per unit volume, consistent with emphysema. These changes qualitatively resemble the lung pathology seen in SP-D-deficient mice. These doubly deficient mice will be useful in dissecting the potential overlap in function between SP-A and SP-D in host defense.
AJP Lung Cellular and Molecular Physiology 12/2002; 283(5):L1002-10. · 3.66 Impact Factor
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[show abstract]
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ABSTRACT: Induction or overexpression of pulmonary manganese superoxide dismutase (MnSOD) has been shown to protect against oxygen (O2) toxicity. Genetic inactivation of MnSOD (Sod2) results in multiple organ failure and early neonatal death. However, lungs or O2-tolerance of Sod2 knockout mice have not been investigated. We evaluated survival, lung histopathology, and other pulmonary antioxidants (glutathione cycle) of homozygous (-/-) and heterozygous (+/-) Sod2 mutant mice compared with wild-type controls (Sod2+/+) following 48 h exposure to either room air or to O2. The ability of antioxidant N-acetylcysteine to compensate for the loss of MnSOD was explored. Mortality of Sod2-/- mice increased from 0% in room air to 18 and 83% in 50 and 80% O2, respectively. N-acetylcysteine did not alter mortality of Sod2-/- mice. Histopathological analysis revealed abnormalities in saccules of Sod2-/- mice exposed either to room air or to 50% O2 suggestive of delayed postnatal lung development. In 50% O2, activities of glutamate-cysteine ligase (GCL) (previously known as gamma-glutamylcysteine synthetase, gamma-GCS) and glutathione peroxidase increased in Sod2-/- (35 and 70%, respectively) and Sod2+/- (12 and 70%, respectively) mice, but glutathione levels remained unaltered. We conclude that MnSOD is required for normal O2 tolerance and that in the absence of MnSOD there is a compensatory increase in pulmonary glutathione-dependent antioxidant defense in hyperoxia.
Free Radical Biology and Medicine 02/2002; 32(2):175-86. · 5.42 Impact Factor
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Carlos Botas,
Francis Poulain,
Jennifer Akiyama,
Cindy Brown,
Lennell Allen,
Jon Goerke,
John Clements, Elaine Carlson,
Anne Marie Gillespie,
Charles Epstein,
Samuel Hawgood
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ABSTRACT: Surfactant protein D (SP-D) is one of two collectins found in the pulmonary alveolus. On the basis of homology with other
collectins, potential functions for SP-D include roles in innate immunity and surfactant metabolism. The SP-D gene was disrupted
in embryonic stem cells by homologous recombination to generate mice deficient in SP-D. Mice heterozygous for the mutant SP-D
allele had SP-D concentrations that were approximately 50% wild type but no other obvious phenotypic abnormality. Mice totally
deficient in SP-D were healthy to 7 months but had a progressive accumulation of surfactant lipids, SP-A, and SP-B in the
alveolar space. By 8 weeks the alveolar phospholipid pool was 8-fold higher than wild-type littermates. There was also a 10-fold
accumulation of alveolar macrophages in the null mice, and many macrophages were both multinucleated and foamy in appearance.
Type II cells in the null mice were hyperplastic and contained giant lamellar bodies. These alterations in surfactant homeostasis
were not associated with detectable changes in surfactant surface activity, postnatal respiratory function, or survival. The
findings in the SP-D-deficient mice suggest a role for SP-D in surfactant homeostasis.
Proceedings of the National Academy of Sciences 09/1998; 95(20):11869-11874. · 9.68 Impact Factor
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[show abstract]
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ABSTRACT: The subacute and long-term biochemical effects of methylenedioxymeth-amphetamine (MDMA) were assessed in homozygous and heterozygous transgenic (Tg) mice that carry the complete sequence of the human copper-zinc (CuZn) superoxide dismutase (SOD) gene. Non-transgenic (Non-Tg) mice showed significant decreased in striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels both at 24 h and at 2 weeks after a single injection of MDMA (50 mg/kg). Heterozygous SOD-Tg mice showed DA depletion only at the 24 h time point. In contrast, homozygous SOD-Tg mice show no DA or DOPAC depletion at either the 24 h or at the 2 week time points. Moreover, three injections of MDMA (50 mg/kg) given 24 h apart also caused marked reduction of striatal DA and DOPAC in Non-Tg mice when these substances were measured 2 weeks after the last MDMA injection. That injection schedule also caused small decreases in DA levels in the heterozygous animals but no changes in the homozygous mice; DOPAC levels were not affected in the heterozygous nor in the homozygous SOD-Tg mice. Furthermore, the multiple injection schedule caused significant decreases in DA and DOPAC in female Non-Tg mice but not in the two strains of transgenic mice. Neither the single dose nor the multiple dose schedule of MDMA injections affected striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIM)levels in any of the three strains of mice. These results support previous observations that MDMA-induced biochemical effects are observed in the DA systems of mice, whereas these effects are seen in the 5-HT systems of rats. The present observations also document for the first time a role for the production of superoxide radicals in these effects of MDMA. These mice are an important tool for dissecting pathways involved in drug-induced neurotoxicity. © 1995 Wiley-Liss, Inc.†
Synapse 09/1995; 21(2):169 - 176. · 2.94 Impact Factor
