Two dual specificity kinases are preferentially induced by wild-type rather than by oncogenic RAS-P21 in Xenopus oocytes

10.2741/1979 ◽  
2006 ◽  
Vol 11 (1) ◽  
pp. 2420 ◽  
Author(s):  
Yongxia Qu
Keyword(s):  
Xenopus Oocytes ◽  
Wild Type ◽  
Oncogenic Ras ◽  
Dual Specificity ◽  
Ras P21

scholarly journals Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis

2012 ◽  
Vol 3 (1) ◽  
Author(s):  
Hao-Hsuan Jeng ◽  
Laura J Taylor ◽  
Dafna Bar-Sagi
Keyword(s):  
Wild Type ◽  
Oncogenic Ras

Molecular Biology of GAP and its Interaction with Oncogenic ras p21

ras Oncogenes ◽  
1989 ◽  
pp. 303-309
Author(s):  
U. S. Vogel ◽  
R. E. Diehl ◽  
M. S. Marshall ◽  
M. D. Schaber ◽  
R. B. Register ◽  
...  
Keyword(s):  
Molecular Biology ◽  
Oncogenic Ras ◽  
Ras P21

scholarly journals State‐dependent barium block of wild‐type and inactivation‐deficient HERG channels in Xenopus oocytes

2000 ◽  
Vol 526 (2) ◽  
pp. 265-278 ◽  
Author(s):  
Manjula Weerapura ◽  
Stanley Nattel ◽  
Marc Courtemanche ◽  
David Doern ◽  
Nathalie Ethier ◽  
...  
Keyword(s):  
Xenopus Oocytes ◽  
Wild Type ◽  
State Dependent ◽  
Barium Block ◽  
Herg Channels

Effect of PCMBS on CO2permeability of Xenopus oocytes expressing aquaporin 1 or its C189S mutant

1998 ◽  
Vol 275 (6) ◽  
pp. C1481-C1486 ◽  
Author(s):  
Gordon J. Cooper ◽  
Walter F. Boron
Keyword(s):  
Carbonic Anhydrase ◽  
Intracellular Ph ◽  
Xenopus Oocytes ◽  
Membrane Lipid ◽  
Wild Type ◽  
Aquaporin 1 ◽  
Gas Channel ◽  
A Cell ◽  
Pass Through ◽  
Rule Out

A recent study on Xenopus oocytes [N. L. Nakhoul, M. F. Romero, B. A. Davis, and W. F. Boron. Am. J. Physiol. 274 ( Cell Physiol. 43): C543–548, 1998] injected with carbonic anhydrase showed that expressing aquaporin 1 (AQP1) increases by ∼40% the rate at which exposing the cell to CO2 causes intracellular pH to fall. This observation is consistent with several interpretations. Overexpressing AQP1 might increase apparent CO2 permeability by 1) allowing CO2 to pass through AQP1, 2) stimulating injected carbonic anhydrase, 3) enhancing the CO2 solubility of the membrane’s lipid, or 4) increasing the expression of a native “gas channel.” The purpose of the present study was to distinguish among these possibilities. We found that expressing the H2O channel AQP1 in Xenopus oocytes increases the CO2 permeability of oocytes in an expression-dependent fashion, whereas expressing the K+ channel ROMK1 has no effect. The mercury derivative p-chloromercuriphenylsulfonic acid (PCMBS), which inhibits the H2O movement through AQP1, also blocks the AQP1-dependent increase in CO2 permeability. The mercury-insensitive C189S mutant of AQP1 increases the CO2 permeability of the oocyte to the same extent as does the wild-type channel. However, the C189S-dependent increase in CO2permeability is unaffected by treatment with PCMBS. These data rule out options 2–4 listed above. Thus our results suggest that CO2passes through the pore of AQP1 and are the first data to demonstrate that a gas can enter a cell by a means other than diffusing through the membrane lipid.

scholarly journals Bcor Mutations Cooperate with Tet2 Deficiency to Promote RAS Transformation of Mouse Hematopoietic Progenitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 888-888
Author(s):  
Iman Fares ◽  
Rahul S. Vedula ◽  
Shabbir M. Vahanvaty ◽  
Christopher S Waters ◽  
Marlise R. Luskin ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Somatic Mutations ◽  
Genetic Alterations ◽  
Ras Signaling ◽  
Wild Type ◽  
Ras Pathway ◽  
Tp53 Mutations ◽  
Oncogenic Ras ◽  
Mdm2 Overexpression

Abstract Somatic mutations can have highly stereotyped positions in the myeloid clonal hierarchy and distinct patterns of co-occurring mutations. Gene mutations that cause aberrant activation of RAS/MAPK signaling are typically late events in myeloid disease progression and are closely associated with leukemic transformation. We hypothesized that the phenotypic output of oncogenic RAS signaling is dynamically reprogrammed during leukemogenesis based on evolving genetic and epigenetic context. To identify genetic alterations that may modulate RAS-mediated transformation, we evaluated 1273 adults with myelodysplastic syndrome, including 150 with mutations in NRAS, KRAS, PTPN11, CBL, RIT1, NF1, or FLT3. Somatic mutations in ASXL1 (q<0.0001), RUNX1 (q<0.0001), EZH2 (q<0.0001), BCOR (q=0.0002), and STAG2 (q=0.001) were most significantly associated with co-occurring RAS pathway mutations, compared to those without RAS pathway mutations, while TP53 mutations were less frequent (q=0.059). We validated these observations in an independent cohort of 6343 unselected patients, including 1081 patients harboring either RAS pathway mutations (n=651),TP53 mutations (n=494), or both (n=57). To define the effects of sequential acquisition of driver mutations, we developed a mouse serial transplantation model of somatic myeloid transformation. First, we used in vivo pI:pC treatment to induce biallelic inactivation of Tet2 in adult Mx1-Cre/Tet2flox/floxmice. After 12 weeks, we purified Tet2-/-or control hematopoietic stem and progenitor cells (HSPCs) and used CRISPR/Cas9 to separately introduce inactivating mutations in Ezh2, Asxl1-exon12, Stag2, or Bcor, then evaluated their functional effects using ex vivo serial replating or in vivo competitive transplantation. Tet2-/-HSPCs with control sgRNA showed a modest enhancement of serial replating compared to Tet2-wild type HSPCs, while Tet2-/-HSPCs Asxl1, Stag2, and Bcor, but not Ezh2 sgRNA had markedly enhanced serial replating capacity (>6 platings in all replicates). In primary transplantation, secondary mutations caused in vivo clonal advantage after 16 weeks, but never resulted in histologic transformation to acute leukemia. We next evaluated the impact of tertiary NRASG12Dmutations in each pairwise Tet2-/-CRISPR combination (Asxl1, Bcor, Ezh2, Stag2, control). We purified HSPCs from recipient mice 16 weeks after primary transplantation, transduced with a lentiviral NRASG12Dexpression vector and transplanted into secondary recipients. Recipients of Tet2/Bcor/NRAS, Tet2/Asxl1/NRAS, or Tet2/Ezh2/NRAS cells succumbed to CD11b+myeloid disease with variable latency in Bcor (14 days), Ezh2 (50 days), and Asxl1 (120 days) cells, suggesting that combined Tet2 and PRC1/2 alterations may modify the effects of oncogenic RAS signaling. To determine whether pre-existing epigenetic mutations cooperate to alter the transcriptional response to acute oncogenic stress compared to wild type cells, weperformed RNA-seq 12 and 24 hours after induced expression of NRASG12D in isogenic immortalized mouse progenitor cells deficient for Tet2, Bcor, or both Tet2 and Bcor. We observed rapid activation of inflammatory and cellular senescence programs in all conditions, suggesting a genotype-independent immediate early response to oncogenic signaling. However, we also identified genotype-specific regulation of tumor suppressor and cell cycle checkpoint pathways. While Cdnk1a expression was strongly induced in all conditions, Cdnk2a expression (and p16Ink4a and p19ARF protein levels) was preferentially upregulated in the context of Bcor deficiency. Moreover, expression of the p53 negative regulator Mdm2 was increased 11-fold in Tet2/Bcor-deficient cells, but only 4 to 5-fold in wild type, Tet2-, or Bcor-deficient cells. Tet2/Bcor-deficient cells were significantly more sensitive to treatment with the Mdm2 antogonist, Nutlin, upon induction of NRAS expression than were wild-type cells, suggesting that Mdm2 overexpression directly mediates acquired tolerance of oncogene stress. These human genetic data and mouse models suggest that epigenetic alterations occurring during early myeloid leukemogenesis may enable evasion of oncogene protection mechanism. Bcor mutations can pair with initiating Tet2 mutations to facilitate RAS mediated transformation while incurring a dependency on Mdm2 overexpression. Disclosures No relevant conflicts of interest to declare.

scholarly journals Proteomic Characterization of a Mouse Model of Familial Danish Dementia

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Monica Vitale ◽  
Giovanni Renzone ◽  
Shuji Matsuda ◽  
Andrea Scaloni ◽  
Luciano D'Adamio ◽  
...  
Keyword(s):  
Ion Trap ◽  
Scaffold Protein ◽  
Synaptic Function ◽  
Differentially Expressed Proteins ◽  
Wild Type ◽  
Dominant Mutation ◽  
Immunoblotting Analysis ◽  
Familial Danish Dementia ◽  
Dual Specificity

A dominant mutation in theITM2B/BRI2gene causes familial Danish dementia (FDD) in humans. To model FDD in animal systems, a knock-in approach was recently implemented in mice expressing a wild-type and mutant allele, which bears the FDD-associated mutation. Since theseFDDKImice show behavioural alterations and impaired synaptic function, we characterized their synaptosomal proteome via two-dimensional differential in-gel electrophoresis. After identification by nanoliquid chromatography coupled to electrospray-linear ion trap tandem mass spectrometry, the differentially expressed proteins were classified according to their gene ontology descriptions and their predicted functional interactions. The Dlg4/Psd95 scaffold protein and additional signalling proteins, including protein phosphatases, were revealed by STRING analysis as potential players in the altered synaptic function ofFDDKImice. Immunoblotting analysis finally demonstrated the actual downregulation of the synaptosomal scaffold protein Dlg4/Psd95 and of the dual-specificity phosphatase Dusp3 in the synaptosomes ofFDDKImice.

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