FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2148309992> ?p ?o ?g. }

• W2148309992 endingPage "2" @default.
• W2148309992 startingPage "2" @default.
• W2148309992 abstract "<strong>Background:</strong> Activation of the mammalian Ras-Raf-MEK-ERK MAPK signaling cascade promotes cellular proliferation, and activating Ras mutations are implicated in cancer onset and maintenance. This pathway, a therapeutic target of interest, is highly conserved and required for vulval development in <em>C. elegans.</em> Gain-of-function mutations in the Ras ortholog lead to constitutive pathway signaling and a multivulva (Muv) phenotype. MCP compounds were identified in a yeast two-hybrid screen for their ability to disrupt Ras-Raf interactions. However, this had not been confirmed in another system, and conflicting results were reported regarding selective MCP-mediated blockade of Ras- and Rafmediated biological activities in mammalian cells. Here we used the easily-scored Muv phenotype as an <em>in vivo</em> readout to characterize the selectivity of MCP110 and its analogs, and performed biochemical studies in mammalian cells to determine whether MCP treatment results in impaired interaction between Ras and its effector Raf. <strong>Results:</strong> Our genetic analyses showed significant dose-dependent MCP-mediated reduction of Muv in C. elegans strains with activating mutations in orthologs of Ras (LET-60) or Raf (LIN-45), but not MAP kinases or an Ets-like transcription factor. Thus, these inhibitors selectively impair pathway function downstream of Ras and upstream of or at the level of Raf, consistent with disruption of the Ras/Raf interaction. Our biochemical analyses of MCP110- mediated disruption of Ras-Raf interactions in mammalian cells showed that MCP110 dose-dependently reduced Raf-RBD pulldown of Ras, displaced a fluorescently-tagged Raf-RBD probe from plasma membrane locations of active Ras to the cytosol and other compartments, and decreased active, phosphorylated ERK1/2. <strong>Conclusions:</strong> We have effectively utilized <em>C. elegans</em> as an in vivo genetic system to evaluate the activity and selectivity of inhibitors intended to target the Ras-Raf-MAPK pathway. We demonstrated the ability of MCP110 to disrupt, at the level of Ras/Raf, the Muv phenotype induced by chronic activation of this pathway in <em>C. elegans</em>. In mammalian cells, we not only demonstrated MCP-mediated blockade of the physical interaction between Ras and Raf, but also narrowed the site of interaction on Raf to the RBD, and showed consequent functional impairment of the Ras-Raf-MEK-ERK pathway in both <em>in vivo</em> and cell-based systems." @default.
• W2148309992 created "2016-06-24" @default.
• W2148309992 creator A5005839868 @default.
• W2148309992 creator A5008119718 @default.
• W2148309992 creator A5012585635 @default.
• W2148309992 creator A5022408460 @default.
• W2148309992 creator A5027303790 @default.
• W2148309992 creator A5043170852 @default.
• W2148309992 creator A5063852287 @default.
• W2148309992 creator A5077604995 @default.
• W2148309992 date "2010-02-23" @default.
• W2148309992 modified "2023-10-10" @default.
• W2148309992 title "Genetic and functional characterization of putative Ras/Raf interaction inhibitors in <em>C. elegans</em> and mammalian cells" @default.
• W2148309992 cites W136513817 @default.
• W2148309992 cites W137936598 @default.
• W2148309992 cites W14258228 @default.
• W2148309992 cites W1489169778 @default.
• W2148309992 cites W1498900438 @default.
• W2148309992 cites W1500667430 @default.
• W2148309992 cites W1518639206 @default.
• W2148309992 cites W1547066932 @default.
• W2148309992 cites W1564499430 @default.
• W2148309992 cites W1575730129 @default.
• W2148309992 cites W1597756947 @default.
• W2148309992 cites W1604292883 @default.
• W2148309992 cites W1608367307 @default.
• W2148309992 cites W1608885177 @default.
• W2148309992 cites W179114848 @default.
• W2148309992 cites W1873788002 @default.
• W2148309992 cites W1944127002 @default.
• W2148309992 cites W1946787458 @default.
• W2148309992 cites W1963042350 @default.
• W2148309992 cites W1964489808 @default.
• W2148309992 cites W1966935234 @default.
• W2148309992 cites W1967835627 @default.
• W2148309992 cites W1968826282 @default.
• W2148309992 cites W1970694857 @default.
• W2148309992 cites W1972135985 @default.
• W2148309992 cites W1972812612 @default.
• W2148309992 cites W1973554661 @default.
• W2148309992 cites W1973973036 @default.
• W2148309992 cites W1974091059 @default.
• W2148309992 cites W1979027806 @default.
• W2148309992 cites W1980981080 @default.
• W2148309992 cites W1984455350 @default.
• W2148309992 cites W1985238450 @default.
• W2148309992 cites W1985309852 @default.
• W2148309992 cites W1986006829 @default.
• W2148309992 cites W1989480480 @default.
• W2148309992 cites W1989839956 @default.
• W2148309992 cites W1990750680 @default.
• W2148309992 cites W1991760443 @default.
• W2148309992 cites W1994413156 @default.
• W2148309992 cites W1996344630 @default.
• W2148309992 cites W1996962669 @default.
• W2148309992 cites W1997270847 @default.
• W2148309992 cites W1997656209 @default.
• W2148309992 cites W1997813173 @default.
• W2148309992 cites W1998195598 @default.
• W2148309992 cites W2001521752 @default.
• W2148309992 cites W2001679453 @default.
• W2148309992 cites W2004136952 @default.
• W2148309992 cites W2004220006 @default.
• W2148309992 cites W2004275852 @default.
• W2148309992 cites W2007179773 @default.
• W2148309992 cites W2007537308 @default.
• W2148309992 cites W2007660746 @default.
• W2148309992 cites W2009235369 @default.
• W2148309992 cites W2009796716 @default.
• W2148309992 cites W2010207338 @default.
• W2148309992 cites W2011826559 @default.
• W2148309992 cites W2015805460 @default.
• W2148309992 cites W2015836174 @default.
• W2148309992 cites W2016171370 @default.
• W2148309992 cites W2017098460 @default.
• W2148309992 cites W2019528050 @default.
• W2148309992 cites W2021170096 @default.
• W2148309992 cites W2022076650 @default.
• W2148309992 cites W2025872894 @default.
• W2148309992 cites W2028086814 @default.
• W2148309992 cites W2028634080 @default.
• W2148309992 cites W2031951506 @default.
• W2148309992 cites W2032630649 @default.
• W2148309992 cites W2033125632 @default.
• W2148309992 cites W2034678670 @default.
• W2148309992 cites W2034681985 @default.
• W2148309992 cites W2036048603 @default.
• W2148309992 cites W2036082581 @default.
• W2148309992 cites W2037480365 @default.
• W2148309992 cites W2038224489 @default.
• W2148309992 cites W2039750761 @default.
• W2148309992 cites W2041098455 @default.
• W2148309992 cites W2041966576 @default.
• W2148309992 cites W2042549365 @default.
• W2148309992 cites W2043668746 @default.
• W2148309992 cites W2043698607 @default.
• W2148309992 cites W2044721076 @default.
• W2148309992 cites W2044865509 @default.

• next