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• W7533341 abstract "BACKGROUND: Human gliomas account for the most common and malignant tumors in the central nervous system (CNS). Despite optimal treatments, survival of patients with high-grade glioblastoma multiforme (GBM) remains poor. Recent coordinated genomic analyses of a large cohort of clinical GBM specimens identified frequent co-alterations of genes in three core pathways—the P53, retinoblastoma (RB), and receptor tyrosine kinase (RTK) pathways that are crucial in gliomagenesis. Further multi-institutional efforts have sub-classified GBMs into four clinical relevant subtypes based on their signature genetic lesions. Among them, PDGFRA overexpression is concomitant with a loss of CDKN2A locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of GBMs. To better understand and design therapeutic strategies against gliomas driven by abnormal platelet-derived growth factor (PDGF) signaling, functional studies using human or mouse models are needed. MAJOR FINDINGS: In order to establish a model that allows us to assess contributions of different signaling pathways to PDGFRα-induced glioma formation, we generated Ink4a/Arf-deficient primary mouse astrocytes (referred to as mAst hereafter) and human glioma cells that overexpress PDGFRα and/or PDGF-A. We found that activation of PDGFRα confers tumorigenicity to Ink4a/Arf-deficient mAst and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF by retroviral transduction suppresses PDGFRα-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFRα that lost capacity to bind to SH-2-containing phosphotyrosine phosphatase SHP-2 or Phosphoinositol 3'-Kinase (PI3K) significantly diminished PDGFRα-promoted tumorigenesis. Furthermore, inhibition of SHP-2 by shRNAs or pharmacological inhibitors disrupted the interaction of PI3K with PDGFRα, suppressed downstream AKT/mTOR activation, and impaired tumorigenesis of Ink4a/Arf-null cells, whereas expression of an activated PI3K mutant rescued the effect of SHP-2 inhibition on tumorigenicity. In clinical glioblastoma specimens, PDGFRα and PDGF-A are co-expressed and such co-expression is linked with activation of SHP-2/AKT/mTOR-signaling. Our data thus suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFRα promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity.SIGNIFICANCE: We expect these findings will improve our understanding of the formation of the gliomas with PDGFRA and INK4A/ARF aberrations. There were studies that predicted SHP-2/PTPN11 as one of the linker genes in clinical GBMs that interact with multiple commonly altered genes. Our results functionally validate this hypothesis and identify SHP-2 as a converge point of several signaling pathways such as PDGFR, EGFR, PI3K, and mTOR that are frequently deregulated in GBMs. It thus represents a promising target for treatments against this fatal disease." @default.
• W7533341 created "2016-06-24" @default.
• W7533341 creator A5009346189 @default.
• W7533341 date "2011-06-02" @default.
• W7533341 modified "2023-09-27" @default.
• W7533341 title "Platelet-derived growth factor receptor alpha overexpression cooperates with ink4a/arf loss to promote gliomagenesis---roles of shp-2 and pi3k pathways" @default.
• W7533341 cites W1480603181 @default.
• W7533341 cites W1487831133 @default.
• W7533341 cites W1495551511 @default.
• W7533341 cites W1499660750 @default.
• W7533341 cites W1527684295 @default.
• W7533341 cites W1534734027 @default.
• W7533341 cites W1560814177 @default.
• W7533341 cites W1570869769 @default.
• W7533341 cites W1587419561 @default.
• W7533341 cites W1595064915 @default.
• W7533341 cites W1602223278 @default.
• W7533341 cites W1607516807 @default.
• W7533341 cites W1673016819 @default.
• W7533341 cites W1703816965 @default.
• W7533341 cites W1843891279 @default.
• W7533341 cites W1852153956 @default.
• W7533341 cites W1862775231 @default.
• W7533341 cites W1868766650 @default.
• W7533341 cites W1894124425 @default.
• W7533341 cites W191597278 @default.
• W7533341 cites W1931031804 @default.
• W7533341 cites W1948282121 @default.
• W7533341 cites W194867514 @default.
• W7533341 cites W1965157625 @default.
• W7533341 cites W1965491357 @default.
• W7533341 cites W1966426211 @default.
• W7533341 cites W1966803171 @default.
• W7533341 cites W1966879473 @default.
• W7533341 cites W1969702279 @default.
• W7533341 cites W1970537251 @default.
• W7533341 cites W1971092719 @default.
• W7533341 cites W1971343062 @default.
• W7533341 cites W1973358829 @default.
• W7533341 cites W1973886069 @default.
• W7533341 cites W1974530971 @default.
• W7533341 cites W1974967725 @default.
• W7533341 cites W1975422371 @default.
• W7533341 cites W1975936604 @default.
• W7533341 cites W1975998045 @default.
• W7533341 cites W1976569872 @default.
• W7533341 cites W1977103562 @default.
• W7533341 cites W1977218716 @default.
• W7533341 cites W1977706798 @default.
• W7533341 cites W1978216021 @default.
• W7533341 cites W1979286083 @default.
• W7533341 cites W1980878904 @default.
• W7533341 cites W1981050269 @default.
• W7533341 cites W1982020713 @default.
• W7533341 cites W1982711630 @default.
• W7533341 cites W1983041452 @default.
• W7533341 cites W1983348452 @default.
• W7533341 cites W1984246155 @default.
• W7533341 cites W1986755373 @default.
• W7533341 cites W1986763150 @default.
• W7533341 cites W1987704199 @default.
• W7533341 cites W1987885030 @default.
• W7533341 cites W1989168159 @default.
• W7533341 cites W1989476856 @default.
• W7533341 cites W1990203082 @default.
• W7533341 cites W1991401607 @default.
• W7533341 cites W1992245559 @default.
• W7533341 cites W1993189113 @default.
• W7533341 cites W1994379208 @default.
• W7533341 cites W1995104464 @default.
• W7533341 cites W1996611512 @default.
• W7533341 cites W1997073961 @default.
• W7533341 cites W1997304999 @default.
• W7533341 cites W1997664696 @default.
• W7533341 cites W1998557621 @default.
• W7533341 cites W1999224816 @default.
• W7533341 cites W2000348274 @default.
• W7533341 cites W2000374535 @default.
• W7533341 cites W2002444372 @default.
• W7533341 cites W2002973959 @default.
• W7533341 cites W2003516811 @default.
• W7533341 cites W2003766681 @default.
• W7533341 cites W2004649105 @default.
• W7533341 cites W2005969089 @default.
• W7533341 cites W2007205613 @default.
• W7533341 cites W2007338142 @default.
• W7533341 cites W2008006907 @default.
• W7533341 cites W2008797552 @default.
• W7533341 cites W2009738798 @default.
• W7533341 cites W2009946441 @default.
• W7533341 cites W2010587462 @default.
• W7533341 cites W2011454523 @default.
• W7533341 cites W2011957331 @default.
• W7533341 cites W2012228544 @default.
• W7533341 cites W2013681684 @default.
• W7533341 cites W2015145874 @default.
• W7533341 cites W2015338496 @default.
• W7533341 cites W2017235640 @default.
• W7533341 cites W2019498844 @default.
• W7533341 cites W2020231800 @default.

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