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  • Increased KIT signalling with up-regulation of cyclin D correlates to accelerated proliferation and shorter disease-free survival in gastrointestinal stromal tumours (GIS ... 18729075

    Gastrointestinal stromal tumours (GISTs) with deletions in KIT exon 11 are characterized by higher proliferation rates and shorter disease-free survival times, compared to GISTs with KIT exon 11 point mutations. Up-regulation of cyclin D is a crucial event for entry into the G1 phase of the cell cycle, and links mitogenic signalling to cell proliferation. Signalling from activated KIT to cyclin D is directed through the RAS/RAF/ERK, PI3K/AKT/mTOR/EIF4E, and JAK/STATs cascades. ERK and STATs initiate mRNA transcription of cyclin D, whereas EIF4E activation leads to increased translation efficiency and reduced degradation of cyclin D protein. The aim of the current study was to analyse the mRNA and protein expression as well as protein phosphorylation of central hubs of these signalling cascades in primary GISTs, to evaluate whether tumours with KIT exon 11 deletions and point mutations differently utilize these pathways. GISTs with KIT exon 11 deletions had significantly higher mitotic counts, higher proliferation rates, and shorter disease-free survival times. In line with this, they had significantly higher expression of cyclin D on the mRNA and protein level. Furthermore, there was a significantly higher amount of phosphorylated ERK1/2, and a higher protein amount of STAT3, mTOR, and EIF4E. PI3K and phosphorylated AKT were also up-regulated, but this was not significant. Ultimately, GISTs with KIT exon 11 deletions had significantly higher phosphorylation of the central negative cell-cycle regulator RB. Phosphorylation of RB is accomplished by activated cyclin D/CDK4/6 complex, and marks a central event in the release of the cell cycle. Altogether, these observations suggest increased KIT signalling with up-regulation of cyclin D as the basis for the unfavourable clinical course in GISTs with KIT exon 11 deletions.
    Document Type:
    Reference
    Product Catalog Number:
    05-157

  • Kit, active - 1628203-C

    Document Type:
    Certificate of Analysis
    Lot Number:
    1628203-C
    Product Catalog Number:
    14-559
    Product Catalog Name:
    c-Kit Protein, active, 10 µg

  • Kit (V654A), active - 1643500-B

    Document Type:
    Certificate of Analysis
    Lot Number:
    1643500-B
    Product Catalog Number:
    14-733
    Product Catalog Name:
    c-Kit (V654A) Protein, active, 10 µg

  • Oncogenic kit triggers Shp2/Erk1/2 pathway to down-regulate the pro-apoptotic protein Bim and to promote apoptosis resistance in leukemic cells. 23145067

    Oncogenic mutations leading to persistent kinase activities are implicated in various human malignancies. Thereby, signaling pathway-targeted therapies are powerful customized treatment to eradicate cancer cells. In murine and human leukemia cells harboring mutations in Kit, we previously showed that distinct and independent pathways controlled resistance to apoptosis or cell cycle. A treatment with PI3Kinase inhibitors to reduce cell proliferation combined with inhibitors of Erk1/2 activity to promote apoptosis had synergistic effects allowing eradication of leukemia cell growth. We reported here that Bim(EL), a pro-apoptotic member of the Bcl2 family proteins, is the target of Erk1/2 signaling and that its down-regulation is responsible for the apoptosis resistance of murine and human leukemic cells. Downstream of Kit mutant, the tyrosine phosphatase Shp2 maintains Bim(EL) expression at a low level, through Erk/2 activation and proteosomal Bim(EL) degradation. This process is controlled by Shp2 independently of other signaling pathways activated downstream of oncogenic Kit, demonstrating that Shp2 is a key regulator of Bim expression in the context of an oncogenic signaling. The increase in Bim(EL) expression is associated to an increased apoptosis. Moreover, the depletion of Bim overcomes apoptosis associated with Erk1/2 inactivation in UO126-treated leukemic cells, thereby establishing the contribution of Bim to drug-induced apoptosis. These data provide a molecular rationale for using BH3 mimetics in combination with PI3K inhibitors to treat leukemia, especially in the case of an oncogenic signaling refractory to Tyrosine Kinase inhibitors.
    Document Type:
    Reference
    Product Catalog Number:
    36-004

  • Kit - D11HP002N-A

    Document Type:
    Certificate of Analysis
    Lot Number:
    D11HP002N-A
    Product Catalog Number:
    23-043
    Product Catalog Name:
    Kit Protein, 10 µg

  • Kit (V560G), active - 33074U-E

    Document Type:
    Certificate of Analysis
    Lot Number:
    33074U-E
    Product Catalog Number:
    14-730
    Product Catalog Name:
    c-Kit (V560G) Protein, active, 10 µg

  • Kit, active - 1659398

    Document Type:
    Certificate of Analysis
    Lot Number:
    1659398
    Product Catalog Number:
    14-559M
    Product Catalog Name:
    c-Kit Protein, active, 250 µg

  • Kit - D11HP002NA

    Document Type:
    Certificate of Analysis
    Lot Number:
    D11HP002NA
    Product Catalog Number:
    23-043
    Product Catalog Name:
    Kit Protein, 10 µg