Stem cell factor-mediated wild-type KIT receptor activation is critical for gastrointestinal stromal tumor cell growth

The p21WAF-1 gene is positively regulated by the wild-type p53 protein. p21WAF-1 has been shown to interact with several cyclin-dependent kinase complexes and block the activity of G1 cyclin-dependent kinases (cdks). Mutational analysis with the p21WAF-1 gene localized a site, at amino acid residues 21 and 24 in the amino terminus of the protein, for p21WAF-1 binding to cyclins D and E. This region of the protein is conserved (residues 21 to 26) in other p21WAF-1 family members, p27kip-1 and p57kip-2. The same p21WAF-121,24 mutant also fails to bind to cyclin D1-cdk 4 or cyclin E-cdk 2 complexes in vitro, suggesting that amino acid residues 21 and 24 are important for p21WAF-1-cdk-cyclin trimeric complex interactions. The p21WAF-1 wild-type protein will suppress tumor cell growth in culture while p21WAF-1 mutant proteins with defects in residues 21 and 24 fail to suppress tumor cell growth. The overexpression of cyclin D or E in these cells will partially overcome the growth suppression of wild-type p21WAF-1 protein in cells. These results provide evidence that p21WAF-1 acts through cyclin D1-cdk4 and cyclin E-cdk2 complexes in vivo to induce the growth suppression. The p21WAF-1 binding sites for cyclins (residues 21 to 26), cdk2 (residues 49 to 71), and proliferating-cell nuclear antigen (residues 124 to 164) have all been mapped to discrete sites on the protein.

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A bispecific transmembrane antibody simultaneously targeting intra- and extracellular epitopes of the epidermal growth factor receptor inhibits receptor activation and tumor cell growth

International Journal of Cancer ◽

10.1002/ijc.28585 ◽

2013 ◽

Vol 134 (11) ◽

pp. 2547-2559 ◽

Cited By ~ 3

Author(s):

Nina Müller ◽

Cord Hartmann ◽

Sabrina Genßler ◽

Joachim Koch ◽

Andrea Kinner ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Cell Growth ◽

Epidermal Growth Factor ◽

Tumor Cell ◽

Growth Factor Receptor ◽

Receptor Activation ◽

Tumor Cell Growth ◽

Epidermal Growth

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Gastrointestinal Stromal Tumor in the Cecum of a Horse

Case Reports in Veterinary Medicine ◽

10.1155/2012/301498 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5

Author(s):

S. Stephan ◽

S. Hug ◽

M. Hilbe

Keyword(s):

Stem Cell ◽

Gastrointestinal Stromal Tumor ◽

Progenitor Cells ◽

Stem Cell Factor ◽

Gastrointestinal Stromal Tumors ◽

Stromal Tumor ◽

Gi Tract ◽

Pacemaker Cells ◽

Stromal Tumors ◽

Cells Of Cajal

Gastrointestinal stromal tumors (GISTs) are defined as specific CD117-(Kit, stem cell factor receptor) expressing tumors of the gastrointestinal (GI) tract. They are believed to originate from the interstitial pacemaker cells of Cajal (ICC) or their progenitor cells. In horses only a few cases of GISTs are described in the literature. In the present paper the macroscopical, histological, immunohistochemical, and ultrastructural features of an equine cecal GIST are described.

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Matrix Metalloproteinase-9 Production, a Newly Identified Function of Mast Cell Progenitors, Is Downregulated by c-kit Receptor Activation

Blood ◽

10.1182/blood.v94.7.2390.419k16_2390_2395 ◽

1999 ◽

Vol 94 (7) ◽

pp. 2390-2395 ◽

Cited By ~ 45

Author(s):

Akane Tanaka ◽

Katsuhiko Arai ◽

Yukihiko Kitamura ◽

Hiroshi Matsuda

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Mast Cells ◽

Matrix Metalloproteinase ◽

Stem Cell Factor ◽

Receptor Activation ◽

Interleukin 3 ◽

Kit Receptor ◽

Kit Gene ◽

Metalloproteinase 9

Mast cell precursors invade from the peripheral blood into local tissues where they differentiate to their mature phenotypes. However, the mechanism of this migration process has been unclear. We clearly demonstrated here the production and release of matrix metalloproteinase-9 (MMP-9), a matrix-degrading enzyme necessary for leukocyte transmigration, by interleukin-3–dependent mouse mast cell progenitors: bone marrow-derived cultured mast cells and IC-2 mast cells. Because several interleukin-3–independent mast cell lines with active mutations in the c-kit gene did not release MMP-9, the possible involvement of c-kit receptor activation in downregulation of MMP-9 production was predicted. c-kitreceptor activation by stem cell factor led to a significant decrease in MMP-9 production of cultured mast cells and IC-2 mast cells transfected with the c-kit gene. Thus, the present results suggest that mast cell precursors are able to produce MMP-9, which may be essential for mast cell migration into tissues, and that stem cell factor may downregulate the MMP-9 production, resulting in engagement of mast cells to matrix components.

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