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How does iDimerize technology work?

How does iDimerize technology work? A chemical inducer of dimerization, or “dimerizer”, is a cell-permeant organic small molecule with two separate motifs that each bind with high affinity to a specific protein module (Dmr domain) fused onto the protein(s) of interest. Addition of the dimerizer brings the chimeric protein subunits into very close proximity to each other, mimicking the activation of the cellular event that dimerization of interest controls. B/B Homodimerizer induces self-association of two copies of the same protein whereas A/C Heterodimerizer induces association of two different proteins. Conversely, a reverse dimerizer ligand (D/D Solubilizer) will bind to and dissociate a protein that aggregates in its absence.

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Activation of a signal transduction pathway through dimerization of a cell surface receptor protein

Activation of a signal transduction pathway through dimerization of a cell surface receptor protein. Cell surface receptor proteins fused to the DmrB domain do not interact until the B/B Homodimerizer is added. This cell-permeant ligand induces the fusion proteins to interact, activating a downstream event.

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Signal transduction example 2

Signal transduction example 2. Inducible mouse model for prostate cancer. iDimerize Inducible Homodimer technology was used to characterize the role of different FGF receptor subtypes (FGFR1 and FGFR2) in prostate cancer. Transgenic mice (which express conditionally active alleles of FGFR1 or FGFR2 in prostate tissue) were treated with B/B Homodimerizer and monitored for prostate cancer. FGFR1, but not FGFR2, was found to play a role in prostate cancer development [Freeman, K. W., et al. (2003) Cancer Res. 63(23):8256–8563].

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Signal transduction example 1: Inducing a Programmed Cell Death Pathway (Inducible Apoptosis)

Signal transduction example 1: Inducing a Programmed Cell Death Pathway (Inducible Apoptosis). The Fas receptor (FasR) is a transmembrane protein located on the surface of cells that activates programmed cell death (apoptosis) when induced to trimerize by fas ligand (FasL) molecules located on the surface of adjacent cells (e.g., cytotoxic T cells). FasR-FasL binding plays an important role in the regulation of the immune system and cancer progression. This trimerization (and the resulting apoptotic signaling cascade) can be mimicked using the iDimerize Inducible Homodimer System: cells expressing a FasR-DmrB fusion protein can induce cell death on demand, simply by adding the B/B Homodimerizer. An in vivo model [the MaFIA mouse; Burnett, S. H. et al. (2004) J. Leukoc. Biol. 75(4):612–623] utilizes the Fas receptor to systematically and reversibly eliminate macrophages from transgenic mice.

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Exploiting fas-mediated apoptosis to induce programmed cell death

Exploiting fas-mediated apoptosis to induce programmed cell death. Fas-mediated apoptosis is triggered by trimerization of the fas receptor (FasR) via its interaction with the fas ligand (FasL) on an adjacent cell (left). This FasR trimerization event activates the caspase 8 pathway. In the MaFIA mouse model, the fas death domain is fused to two repeats of a dimerization domain and expressed from a myeloid-specific promoter. Apoptosis of macrophage cells in this mouse is induced by treatment with B/B Homodimerizer (AP20187) (right).

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635069: B/B Homodimerizer

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Signal transduction example 2

Signal transduction example 2. Inducible mouse model for prostate cancer. iDimerize Inducible Homodimer technology was used to characterize the role of different FGF receptor subtypes (FGFR1 and FGFR2) in prostate cancer. Transgenic mice (which express conditionally active alleles of FGFR1 or FGFR2 in prostate tissue) were treated with B/B Homodimerizer and monitored for prostate cancer. FGFR1, but not FGFR2, was found to play a role in prostate cancer development [Freeman, K. W., et al. (2003) Cancer Res. 63(23):8256–8563].

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Signal transduction example 1: Inducing a Programmed Cell Death Pathway (Inducible Apoptosis)

Signal transduction example 1: Inducing a Programmed Cell Death Pathway (Inducible Apoptosis). The Fas receptor (FasR) is a transmembrane protein located on the surface of cells that activates programmed cell death (apoptosis) when induced to trimerize by fas ligand (FasL) molecules located on the surface of adjacent cells (e.g., cytotoxic T cells). FasR-FasL binding plays an important role in the regulation of the immune system and cancer progression. This trimerization (and the resulting apoptotic signaling cascade) can be mimicked using the iDimerize Inducible Homodimer System: cells expressing a FasR-DmrB fusion protein can induce cell death on demand, simply by adding the B/B Homodimerizer. An in vivo model [the MaFIA mouse; Burnett, S. H. et al. (2004) J. Leukoc. Biol. 75(4):612–623] utilizes the Fas receptor to systematically and reversibly eliminate macrophages from transgenic mice.

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Molecular weights of iDimerize ligands

Molecular weights of iDimerize ligands.

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Signal transduction example 2

Signal transduction example 2. Inducible mouse model for prostate cancer. iDimerize Inducible Homodimer technology was used to characterize the role of different FGF receptor subtypes (FGFR1 and FGFR2) in prostate cancer. Transgenic mice (which express conditionally active alleles of FGFR1 or FGFR2 in prostate tissue) were treated with B/B Homodimerizer and monitored for prostate cancer. FGFR1, but not FGFR2, was found to play a role in prostate cancer development [Freeman, K. W., et al. (2003) Cancer Res. 63(23):8256–8563].

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Molecular structure of the B/B Homodimerizer

Molecular structure of the B/B Homodimerizer.

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Signal transduction example 1: Inducing a Programmed Cell Death Pathway (Inducible Apoptosis)

Signal transduction example 1: Inducing a Programmed Cell Death Pathway (Inducible Apoptosis). The Fas receptor (FasR) is a transmembrane protein located on the surface of cells that activates programmed cell death (apoptosis) when induced to trimerize by fas ligand (FasL) molecules located on the surface of adjacent cells (e.g., cytotoxic T cells). FasR-FasL binding plays an important role in the regulation of the immune system and cancer progression. This trimerization (and the resulting apoptotic signaling cascade) can be mimicked using the iDimerize Inducible Homodimer System: cells expressing a FasR-DmrB fusion protein can induce cell death on demand, simply by adding the B/B Homodimerizer. An in vivo model [the MaFIA mouse; Burnett, S. H. et al. (2004) J. Leukoc. Biol. 75(4):612–623] utilizes the Fas receptor to systematically and reversibly eliminate macrophages from transgenic mice.

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Molecular weights of iDimerize ligands

Molecular weights of iDimerize ligands.

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Exploiting fas-mediated apoptosis to induce programmed cell death

Exploiting fas-mediated apoptosis to induce programmed cell death. Fas-mediated apoptosis is triggered by trimerization of the fas receptor (FasR) via its interaction with the fas ligand (FasL) on an adjacent cell (left). This FasR trimerization event activates the caspase 8 pathway. In the MaFIA mouse model, the fas death domain is fused to two repeats of a dimerization domain and expressed from a myeloid-specific promoter. Apoptosis of macrophage cells in this mouse is induced by treatment with B/B Homodimerizer (AP20187) (right).

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635058: B/B Homodimerizer