Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001511 (Adhesion)
 5,955 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many proteins involved in cell-cell and cell-matrix adhesion are regulated by signal transduction pathways and can activate signal transduction on ligation. Adhesion-related signal transduction is important throughout development, hemostasis, immunity, and in diseases such as cancer. Therefore, the identification of the various signaling pathways that are involved is crucial. Expression cloning is an unbiased way to isolate proteins with specific biological functions. This methodology has been adapted for the identification of proteins involved in cell signaling pathways that are mediated by cell-cell and cell-matrix interactions. We have successfully developed and used a novel expression cloning strategy to isolate the integrin-regulated apoptosis signaling protein BIT-1. This screen was based on previous observations that integrin-mediated adhesion upregulates the anti-apoptotic protein bcl-2. Our strategy described in this chapter uses flow cytometry and a reporter construct in which the bcl-2 promoter is linked to enhanced green fluorescence protein. The advantage of using flow cytometry in expression cloning is that it increases the sensitivity of the screen by enabling us to examine function quantitatively at the level of a single cell millions of times in one experiment. The following protocol provides a detailed method for the isolation of proteins that are regulated by cell adhesion.
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PMID:Expression cloning of signaling proteins regulated by cell adhesion. 1679 97

Homoharringtonine (HHT) is a known anti-leukemia drug that inhibits multiple myeloma (MM) cells both in vitro and in vivo. Our prior study demonstrated that the potency of HHT in MM cells was compromised significantly when myeloma cells were co-cultured with BM stromal cells. This study aimed to investigate whether PI3K/Akt inhibitor LY294002 could potentiate the antimyeloma activity of HHT against MM cells adhered to BM stromal cells and in vivo xenograft models. A co-culture system composed of MM cells and human stromal cells was employed to mimic MM cells in bone marrow niche. The inhibitory and pro-apoptotic effect of HHT and LY294002 was determined by CCK-8 assay or flow cytometry. Expression of PI3K/Akt signaling molecules and anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) was assessed by western blot analysis and/or reverse transcription real-time quantitative PCR (RT-qPCR). MM xenografts were used to evaluate antitumor effect of combined therapy with HHT and LY294002. Adhesion to BM stromal cells rendered MM cells resistant to HHT whereas silencing Mcl-1 partly reversed the resistance. LY294002 induced apoptosis in MM cells and potentiated the antimyeloma effects of HHT by inhibiting the PI3K/Akt signal pathway which was abnormally activated during adhesion. LY294002 also enhanced the antimyeloma effect of HHT in in vivo xenograft models. These findings suggest that activation of PI3K/Akt signal pathway was responsible for the resistance to HHT in MM cells adhered to stromal cells. LY294002 can potentiate the antimyeloma activity of HHT both in vitro and in vivo, which may represent a new clinical treatment in MM.
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PMID:PI3K/Akt inhibitor LY294002 potentiates homoharringtonine antimyeloma activity in myeloma cells adhered to stromal cells and in SCID mouse xenograft. 2945 Jun 44