MAP Kinases in Plant Signal Transduction: VersatileTools for Signaling Stress, Cell Cycle, and More

Abstract Context: The aberrant silencing of iodide-handling genes accompanied by up-regulation of glucose metabolism presents a major challenge for radioiodine treatment of papillary thyroid cancer (PTC). Objective: This study aimed to evaluate the effect of tyrosine kinase inhibitors on iodide-handling and glucose-handling gene expression in BHP 2-7 cells harboring RET/PTC1 rearrangement. Main Outcome Measures: In this in vitro study, the effects of sorafenib or cabozantinib on cell growth, cycles, and apoptosis were investigated by cell proliferation assay, cell cycle analysis, and Annexin V-FITC apoptosis assay, respectively. The effect of both agents on signal transduction pathways was evaluated using the Western blot. Quantitative real-time PCR, Western blot, immunofluorescence, and radioisotope uptake assays were used to assess iodide-handling and glucose-handling gene expression. Results: Both compounds inhibited cell proliferation in a time-dependent and dose-dependent manner and caused cell cycle arrest in the G0/G1 phase. Sorafenib blocked RET, AKT, and ERK1/2 phosphorylation, whereas cabozantinib blocked RET and AKT phosphorylation. The restoration of iodide-handling gene expression and inhibition of glucose transporter 1 and 3 expression could be induced by either drug. The robust expression of sodium/iodide symporter induced by either agent was confirmed, and 125I uptake was correspondingly enhanced. 18F-fluorodeoxyglucose accumulation was significantly decreased after treatment by either sorafenib or cabozantinib. Conclusions: Sorafenib and cabozantinib had marked effects on cell proliferation, cell cycle arrest, and signal transduction pathways in PTC cells harboring RET/PTC1 rearrangement. Both agents could be potentially used to enhance the expression of iodide-handling genes and inhibit the expression of glucose transporter genes.

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Expression and modulation of map kinases and cell cycle regulatory proteins during pancreas regeneration

Gastroenterology ◽

10.1016/s0016-5085(98)81819-2 ◽

1998 ◽

Vol 114 ◽

pp. A450

Author(s):

J. Cristobal Aliaga ◽

E. Calvo ◽

J. Morisset ◽

N. Rivard

Keyword(s):

Cell Cycle ◽

Map Kinases ◽

Regulatory Proteins ◽

Pancreas Regeneration ◽

Cell Cycle Regulatory Proteins

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Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors.

The Journal of Cell Biology ◽

10.1083/jcb.135.6.1633 ◽

1996 ◽

Vol 135 (6) ◽

pp. 1633-1642 ◽

Cited By ~ 536

Author(s):

S Miyamoto ◽

H Teramoto ◽

J S Gutkind ◽

K M Yamada

Keyword(s):

Signal Transduction ◽

Growth Factors ◽

Growth Factor ◽

Map Kinase ◽

Tyrosine Kinases ◽

Map Kinases ◽

Egf Receptor ◽

Growth Factor Receptor ◽

Kinase Activation ◽

Transient Activation

Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.

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