Dataset Information

Expression of ERK signaling inhibitors Dusp6, Dusp7, and Dusp9 during mouse ear development.

ABSTRACT: The levels of fibroblast growth factor (FGF) signaling play important roles in coordinating development of the mouse inner, middle, and outer ears. Extracellular signal-regulated kinases (ERKs) are among the effectors that transduce the FGF signal to the nucleus and other cellular compartments. Attenuation of ERK activity by dephosphorylation is necessary to modulate the magnitude and duration of the FGF signal. Recently, we showed that inactivation of the ERK phosphatase, dual specificity phosphatase 6 (DUSP6), causes partially penetrant postnatal lethality, hearing loss and skeletal malformations. To determine whether other Dusps may function redundantly with Dusp6 during otic development, we surveyed the expression domains of the three ERK-specific DUSP transcripts, Dusp6, Dusp7, and Dusp9, in the embryonic mouse ear. We show that each is expressed in partially overlapping patterns that correspond to regions of active FGF signaling, suggesting combinatorial roles in negative regulation of this pathway during ear development.

SUBMITTER: Urness LD

PROVIDER: S-EPMC2377012 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Expression of ERK signaling inhibitors Dusp6, Dusp7, and Dusp9 during mouse ear development.

Urness Lisa D LD Li Chaoying C Wang Xiaofen X Mansour Suzanne L SL

Developmental dynamics : an official publication of the American Association of Anatomists 20080101 1

The levels of fibroblast growth factor (FGF) signaling play important roles in coordinating development of the mouse inner, middle, and outer ears. Extracellular signal-regulated kinases (ERKs) are among the effectors that transduce the FGF signal to the nucleus and other cellular compartments. Attenuation of ERK activity by dephosphorylation is necessary to modulate the magnitude and duration of the FGF signal. Recently, we showed that inactivation of the ERK phosphatase, dual specificity phosp ...[more]

PMID: 18058922

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Project description:Objective: DUSP6 is a negative regulator of the ERK signaling pathway and plays an important role in chemotherapy-resistance. Previously we showed that DUSP6 is overexpressed in ovarian cancer side population (SP) cells that possess cancer stem cell-like properties and are quiescent and chemotherapy-resistant. Here, we explore the effects of DUSP6 on chemotherapy-resistance by examining its regulation of the ERK signaling pathway and G0/G1 cell cycle arrest. Methods: mRNA and protein expression of DUSP6 and G0/G1 cell cycle checkpoint regulating proteins (CyclinD1, CyclinD3 and CyclinE2) was evaluated among ovarian cancer cell lines and tissue samples. Ovarian cancer cells were transiently transfected to overexpress DUSP6. After treatment with cisplatin, cell viability was measured by the MTS assay at 48 hours and the half maximal inhibitory concentration (IC50) for each cell line was calculated. Subcellular localization and cell cycle analysis were determined by using immunofluorescence and FACS, respectively. Results: SKOV3 and OVCAR8 SP cells were shown to express higher levels of DUSP6 and lower levels of CyclinD3 compared with non-SP (NSP) cells (P<0.001). Among 39 ovarian cancer tissue samples, expression of DUSP6 in the chemotherapy-resistant group (12 samples) was higher than in the chemotherapy-sensitive group (27 samples) (P<0.05). While a lower level of expression of CyclinD3 was seen in the chemotherapy-resistant group, it was not statistically different from the chemotherapy-sensitive group. HO8910 cells where shown to have higher IC50 to cisplatin than SKOV3 or OVCAR8 cells, and this correlated with higher levels of DUSP6 expression. Overexpression of DUSP6 in SKOV3 cells led to an increase in cisplatin IC50 values (P<0.05), and also markedly reduced the expression levels of phospho-ERK1/2 and CyclinD3 and to the predominance of cells in the G0/G1 phase. Conclusion: Our findings reveal an enhancement of chemotherapy-resistance and a predominance of cells in G1 cell cycle arrest in DUSP6-overexpressing ovarian cancer cells. This suggests that overexpression of DUSP6 promotes chemotherapy-resistance through the negative regulation of the ERK signaling pathway, increasing the G0/G1 phase ratio among ovarian cancer cells, and leading to cellular quiescence.

Dataset Information

Expression of ERK signaling inhibitors Dusp6, Dusp7, and Dusp9 during mouse ear development.

Publications

Expression of ERK signaling inhibitors Dusp6, Dusp7, and Dusp9 during mouse ear development.

Similar Datasets

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