Therefore coordinated transcriptional and post-translational repression of pro-apoptotic MLK3 probably is one of the mechanisms by which ER+ breast cancer cells proliferate and survive.
Here we report that in non-metastatic, estrogen receptor-positive breast cancer (ER+ BC) cells, induced MLK3 expression robustly upregulates the oncogenic transcription factor, FOS-related antigen-1 (FRA-1), which is accompanied by elevation of matrix metalloproteinases (MMPs), MMP-1 and MMP-9.
These results suggest that mammalian PAK1 does not act as a MAP4K and MLK3-induced direct activation of PAK1 plays a key role in breast cancer tumorigenesis.
To assess MLK3's contribution to the breast cancer malignant phenotype in a more physiological setting, we implemented a strategy to inducibly express active MLK3 in the preformed acini of MCF10A cells grown in 3D Matrigel.
Furthermore, S705A-S758A-FLAG-MLK3 demonstrated decreased oxidative-stress induced colon cancer cell invasion, but increased interaction with GST-B-Raf as compared with wild-type-FLAG-MLK3 in H<sub>2</sub>O<sub>2</sub>-treated cells.
DUSP2 rs1724120 [hazard rate ratio (HRR) = 0.72, 95%CI = 0.54, 0.96; AA versus GG/GA), MAP3K10 rs112956 (HRR = 1.40, 95% CI = 1.10, 1.76; CT/TT versus CC) and MAP3K11 (HRR = 1.76, 95% CI 1.18, 2.62 TT versus GG/GT) influenced survival after diagnosis with colon cancer; MAP2K1 rs8039880 (HRR = 2.53, 95% CI 1.34, 4.79 GG versus AG/GG) and Raf1 rs11923427 (HRR = 0.59 95% CI = 0.40, 0.86; AA versus TT/TA) were associated with rectal cancer survival.
Based on the facts that MLK3 is one client protein of HSP90 and MLK3 pathway induces FasL expression in ischemic brain injury, our study suggests one of the mechanisms of neuroprotection against brain ischemia from GA.
The results provide an overall view of the expression profile associated with mutant MLK3, and they support the functional role of mutant MLK3 by showing a deregulation of several signaling pathways known to play important roles in the development and progression of colorectal cancer.
In human colorectal carcinoma (HCT116) cells treated with H<sub>2</sub>O<sub>2</sub>, extracellular signal-regulated kinases 1 and 2 (ERK1/2) were activated and MLK3 exhibited reduced electrophoretic mobility (shift) in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), which was eliminated by phosphatase treatment.
Our studies indicated that MLK3 can induce β-catenin expression via post-translational stabilization in various cancer cells, including prostate cancer.
Mixed lineage kinase 3 connects reactive oxygen species to c-Jun NH2-terminal kinase-induced mitochondrial apoptosis in genipin-treated PC3 human prostate cancer cells.
Mixed lineage kinase 3 connects reactive oxygen species to c-Jun NH2-terminal kinase-induced mitochondrial apoptosis in genipin-treated PC3 human prostate cancer cells.
Our studies indicated that MLK3 can induce β-catenin expression via post-translational stabilization in various cancer cells, including prostate cancer.
These results suggest that mammalian PAK1 does not act as a MAP4K and MLK3-induced direct activation of PAK1 plays a key role in breast cancer tumorigenesis.
To assess MLK3's contribution to the breast cancer malignant phenotype in a more physiological setting, we implemented a strategy to inducibly express active MLK3 in the preformed acini of MCF10A cells grown in 3D Matrigel.
In this study, 174 primary gastrointestinal cancers (48 hereditary and 126 sporadic forms) and 7 colorectal cancer cell lines were screened for MLK3 mutations.
Furthermore, S705A-S758A-FLAG-MLK3 demonstrated decreased oxidative-stress induced colon cancer cell invasion, but increased interaction with GST-B-Raf as compared with wild-type-FLAG-MLK3 in H<sub>2</sub>O<sub>2</sub>-treated cells.
DUSP2 rs1724120 [hazard rate ratio (HRR) = 0.72, 95%CI = 0.54, 0.96; AA versus GG/GA), MAP3K10 rs112956 (HRR = 1.40, 95% CI = 1.10, 1.76; CT/TT versus CC) and MAP3K11 (HRR = 1.76, 95% CI 1.18, 2.62 TT versus GG/GT) influenced survival after diagnosis with colon cancer; MAP2K1 rs8039880 (HRR = 2.53, 95% CI 1.34, 4.79 GG versus AG/GG) and Raf1 rs11923427 (HRR = 0.59 95% CI = 0.40, 0.86; AA versus TT/TA) were associated with rectal cancer survival.