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The Regulation of Mixed Lineage Kinase 3 by Extracellular Signal-Regulated Kinases 1 and 2 and Stress Stimuli in Colorectal and Ovarian Cancer Cells

Schroyer, April L
http://orcid.org/0000-0002-1711-1765
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1513345931716064

Abstract Details

2017, Doctor of Philosophy, University of Toledo, Biology (Cell-Molecular Biology).
Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K), which activates the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAPK pathways. Interestingly, MLK3 can activate the ERK1/2 pathway through either kinase-dependent or -independent mechanisms; in the latter, MLK3 serves as a scaffold for transactivation of v-Raf murine sarcoma viral oncogene homolog B (B-Raf) and v-Raf-1 murine leukemia viral oncogene homolog 1 (Raf-1). MLK3 can transform NIH 3T3 cells and functions in migration and/or invasion of several human cancers. Computational studies recently suggested both MLK3 and ERK2 as master regulators of colorectal cancer (CRC) invasion. Human colorectal tumors display increased levels of reactive oxygen species (ROS) or oxidative stress, which activates both MLK3 and MAPK signaling pathways in specific cellular contexts and is important for carcinogenesis. Therefore, we examined whether MLK3 promoted a malignant phenotype in CRC cells under oxidative stress. We found a ROS- and ERK1/2-dependent phosphorylation of MLK3 in H2O2-treated human colorectal carcinoma (HCT116) cells as well as an interaction between endogenous MLK3 and both endogenous ERK1/2 and B-Raf. Active ERK1 phosphorylated kinase dead FLAG-MLK3 in vitro, whereas ERK1 phosphorylation of kinase dead FLAG-MLK3-S705A-S758A was reduced. MLK3 siRNA knockdown as well as FLAG-MLK3-S705A-S758A expression decreased both ERK1/2 activation and CRC cell invasion in H2O2-treated cells. These results suggest oxidative stress stimulates an ERK1/2-dependent phosphorylation of MLK3 on Ser705 and Ser758, which promotes MLK3-dependent B-Raf, MEK1/2, and ERK1/2 activation; this positive feedback loop (PFL) enhances the invasion of colon cancer cells. We also explored mechanisms to control the amount of MLK3 protein in cancer cells and discovered geldanamycin (GA), heat shock, and osmotic stress all reduced the abundance of endogenous MLK3 protein in ovarian cancer cells.
Deborah Chadee, Ph.D. (Committee Chair)
William Taylor, Ph.D. (Committee Member)
Malathi Krishnamurthy, Ph.D. (Committee Member)
Ajith Karunarathne, Ph.D. (Committee Member)
Shah Zahoor, Ph.D. (Committee Member)
143 p.
Biology
MLK3; ERK1; ERK2; B-Raf; oxidative stress; colorectal cancer; geldanamycin

Recommended Citations

Citations

  • Schroyer, A. L. (2017). The Regulation of Mixed Lineage Kinase 3 by Extracellular Signal-Regulated Kinases 1 and 2 and Stress Stimuli in Colorectal and Ovarian Cancer Cells [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1513345931716064

    APA Style (7th edition)

  • Schroyer, April. The Regulation of Mixed Lineage Kinase 3 by Extracellular Signal-Regulated Kinases 1 and 2 and Stress Stimuli in Colorectal and Ovarian Cancer Cells. 2017. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1513345931716064.

    MLA Style (8th edition)

  • Schroyer, April. "The Regulation of Mixed Lineage Kinase 3 by Extracellular Signal-Regulated Kinases 1 and 2 and Stress Stimuli in Colorectal and Ovarian Cancer Cells." Doctoral dissertation, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1513345931716064

    Chicago Manual of Style (17th edition)

toledo1513345931716064
377
© 2017, some rights reserved.Creative Commons License The Regulation of Mixed Lineage Kinase 3 by Extracellular Signal-Regulated Kinases 1 and 2 and Stress Stimuli in Colorectal and Ovarian Cancer Cells by April L Schroyer is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Toledo and OhioLINK.