Journal
CANCER CELL
Volume 29, Issue 3, Pages 367-378Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2016.02.012
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Funding
- National Institutes of Health [R01 CA081436-18, R21 CA151250-02, R01 CA14090-05]
- James and Esther King Biomedical Research Program [1KG-05-33971]
- Mayo Clinic Center for Individualized Medicine
- NIH Research Supplement to Promote Diversity in Health-related Research Award from the National Cancer Institute
- Edward C. Kendall Fellowship in Biochemistry from Mayo Clinic Graduate School
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We report that the protein kinase C iota (PKC iota) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKC iota activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKC iota-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKC iota-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKC iota and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKC iota-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC.
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