Advisory Committee Chair
J Michael Ruppert
Advisory Committee Members
Stuart Frank
Jeffrey Kudlow
Weei-Chin Lin
Susan Lobo-Ruppert
Document Type
Dissertation
Date of Award
2006
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Notch1 and KLF4 function in the specification of epithelial cell fates, and each can act as a context-dependent oncogene or tumor suppressor. We report that KLF4 directly regulates transcription of Notch1 and that cleavage of full-length Notch1 to the active intracellular form, N1IC, is necessary for transformation by KLF4. Paradoxically, KLF4 suppresses canonical Notch1-CSL signaling by up-regulating Hairless, an antagonist of this pathway. Dominant-negative inhibitors of the canonical Notch1 signaling pathway do not block transformation of epithelial cells by KLF4, while they greatly reduce the efficiency of transformation by N1IC. Thus, N1IC can transform cells by two distinct mechanisms: the canonical pathway in the absence of KLF4 and a noncanonical pathway in its presence. In human breast tumors, as in the skin of KLF4- transgenic mice, we observed a strong correlation between the expression of KLF4 and Notch1. The results identify KLF4 as a transcriptional regulator of Notch1 and a modulator of Notch1 signaling.
Recommended Citation
Liu, Zhaoli, "Klf4 Regulates Notch1 Expression And Signaling During Epithelial Transformation" (2006). All ETDs from UAB. 3752.
https://digitalcommons.library.uab.edu/etd-collection/3752
