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Published on: October 6, 2014
Krüppel-like factor 5 mediates cellular transformation during oncogenic KRAS-induced intestinal tumorigenesis
Mandayam O Nandan1, Beth B McConnell, Amr M Ghaleb
1Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia, USA.
Background & Aims:
Krüppel-like factor 5 (KLF5) is a zinc finger-transcription factor that regulates cell proliferation. Oncogenic KRAS mutations are commonly found in colorectal cancers. We aimed to determine whether KLF5 mediates KRAS functions during intestinal tumorigenesis.
Methods:
The effects of KLF5 on proliferation and transformation were examined in IEC-6 intestinal epithelial cells stably transfected with inducible KRAS(V12G). KLF5 expression was examined in intestinal tumors derived from transgenic mice expressing KRAS(V12G) under villin promoter and in human colorectal cancers with mutated KRAS.
Results:
Induction of KRAS(V12G) in IEC-6 cells resulted in increased expression of KLF5, accompanied by increased rates of proliferation and anchorage-independent growth. Inhibition of KLF5 expression by mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitors or KLF5-specific small interfering RNA reduced proliferation and anchorage-independent growth despite KRAS(V12G) induction. Human colorectal cancer cell lines with mutated KRAS contained high levels of KLF5 and reduction of KLF5 by MEK inhibitors or KLF5 small interfering RNA also led to reduced proliferation and transformation. In vivo, both intestinal tumors derived from mice transgenic for villin-KRAS(V12G) and human primary colorectal cancers with mutated KRAS contained high levels of KLF5 and increased staining of the proliferative marker Ki67.
Conclusions:
Elevated levels of KLF5 protein are strongly correlated with activating KRAS mutations in intestinal tumors in vitro and in vivo. Inhibition of KLF5 expression in tumor cells resulted in significantly reduced rates of proliferation and transforming activities. We conclude that KLF5 is an important mediator of oncogenic KRAS transforming functions during intestinal tumorigenesis.
Insights
Krüppel-like factor 5 (KLF5) mediates oncogenic KRAS functions in colorectal cancer. Inhibiting KLF5 reduces tumor cell proliferation and transformation, highlighting its role in intestinal tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Krüppel-like factor 5 (KLF5) is a transcription factor regulating cell proliferation.
- Activating KRAS mutations are prevalent in colorectal cancers.
- The role of KLF5 in KRAS-driven intestinal tumorigenesis requires elucidation.
Purpose of the Study:
- To investigate if KLF5 mediates KRAS functions during intestinal tumorigenesis.
- To assess the impact of KLF5 inhibition on KRAS-mutated cancer cells.
Main Methods:
- Examined KLF5 effects on intestinal epithelial cell proliferation and transformation.
- Utilized inducible KRAS(V12G) expression in IEC-6 cells.
- Analyzed KLF5 expression in mouse models and human colorectal cancers with KRAS mutations.
Main Results:
- KRAS(V12G) induction increased KLF5 expression, proliferation, and anchorage-independent growth.
- MEK inhibitors or KLF5 siRNA reduced proliferation and transformation despite KRAS(V12G).
- Human colorectal cancers with KRAS mutations showed high KLF5 levels and proliferation.
Conclusions:
- Elevated KLF5 protein correlates with activating KRAS mutations in intestinal tumors.
- KLF5 inhibition significantly reduced tumor cell proliferation and transformation.
- KLF5 is a key mediator of oncogenic KRAS transforming functions in intestinal tumorigenesis.
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