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12635 E. Montview Blvd., Suite 270
Aurora, CO 80045
P: (720) 859-4149
F: (720) 859-4158
Study of the radio-protective role of Kruppel-like Factor 4 following gamma-radiation induced gut injury
Investigator: Daniel Talmasov
Mentors: Vincent Yang, MD, PhD; Amr Ghaleb, PhD
Background: The zinc finger transcription factor, Krüppellike factor 4 (Klf4), is expressed in differentiated epithelial cells of small intestinal mucosa, and is associated with growth arrest. Our previous studies show that Klf4 inhibits apoptosis and induces cell-cycle arrest in irradiated cells in vitro.
Aim: To determine whether intestinal Klf4 contributes to mouse survival following whole body irradiation through actions in gut epithelium.
Methods: Mice with an intestinal epithelial specific deletion of Klf4 (Klf4ΔIS) and WT mice with floxed Klf4 gene (Klf4fl/fl) were exposed to total body γirradiation at 12Gy, and survival was tracked in a timecourse following irradiation. Mice were also sacrificed 6h, 24h, and 96h following irradiation. Immunofluorescence staining for Klf4, the apoptotic marker cleaved caspase3 and the proliferative marker Ki67, and p53 was performed on the small intestine. Numbers of positively stained cells were counted and irradiated groups were compared to each other and to nonirradiated controls.
Results: Survivorship was higher in Klf4fl/fl than in Klf4ΔIS mice. There was significantly greater apoptosis in Klf4ΔIS mice than in the Klf4fl/fl group at 6 hours, 24 hours, and 96 hours following irradiation. There was also significantly greater p53 expression in Klf4ΔIS than in Klf4fl/fl mice 6 hours and 24 hours following irradiation. At 96 hours following irradiation, there were slightly more actively cycling cells expressing Ki67 in Klf4fl/fl than in Klf4ΔIS mice, concurrent with this there was a change in the expression pattern of both Klf4 and Ki67 in Klf4fl/fl mice compared to unirradiated controls, with much a higher number of Klf4/Ki67 double positive cells, and an increased number of Klf4 positive cells in the proliferative zone marked by Ki67 expression.
Conclusion: Klf4 contributes to mouse survival following total body γ-irradiation, and its absence results in greater apoptosis and greater p53 expression. Klf4 is also associated with the regenerative response of gut epithelium in the days following irradiation.
**Previously presented at the 2014 ASCI/AAP Joint Meeting.
Last Updated: 7/31/2014
Updated on July 31, 2014.