Interplay among p21^Waf1/Cip1, MUSASHI-1 and Krüppel-like factor 4 in activation of Bmi1-Cre^ER reserve intestinal stem cells after gamma radiation-induced injury.

Gamma radiation is a commonly used adjuvant treatment for abdominally localized cancer. Since its therapeutic potential is limited due to gastrointestinal (GI) syndrome, elucidation of the regenerative response following radiation-induced gut injury is needed to develop a preventive treatment. Previously, we showed that Krüppel-like factor 4 (KLF4) activates certain quiescent intestinal stem cells (ISCs) marked by Bmi1-Cre^ER to give rise to regenerating crypts following γ irradiation. In the current study, we showed that γ radiation-induced expression of p21^Waf1/Cip1 in Bmi1-Cre^ER cells is likely mitigated by MUSASHI-1 (MSI1) acting as a negative regulator of p21^Waf1/Cip1 mRNA translation, which promotes exit of the Bmi1-Cre^ER cells from a quiescent state. Additionally, Bmi1-specific Klf4 deletion resulted in decreased numbers of MSI1⁺ cells in regenerating crypts compared to those of control mice. We showed that KLF4 binds to the Msi1 promoter and activates its expression in vitro. Since MSI1 has been shown to be crucial for crypt regeneration, this finding elucidates a pro-proliferative role of KLF4 during the postirradiation regenerative response. Taken together, our data suggest that the interplay among p21^Waf1/Cip1, MSI1 and KLF4 regulates Bmi1-Cre^ER cell survival, exit from quiescence and regenerative potential upon γ radiation-induced injury.

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