Regulation of Kruppel-like Factor 4 by the Anaphase Promoting Complex Pathway Is Involved in TGF-β Signaling

Kruppel-like factor 4 (KLF4), a zinc finger-containing transcriptional factor, regulates a variety of biological processes, including cell proliferation, differentiation, apoptosis, and stem cell reprogramming. Post-translational modifications of KLF4, including phosphorylation, acetylation, and sumoylation, regulate its transcriptional activity. Most recent studies also demonstrate that KLF4 is targeted for ubiquitin-dependent proteolysis during cell cycle progression. However, the underlying mechanism remains largely unknown. In this study, we demonstrated that KLF4 is profoundly degraded in response to TGF-beta signaling. We have identified the Cdh1-anaphase promoting complex as a putative E3 ligase that governs TGF-beta-induced KLF4 degradation. The TGF-beta-induced KLF4 degradation is mediated by the destruction box on the KLF4. Either depletion of Cdh1 by RNA interference or stabilization of KLF4 by disruption of its destruction box significantly attenuates TGF-beta-induced ubiquitylation and degradation. In addition, depletion of Cdh1 or stabilization of KLF4 antagonizes TGF-beta-induced activation of transcription. Determining the role of KLF4 proteolysis in response to TGF-beta signaling has opened a new perspective to understand the TGF-beta signaling pathway.