TGF-β Pathway Genes Research Articles

A NEW MOLECULAR MODEL FOR REGULATING THE TGFβ RECEPTOR II PROMOTER IN PANCREATIC CELLS

KLF11, a TGFβ-inducible transcription factor that contains three distinct repressor domains, R1, R2, and R3, acts as a tumor suppressor for pancreatic cancer, at least in part, via the interaction of the R1 domain and the corepressor Sin3a-Histone deacetylase complex (HDAC). Although R1 has been credited with the gene repression activity of KLF11, previous results from our lab were seemingly paradoxical, such that KLF11 appears to silence certain promoters as a default long-term mechanism. Even oncogenic cascades, such as the K-ras-MEK-ERK pathway, inactivate the R1-Sin3 interaction, yet KLF11 is still active. Thus, other corepressors are clearly required to provide KLF11 with full gene silencing activity. In this study, we identified a consensus PxVxL HP1-interacting domain within the C-terminus of KLF11. HP1 proteins are "gatekeepers" of epigenetic gene silencing that is mediated by histone H3 lysine-9 methylation, and therefore a good candidate for involvement in KLF11-associated gene repression. Indeed, KLF11 interacts with HP1α in vitro, which is also dysregulated in pancreatic cancer. In addition, we observe an interaction between KLF11 and HP1 in vivo with several pancreatic cancer cells, using immunoprecipitation and biomolecular fluorescence complementation. Deletion of the PxVxL interacting domain eliminates HP1 binding to KLF11, without disrupting interaction with other co-repressor/co-activators. ChIP assays show that both KLF11 and HP1 bind the same promoter regions of important TGFβ pathway genes that KLF11 represses, such as SMAD3 and TGFβRII, suggesting that these proteins interact to regulate key promoters involved in pancreatic homeostasis and diseases, such as pancreatitis and pancreatic cancer. A KLF11 mutant in HP1 binding abolishes the repression activity of KLF11 on the TGFβRII promoter, facilitating activation of the promoter. Thus, these results offer a new model for the function of KLF11 which may not only work in transient repression via HDAC, but also in long term repression via histone methylation/HP1.