The death domain-containing kinase RIP1 regulates p27^Kip1 levels through the PI3K-Akt-forkhead pathway

Elucidating the cross-talk between inflammatory and cell proliferation pathways might provide important insights into the pathogenesis of inflammation-induced cancer. Here, we show that the receptor-interacting protein 1 (RIP1) - an essential mediator of inflammation-induced nuclear factor-κB (NF-κB) activation-regulates p27^Kip1 levels and cell-cycle progression. RIP1 regulates p27^Kip1 levels by an NF-κB-independent signal that involves activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-forkhead pathway. Mouse embryonic fibroblasts (MEFs) from RIP1-knockout mice express high levels of p27^Kip1. Reconstitution of MEFs with RIP1 downregulates p27^Kip1 levels in a PI3K-dependent manner. RIP1 regulates p27^Kip1 at the messenger RNA level by regulating the p27^Kip1 promoter through the forkhead transcription factors. RIP1 expression blocks accumulation of cells in G₁ in response to serum starvation and favours cell-cycle progression. Finally, we show that overexpression of p27^Kip1 blocks the effects of RIP1 on the cell cycle. Thus, our study provides a new insight into how components of inflammatory and immune signalling pathways regulate cell-cycle progression.