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The death domain‐containing kinase RIP1 regulates p27 Kip1 levels through the PI3K–Akt–forkhead pathway
Author(s) -
Park Seongmi,
Ramnarain Deepti B,
Hatanpaa Kimmo J,
Mickey Bruce E,
Saha Debabrata,
Paulmurugan Ramasamy,
Madden Christopher J,
Wright Paul S,
Bhai Salman,
Ali M Aktar,
Puttaparthi Krishna,
Hu Wei,
Elliott Jeffrey L,
Stuve Olaf,
Habib Amyn A
Publication year - 2008
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2008.102
Subject(s) - microbiology and biotechnology , pi3k/akt/mtor pathway , protein kinase b , biology , signal transduction , kinase , transcription factor , cell cycle , mediator , foxo3 , cell growth , foxo1 , cell , biochemistry , gene
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 G 1 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.