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-kappaB (NF-kappaB) activation-regulates p27(Kip1) levels and cell-cycle progression. RIP1 regulates p27(Kip1) levels by an NF-kappaB-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.
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, USA.
Seongmi
S
Park
Deepti B
DB
Ramnarain
Kimmo J
KJ
Hatanpaa
Bruce E
BE
Mickey
Debabrata
D
Saha
Ramasamy
R
Paulmurugan
Christopher J
CJ
Madden
Paul S
PS
Wright
Salman
S
Bhai
M Aktar
MA
Ali
Krishna
K
Puttaparthi
Wei
W
Hu
Jeffrey L
JL
Elliott
Olaf
O
Stuve
Amyn A
AA
Habib
D016475:3T3 Cells; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002453:Cell Cycle; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D002867:Chromones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051858:Forkhead Transcription Factors; D020690:GTPase-Activating Proteins; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C490620:Ralbp1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one