The death domain-containing kinase RIP1 regulates p27Kip1 levels through the PI3K-Akt-forkhead pathway

Seongmi Park, Deepti B. Ramnarain, Kimmo J. Hatanpaa, Bruce E. Mickey, Debabrata Saha, Ramasamy Paulmurugan, Christopher J. Madden, Paul S. Wright, Salman Bhai, M. Aktar Ali, Krishna Puttaparthi, Wei Hu, Jeffrey L. Elliott, Olaf Stuve, Amyn A. Habib

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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 p27Kip1 levels and cell-cycle progression. RIP1 regulates p27Kip1 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 p27Kip1. Reconstitution of MEFs with RIP1 downregulates p27Kip1 levels in a PI3K-dependent manner. RIP1 regulates p27Kip1 at the messenger RNA level by regulating the p27Kip1 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 p27Kip1 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.

Original languageEnglish (US)
Pages (from-to)766-773
Number of pages8
JournalEMBO Reports
Volume9
Issue number8
DOIs
StatePublished - 2008

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Receptor-Interacting Protein Serine-Threonine Kinases
Phosphatidylinositol 3-Kinase
Phosphotransferases
Cells
Cell Cycle
Fibroblasts
Chemical activation
Forkhead Transcription Factors
Inflammation Mediators
Cell proliferation
Starvation
Death Domain
Knockout Mice
Down-Regulation
Cell Proliferation
Inflammation
Messenger RNA
Serum

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

The death domain-containing kinase RIP1 regulates p27Kip1 levels through the PI3K-Akt-forkhead pathway. / 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.

In: EMBO Reports, Vol. 9, No. 8, 2008, p. 766-773.

Research output: Contribution to journalArticle

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. / The death domain-containing kinase RIP1 regulates p27Kip1 levels through the PI3K-Akt-forkhead pathway. In: EMBO Reports. 2008 ; Vol. 9, No. 8. pp. 766-773.
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