Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis

Van, Trieu-My; Polykratis, Apostolos; Straub, Beate K.; Kondylis, Vangelis; Papadopoulou, Nikoletta; Pasparakis, Manolis

doi:10.1172/jci92508

Cited by 31 publications

(35 citation statements)

References 50 publications

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“…59 Lack of RIPK1 kinase activity did not inhibit DEN-induced liver tumor formation, confirming that kinase-independent functions of RIPK1 promote carcinogenesis in a TNFR1-dependent manner. 59 An interesting finding here was that unlike previous studies, RIPK1-LPCKO resulted in impaired NFκB signaling and reduction in the TNF-induced expression of A20, baculoviral IAP repeat-containing 3 (Birc3), nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor-α (Nfkbia), and TNF. 59 It has now been shown in multiple models that knockdown and knockout of RIPK1 in vivo sensitizes hepatocytes to TNF-mediated apoptotic cell death.…”

Section: Ripks In Hepatocellular Carcinomamentioning

confidence: 80%

“…118 Van et al have used the diethylnitrosamine (DEN)-induced HCC model in RIPK1-LPCKO mice and have also observed increase in apoptosis with RIPK1 deletion and reduction in tumor size. 59 Interestingly, while ablation of either RIPK1 or RelA in liver parenchymal cells did not cause spontaneous liver pathology, mice with combined deficiency of RIPK1 and RelA in LPCs showed increased hepatitis, increased hepatocyte apoptosis (cleaved caspase-3), and developed spontaneous chronic liver disease and cancer. 59 Lack of RIPK1 kinase activity did not inhibit DEN-induced liver tumor formation, confirming that kinase-independent functions of RIPK1 promote carcinogenesis in a TNFR1-dependent manner.…”

Section: Ripks In Hepatocellular Carcinomamentioning

confidence: 97%

“…59 Interestingly, while ablation of either RIPK1 or RelA in liver parenchymal cells did not cause spontaneous liver pathology, mice with combined deficiency of RIPK1 and RelA in LPCs showed increased hepatitis, increased hepatocyte apoptosis (cleaved caspase-3), and developed spontaneous chronic liver disease and cancer. 59 Lack of RIPK1 kinase activity did not inhibit DEN-induced liver tumor formation, confirming that kinase-independent functions of RIPK1 promote carcinogenesis in a TNFR1-dependent manner. 59 An interesting finding here was that unlike previous studies, RIPK1-LPCKO resulted in impaired NFκB signaling and reduction in the TNF-induced expression of A20, baculoviral IAP repeat-containing 3 (Birc3), nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor-α (Nfkbia), and TNF.…”

Section: Ripks In Hepatocellular Carcinomamentioning

confidence: 97%

“…Although RIPK1 seems to be dispensable for NFκB activation, some studies have suggested decreased expression of NFκB responsive genes without RIPK1. [57][58][59] RIPK1 and RIPK3 can participate in inflammatory pathways such as TLR signaling, cytokine production, NOD-like receptor protein 3 (NLRP3), and inflammasome activation independent of MLKL and their role as mediators of necroptosis. [60][61][62] The effect of RIPK1 and RIPK3 in inflammation was initially assumed to be due to the inflammatory nature of necroptotic cell death from MLKL-mediated plasma membrane rupture and release of intracellular immunogenic molecules.…”

Section: Ripks and Inflammationmentioning

confidence: 99%

“…The role of the RIPKs has been explored in a few models of HCC. 59,112,113 In the human hepatoma cell line HepG2 cells, deletion of RIPK1 or cFLIP sensitized to TRAIL mediated apoptosis. 114 Surprisingly, low RIPK1 expression which is seen in some human HCCs has been associated with a worse prognosis and decreased survival.…”

Section: Ripks In Hepatocellular Carcinomamentioning

confidence: 99%

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The Receptor Interacting Protein Kinases in the Liver

Dara

2018

Semin Liver Dis

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The Receptor Interacting serine/threonine Kinase1 and 3 (RIPK1, RIPK3) are regulators of cell death and survival. RIPK1 kinase activity is required for necroptosis and apoptosis, while its scaffolding function is necessary for survival. Although both proteins can mediate apoptosis, RIPK1 and RIPK3 are most well-known for their role in the execution of necroptosis via the pseudokinase mixed lineage domain like (MLKL). Necroptosis is a caspase-independent regulated cell death program which was first described in cultured cells with unknown physiologic relevance in the liver. Many recent reports have suggested that RIPK1 and/or RIPK3 participate in liver disease pathogenesis and cell death. Notably, both proteins have been shown to mediate inflammation independent of cell death. Whether necroptosis occurs in hepatocytes, and how it is executed in the presence of an intact caspase machinery is controversial. In spite of this controversy, it is evident that RIPK1 and RIPK3 participate in many experimental liver disease models. Therefore, in addition to cell death signaling, their necroptosis independent role warrants further examination.

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Section: Ripks In Hepatocellular Carcinomamentioning

confidence: 80%

Section: Ripks In Hepatocellular Carcinomamentioning

confidence: 97%

Section: Ripks In Hepatocellular Carcinomamentioning

confidence: 97%

Section: Ripks and Inflammationmentioning

confidence: 99%

Section: Ripks In Hepatocellular Carcinomamentioning

confidence: 99%

See 3 more Smart Citations

The Receptor Interacting Protein Kinases in the Liver

Dara

2018

Semin Liver Dis

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Targeting the Cdc2‐like kinase 2 for overcoming platinum resistance in ovarian cancer

Jiang,

Huang,

Zhang

et al. 2024

MedComm

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Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2‐like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum‐free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum‐induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP‐ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient‐derived xenografts, especially those with wild‐type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

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Receptor-interacting protein kinase-1 ablation in liver parenchymal cells promotes liver fibrosis in murine NASH without affecting other symptoms

et al. 2022

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We are grateful to Pr. M. Bertrand and Pr. P. Vandenabeele, both from the Inflammation Research Center, VIB (Belgium) for the provision of Ripk1 LPC-KO mice. We would like to thanks the "Laboratoire de Biochimie-Toxicologie" from the "CHU de Rennes" for transaminase measurements. For immunohistochemistry analysis, bead-based immunoassays, flow cytometry analysis and animal house facilities, we would like to acknowledge the dedicated platforms (i.e. H2P2, flow cytometry and cell sorting, and animal house platforms) of SFR Biosit -UMS 3480, US_S 018, France.

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Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis

Cited by 31 publications

References 50 publications

The Receptor Interacting Protein Kinases in the Liver

The Receptor Interacting Protein Kinases in the Liver

Targeting the Cdc2‐like kinase 2 for overcoming platinum resistance in ovarian cancer

Receptor-interacting protein kinase-1 ablation in liver parenchymal cells promotes liver fibrosis in murine NASH without affecting other symptoms

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