• 생명과학회지
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• 제26권7호
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• pp.868-874
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• 2016

수용체 상호작용 단백질 인산화 효소 RIPK1 (Receptor-interacting protein kinases 1)과 RIPK3은 고도로 보존된 인산화 효소 부위를 통하여 세린이나 트레오닌의 하이드록실기를 인산화하는 세린 또는 트레오닌-단백질 인산화 효소 군에 속한다. RIPK군은 염증이나 선천성 면역뿐 만 아니라 세포사멸이나 괴사와 같은 프로그램화된 세포사 멸을 중재하는데 중요한 역할을 담당한다. RIPK1과 다른 TNFR1 관련 단백질들의 상호작용은 TNF 수용체 1(TNFR1)에 사이토카인이 결합할 때 생존 촉진 전사인자 NF-κB의 활성을 조절하는 신호전달복합체 I을 조립하는 것으로 알려져 왔다. 뿐만 아니라, RIPK1과 RIPK3은 프로그램화된 세포괴사를 중재하는 RIP 동형 상호작용 모티브(RHIM)를 통하여 상호작용하고, 이러한 괴사는 세포사멸의 유형과는 다른 형태학적 특징을 가진 돌발적이고 제어되지 않는 세포사멸 유형으로 오랫동안 알려져 왔다. RIPK1과 RIPK3에 존재하는 RHIM의 고도로 보존된 서열들이 이들의 상호작용을 조절하며 이들은 necrosome이라 불리는 세포질 내 아밀로이드 복합체의 조립을 유도 한다. 또한 necrosome은 최근에 하위 신호전달을 조절하는 RIPK3의 기질로 확인된 혼합형 인산화 효소 도메인-유사 단백질(MLKL)을 포함한다. 본 리뷰는 TNF 신호전달에서 RIPK와 MLKL의 기능적, 생리적 특징들에 관한 개요를 제공한다.

• BMB Reports
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• 제48권6호
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• pp.303-312
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• 2015

Receptor-interacting protein kinase-3 (RIP3, or RIPK3) is an essential protein in the "programmed", or "regulated" necrosis cell death pathway that is activated in response to death receptor ligands and other types of cellular stress. Programmed necrotic cell death is distinguished from its apoptotic counterpart in that it is not characterized by the activation of caspases; unlike apoptosis, programmed necrosis results in plasma membrane rupture, thus spilling the contents of the cell and triggering the activation of the immune system and inflammation. Here we discuss findings, including our own recent data, which show that RIP3 protein expression is absent in many cancer cell lines. The recent data suggests that the lack of RIP3 expression in a majority of these deficient cell lines is due to methylation-dependent silencing, which limits the responses of these cells to pro-necrotic stimuli. Importantly, RIP3 expression may be restored in many cancer cells through the use of hypomethylating agents, such as decitabine. The potential implications of loss of RIP3 expression in cancer are explored, along with possible consequences for chemotherapeutic response. [BMB Reports 2015; 48(6): 303-312]

• BMB Reports
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• 제51권10호
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• pp.484-485
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• 2018

Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is a serine-threonine kinase largely essential for necroptotic cell death; it also plays a role in some inflammatory diseases. High levels of RIP3 are likely sufficient to activate necroptotic and inflammatory pathways downstream of RIP3 in the absence of an upstream stimulus. For example, we have previously detected high levels or RIP3 in the skin of Toxic Epidermal Necrolysis patients; this correlates with increased phosphorylation of MLKL found in these patients. We have long surmised that there are molecular mechanisms to prevent anomalous activity of the RIP3 protein, and so prevent undesirable cell death and inflammatory effects when inappropriately activated. Recent discovery that Carboxyl terminus of Hsp 70-Interacting Protein (CHIP) could mediate ubiquitylation- and lysosome-dependent RIP3 degradation provides a potential protein that has this capacity. However, while screening for RIP3-binding proteins, we discovered that pellino E3 ubiquitin protein ligase 1 (PELI1) also interacts directly with RIP3 protein; further investigation in this study revealed that PELI1 also targets RIP3 for proteasome-dependent degradation. Interestingly, unlike CHIP, which targets RIP3 more generally, PELI1 preferentially targets kinase active RIP3 that has been phosphorylated on T182, subsequently leading to RIP3 degradation.

• Asian Pacific Journal of Cancer Prevention
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• 제16권6호
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• pp.2569-2574
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• 2015

Necroptosis, also known as "programmed necrosis", has emerged as a critical factor in a variety of pathological and physiological processes and is considered a cell type-specific tightly regulated process with mechanisms that may vary rather greatly due to the change of cell line. Here we used HT-29, a human colon cancer cell line, to establish a necroptosis model and elucidate associated mechanisms. We discovered that cobalt chloride, a reagent that could induce hypoxia-inducible $factor-1{\alpha}(HIF1{\alpha})$ expression and therefore mimic the hypoxic microenvironment of tumor tissue in some aspects induces necroptosis in HT-29 cells when caspase activity is compromised. On the other hand, apoptosis appears to be the predominant death form when caspases are functioning normally. HT-29 cells demonstrated significantly increased RIPK1, RIPK3 and MLKL expression in response to cobalt chloride plus z-VAD treatment, which was accompanied by drastically increased $IL1{\alpha}$ and IL6 expression, substantiating the notion that necrosis can induce profound immune reactions. The RIPK1 kinase inhibitor necrostatin-1 and the ROS scavenger NAC each could prevent necrosis in HT-29 cells and the efficiency was enhanced by combined treatment. Thus by building up a necroptosis model in human colon cancer cells, we uncovered that mechanically RIP kinases collaborate with ROS during necrosis promoted by cobalt chloride plus z-VAD, which leads to inflammation. Necroptosis may present a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death.