更新于：2024-05-01
MLKL
mixed lineage kinase domain like pseudokinase
更新于：2024-05-01
基本信息
别名 FLJ34389、hMLKL、mixed lineage kinase domain like pseudokinase + [3] |
简介 Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Does not have protein kinase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following activation by ZBP1, MLKL is phosphorylated by RIPK3 in the nucleus, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol.following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (By similarity). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (PubMed:29883610). |
关联
靶点 |
作用机制 |
在研机构 |
原研机构 |
在研适应症 |
非在研适应症 |
最高研发阶段 |
首次获批国家/地区 |
首次获批日期 |
100 项与 MLKL 相关的临床结果
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100 项与 MLKL 相关的转化医学
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2024-02-24BMC complementary medicine and therapies
JianPiYiShen formula prevents cisplatin-induced acute kidney injury in mice by improving necroptosis through MAPK pathway.
Article
作者: Zhongtang Li ; Riming He ; Jiahui Liu ; Xiaoming Jin ; Beibei Jiang ; Yunlan Lao ; Shudong Yang
BACKGROUND:
Acute kidney injury (AKI), characterized by necroptosis and activation of MAPK pathway, causes sudden declines in renal function. To date, efficacious treatments are lacking. JianPiYiShen Formula (JPYSF) has a protective effect on the kidneys. The aim of this study is to explore the mechanism of JPYSF in cisplatin-induced AKI.
METHODS:
Male C57/BL6J mice were divided into control group, cisplatin group and cisplatin + JPYSF group. Before establishing the model, the cisplatin + JPYSF group was administered JPYSF (18.35 g/kg/day) by gavage for 5 consecutive days. A single intraperitoneal injection of cisplatin (20 mg/kg) was used to establish AKI model. Measurement of renal function and H&E staining were performed to assess renal damage. WB, PCR, TUNEL staining and immunohistochemistry were used to detect related indicators of mitochondrial function, oxidative stress, necroptosis, inflammation and MAPK pathway. And one-way analysis of variance was used to compare group differences.
RESULTS:
Compared with the cisplatin group, JPYSF can attenuate AKI, reflected by the decrease in Scr and BUN levels, the improvement of renal tubular injury, and the downregulation of NGAL and KIM1. Cisplatin can induce mitochondrial dysfunction and oxidative stress, triggering necroptosis. In this study, JPYSF improved mitochondrial dysfunction to enhance oxidative stress, as manifested by upregulation of OPA1, PGC-1α, SOD and CAT, and downregulation of DRP1 and MFF. Then JPYSF showed a significant protective effect in necroptosis, as embodied by reduced number of TUNEL-positive cells, decreased the gene expression of RIPK3 and MLKL, as well as downregulation the proteins expression of P-RIPK1, P-RIPK3, and P-MLKL. Moreover, necroptosis can aggravate inflammation. JPYSF ameliorated inflammation by improving inflammatory and anti-inflammatory indexes, including downregulation of TNF-α, IL-6, MCP-1 and LY6G, and upregulation of IL-10. In addition, JPYSF also inhibited MAPK pathway to improve necroptosis by decreasing the expression of P-JNK and P-ERK.
CONCLUSION:
Our data showed that JPYSF prevents cisplatin-induced AKI by improving necroptosis through MAPK pathway, which is related to the improvement of mitochondrial dysfunction, oxidative stress, and inflammation.
2024-02-22Scientific reports
Polyunsaturated fatty acids-induced ferroptosis suppresses pancreatic cancer growth.
Article
作者: Akane Suda ; Banlanjo Abdulaziz Umaru ; Yui Yamamoto ; Hiroki Shima ; Yuriko Saiki ; Yijun Pan ; Liang Jin ; Jiaqi Sun ; Yi Ling Clare Low ; Chitose Suzuki ; Takaaki Abe ; Kazuhiko Igarashi ; Toru Furukawa ; Yuji Owada ; Yoshiteru Kagawa
Despite recent advances in science and medical technology, pancreatic cancer remains associated with high mortality rates due to aggressive growth and no early clinical sign as well as the unique resistance to anti-cancer chemotherapy. Current numerous investigations have suggested that ferroptosis, which is a programed cell death driven by lipid oxidation, is an attractive therapeutic in different tumor types including pancreatic cancer. Here, we first demonstrated that linoleic acid (LA) and α-linolenic acid (αLA) induced cell death with necroptotic morphological change in MIA-Paca2 and Suit 2 cell lines. LA and αLA increased lipid peroxidation and phosphorylation of RIP3 and MLKL in pancreatic cancers, which were negated by ferroptosis inhibitor, ferrostatin-1, restoring back to BSA control levels. Similarly, intraperitoneal administration of LA and αLA suppresses the growth of subcutaneously transplanted Suit-2 cells and ameliorated the decreased survival rate of tumor bearing mice, while co-administration of ferrostatin-1 with LA and αLA negated the anti-cancer effect. We also demonstrated that LA and αLA partially showed ferroptotic effects on the gemcitabine-resistant-PK cells, although its effect was exerted late compared to treatment on normal-PK cells. In addition, the trial to validate the importance of double bonds in PUFAs in ferroptosis revealed that AA and EPA had a marked effect of ferroptosis on pancreatic cancer cells, but DHA showed mild suppression of cancer proliferation. Furthermore, treatment in other tumor cell lines revealed different sensitivity of PUFA-induced ferroptosis; e.g., EPA induced a ferroptotic effect on colorectal adenocarcinoma, but LA or αLA did not. Collectively, these data suggest that PUFAs can have a potential to exert an anti-cancer effect via ferroptosis in both normal and gemcitabine-resistant pancreatic cancer.
2024-02-21Recent patents on anti-cancer drug discovery
UBE2L3 Promotes Oxidative Stress-regulated Necroptosis to Accelerate Osteosarcoma Progression.
Article
作者: Xiwu Zhao ; Guoqiang Shan ; Deguo Xing ; Hongwei Gao ; Zhenggang Xiong ; Wenpeng Hui ; Mingzhi Gong
BACKGROUND:
Osteosarcoma is a highly invasive bone marrow stromal tumor with limited treatment options. Oxidative stress plays a crucial role in the development and progression of tumors, but the underlying regulatory mechanisms are not fully understood. Recent studies have revealed the significant involvement of UBE2L3 in oxidative stress, but its specific role in osteosarcoma remains poorly investigated.
OBJECTIVE:
This study aimed to explore the molecular mechanisms by which UBE2L3 promotes oxidative stress-regulated necroptosis to accelerate the progression of osteosarcoma using in vitro cell experiments.
METHODS:
Human osteoblast hFOB1.19 cells and various human osteosarcoma cell lines (MG-63, U2OS, SJSA-1, HOS, and 143B) were cultured in vitro. Plasmids silencing UBE2L3 and negative control plasmids were transfected into U2OS and HOS cells. The cells were divided into the following groups: U2OS cell group, HOS cell group, si-NC-U2OS cell group, si-UBE2L3-U2OS cell group, si-NC-HOS cell group, and si-UBE2L3-HOS cell group. Cell viability and proliferation capacity were measured using the Tunnel method and clonogenic assay. Cell migration and invasion abilities were assessed by Transwell and scratch assays. Cell apoptosis was analyzed by flow cytometry, and ROS levels were detected using immunofluorescence. The oxidative stress levels in various cell groups and the expression changes of necroptosis-related proteins were assessed by PCR and WB. Through these experiments, we aim to evaluate the impact of oxidative stress on necroptosis and uncover the specific mechanisms by which targeted regulation of oxidative stress promotes tumor cell necroptosis as a potential therapeutic strategy for osteosarcoma.
RESULTS:
The mRNA expression levels of UBE2L3 in human osteosarcoma cell lines were significantly higher than those in human osteoblast hFOB1.19 cells (p <0.01). UBE2L3 expression was significantly decreased in U2OS and HOS cells transfected with si-UBE2L3, indicating the successful construction of stable cell lines with depleted UBE2L3. Tunnel assay results showed a significant increase in the number of red fluorescent-labeled cells in si-UBE2L3 groups compared to si-NC groups in both cell lines, suggesting a pronounced inhibition of cell viability. Transwell assay demonstrated a significant reduction in invasion and migration capabilities of si-UBE2L3 groups in osteosarcoma cells. The clonogenic assay revealed significant suppression of proliferation and clonogenic ability in both U2OS and HOS cells upon UBE2L3 knockdown. Flow cytometry confirmed that UBE2L3 knockdown significantly enhanced apoptosis in U2OS and HOS cells. Immunofluorescence results showed that UBE2L3 silencing promoted oxidative stress levels in osteosarcoma cells and facilitated tumor cell death. WB analysis indicated a significant increase in phosphorylation levels of necroptosis-related proteins, RIP1, RIP3, and MLKL, in both osteosarcoma cell lines after UBE2L3 knockdown. In addition, the expression of necrosis-associated proteins was inhibited by the addition of the antioxidant N-acetylcysteine (NAC).
CONCLUSION:
UBE2L3 is upregulated in osteosarcoma cells, and silencing of UBE2L3 promotes oxidative stress in these cells, leading to enhanced necroptosis and delayed progression of osteosarcoma.
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