TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation
TL;DR: It is shown that TMBIM6 regulates AKT activation through mTORC2 assembly and ribosome association and an antagonist of TMBIm6 with anti-tumor properties is identified.
Abstract: Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca2+ channel-like protein, is highly up-regulated in several cancer types. Here, we show that TMBIM6 is closely associated with survival in patients with cervical, breast, lung, and prostate cancer. TMBIM6 deletion or knockdown suppresses primary tumor growth. Further, mTORC2 activation is up-regulated by TMBIM6 and stimulates glycolysis, protein synthesis, and the expression of lipid synthesis genes and glycosylated proteins. Moreover, ER-leaky Ca2+ from TMBIM6, a unique characteristic, is shown to affect mTORC2 assembly and its association with ribosomes. In addition, we identify that the BIA compound, a potentialTMBIM6 antagonist, prevents TMBIM6 binding to mTORC2, decreases mTORC2 activity, and also regulates TMBIM6-leaky Ca2+, further suppressing tumor formation and progression in cancer xenograft models. This previously unknown signaling cascade in which mTORC2 activity is enhanced via the interaction with TMBIM6 provides potential therapeutic targets for various malignancies. TMBIM6, a member of the transmembrane BI-1 motif-containing family of proteins, is overexpressed in many cancer types. Here, the authors show that TMBIM6 regulates AKT activation through mTORC2 assembly and ribosome association and identify an antagonist of TMBIM6 with anti-tumor properties.
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01 Feb 2009
TL;DR: It is shown that transformed human prostate epithelial cells lacking PTEN require mTORC2 to form tumors when injected into nude mice, and that deleting one copy of Rictor protects Pten heterozygous mice from prostate cancer.
Abstract: mTOR complex 2 (mTORC2) contains the mammalian target of rapamycin (mTOR) kinase and the Rictor regulatory protein and phosphorylates Akt. Whether this function of mTORC2 is critical for cancer progression is unknown. Here, we show that transformed human prostate epithelial cells lacking PTEN require mTORC2 to form tumors when injected into nude mice. Furthermore, we find that Rictor is a haploinsufficient gene and that deleting one copy protects Pten heterozygous mice from prostate cancer. Finally, we show that the development of prostate cancer caused by Pten deletion specifically in prostate epithelium requires mTORC2, but that for normal prostate epithelial cells, mTORC2 activity is nonessential. The selective requirement for mTORC2 in tumor development suggests that mTORC2 inhibitors may be of substantial clinical utility.
367 citations
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TL;DR: Wang et al. as mentioned in this paper investigated the functions and underlying mechanisms of TBX1 in CC Online database UALCAN showed that T-box transcription factor 1 (TBX1) was downregulated in CC tissues compared with normal tissues and patients with lower TBX 1 expression level had a poor prognosis.
Abstract: Cervical cancer (CC) is the fourth most common cancers among women worldwide T-box transcription factor 1 (TBX1), a member of the T-box family, has anti-tumor effects in some types of cancer, but its role in CC is yet unknown The aim of this study is to investigate the functions and underlying mechanisms of TBX1 in CC Online database UALCAN showed that TBX1 was down-regulated in CC tissues compared with normal tissues and patients with lower TBX1 expression level had a poor prognosis TBX1 overexpression significantly decreased the proliferation, migration, and invasion of Hela and SiHa cells Conversely, cell apoptosis and chemosensitivity to cisplatin were promoted in TBX1-overexpressing CC cells Moreover, up-regulation of TBX1 inhibited both AKT and MAPK signaling pathways Furthermore, dual luciferase report assay indicated that TBX1 could directly bind to miR-6727-5p In addition, TBX1 expression was inhibited by miR-6727-5p mimic and up-regulated by miR-6727-5p inhibitor Knockdown of TBX1 reversed the inhibitory effect of the miR-6727-5p inhibitor on CC cells This study demonstrates that TBX1, a target gene of miR-6727-5p, acts as a tumor suppressor in CC, indicating that TBX1 may be a new target for CC therapy
15 citations
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TL;DR: In this article , the role of transmembrane BAX inhibitor motif containing 6 (TMBIM6) in septic cardiomyopathy (SCM) was evaluated using mice.
Abstract: The regulatory mechanisms involved in mitochondrial quality control (MQC) dysfunction during septic cardiomyopathy (SCM) remain incompletely characterized. Transmembrane BAX inhibitor motif containing 6 (TMBIM6) is an endoplasmic reticulum protein with Ca2+ leak activity that modulates cellular responses to various cellular stressors.In this study, we evaluated the role of TMBIM6 in SCM using cardiomyocyte-specific TMBIM6 knockout (TMBIM6CKO) and TMBIM6 transgenic (TMBIM6TG) mice.Myocardial TMBIM6 transcription and expression were significantly downregulated in wild-type mice upon LPS exposure, along with characteristic alterations in myocardial systolic/diastolic function, cardiac inflammation, and cardiomyocyte death. Notably, these alterations were further exacerbated in LPS-treated TMBIM6CKO mice, and largely absent in TMBIM6TG mice. In LPS-treated primary cardiomyocytes, TMBIM6 deficiency further impaired mitochondrial respiration and ATP production, while defective MQC was suggested by enhanced mitochondrial fission, impaired mitophagy, and disrupted mitochondrial biogenesis. Structural protein analysis, Co-IP, mutant TMBIM6 plasmid transfection, and molecular docking assays subsequently indicated that TMBIM6 exerts cardioprotection against LPS-induced sepsis by interacting with and preventing the oligomerization of voltage-dependent anion channel-1 (VDAC1), the major route of mitochondrial Ca2+ uptake.We conclude that the TMBIM6-VDAC1 interaction prevents VDAC1 oligomerization and thus sustains mitochondrial Ca2+ homeostasis as well as MQC, contributing to improved myocardial function in SCM.
9 citations
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TL;DR: The role and molecular mechanisms of urease B subunit (UreB) involved in immune microenvironment dysregulation still remain largely unknown as mentioned in this paper, however, it has been shown that UreB-induced PD-L1 expression on BMDMs significantly decreased the proliferation and secretion of granzyme B and perforin of splenic CD8+ T cells isolated from inactivated H. pylori-immunized mice.
Abstract: As a key virulence factor for persistent colonization, urease B subunit (UreB) is considered to be an ideal vaccine antigen against Helicobacter pylori infection. However, the role and molecular mechanisms of UreB involved in immune microenvironment dysregulation still remain largely unknown. In the present study, we evaluated the effects of UreB on macrophage activation and found that UreB induced PD-L1 accumulation on bone marrow-derived macrophages (BMDMs). Co-culture assays further revealed that UreB-induced PD-L1 expression on BMDMs significantly decreased the proliferation and secretion of cytolytic molecules (granzyme B and perforin) of splenic CD8+ T cells isolated from inactivated H. pylori-immunized mice. More importantly, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation techniques, it has been confirmed that myosin heavy chain 9 (Myh9) is a direct membrane receptor for UreB and is required for PD-L1 up-regulation on BMDMs. Molecular studies further demonstrated that the interaction between UreB and Myh9 decreased GCN2 autophosphorylation and enhanced the intracellular pool of amino acids, leading to the up-regulation of S6K phosphorylation, a commonly used marker for monitoring activation of mTORC1 signaling activity. Furthermore, blocking mTORC1 activation with its inhibitor Temsirolimus reversed the UreB-induced PD-L1 up-regulation and the subsequent inhibitory effects of BMDMs on activation of cytotoxic CD8+ T-cell responses. Overall, our data unveil a novel immunosuppressive mechanism of UreB during H. pylori infection, which may provide valuable clues for the optimization of H. pylori vaccine.
8 citations
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TL;DR: In this paper, the authors investigated the previously unknown regulatory mechanism of TMBIM6 during age-associated hepatic abnormalities, and found that the re-expression of TMMI6 reduced IRE1α modifications, preserved ER homeostasis, reduced senescence, and increased hepatic lipid accumulation in aging and aging-associated liver diseases.
Abstract: Age-associated persistent ER stress is the result of declining chaperone systems of the ER that reduces cellular functions, induces apoptosis, and leads to age-related diseases. This study investigated the previously unknown regulatory mechanism of TMBIM6 during age-associated hepatic abnormalities. Wild-type (WT) and the TMBIM6 knockout (TMBIM6-/-) mice liver, human liver samples from different age groups were used to demonstrate the effect of physiological aging on liver. For TMBIM6 rescue experiments, TMBIM6-/- old mice and stable human hepatic cell lines expressing TMBIM 6 were used to study the functional role of TMBIM6 on aging-associated steatosis and its associated mechanisms. In aging humans and mice, we observed declined expression of TMBIM6 and aberrant UPR expression, which were associated with high hepatic lipid accumulation. During aging, TMBIM6-deficient mice had increased senescence than their WT counterparts. We identified redox-mediated posttranslational modifications of IRE1α such as S-nitrosylation and sulfonation were higher in TMBIM6-deficient aging mice and humans, which impaired the ER stress response signaling. Sulfonation of IRE1α enhanced regulated IRE1α-dependent decay (RIDD) activity inducing TMBIM6 decay, whereas S-nitrosylation of IRE1α inhibited XBP1 splicing enhancing the cell death. Moreover, the degradation of miR-338-3p by strong IRE1α cleavage activity enhanced the expression of PTP1B, resulting in diminishing phosphorylation of PERK. The re-expression of TMBIM6 reduced IRE1α modifications, preserved ER homeostasis, reduced senescence and senescence-associated lipid accumulation in human hepatic cells and TMBIM6-depleted mice. S-nitrosylation or sulfonation of IRE1α and its controller, the TMBIM6, might be the potential therapeutic targets for maintaining ER homeostasis in aging and aging-associated liver diseases.
6 citations
References
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01 Apr 2012
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.
6,268 citations
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TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.
5,792 citations
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TL;DR: In this paper, the rictor-mTOR complex was used to identify compounds which modulate Akt activity mediated by the Rictor mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activation.
Abstract: In certain aspects, the invention relates to methods for identifying compounds which modulate Akt activity mediated by the rictor-mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activity.
5,430 citations
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TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR signaling network contributes to human disease is highlighted.
4,719 citations
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TL;DR: Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.
Abstract: In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.
3,641 citations