XMU-MP-1, an inhibitor of the STE20-like MST1/2 kinases of the Hippo signaling pathway, induces hematopoietic tumor cells death
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ABSTRACT:
PROVIDER: PRJNA1171483 | ENA |
REPOSITORIES: ENA
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Project description:In this study we have shown that treatment of hematopoietic cells with XMU-MP-1, the inhibitor of MST1/2, the key components of the Hippo signaling pathway, causes inhibition of cell population growth and increased levels of caspase 3/7 activity. RNA-Seq analysis has demonstrated that XMU-MP-1 suppresses the expression of the key cell cycle regulators in the Namalwa cells: E2F family transcription factors, cell division cycle genes (CDC6; CDC7; CDC20; CDC25A,В,С, and CDC45), cyclins CCNА2, CCNB1, CCNB2; MCM2-7, ORC1 and ORC6. At the same time, XMU-MP-1 triggers the activation of the genes regulating apoptosis, necroptosis, and autophagy. XMU-MP-1 increases the expression of the apoptosis activator genes APAF1, caspases 6 and 7, FAS; BBC3, BCL2A1, MOAP1; XAF1. Some Namalwa cells may undergo necroptosis: XMU-MP-1 causes an increase in the expression of the necroptosis activator genes RIPK1, TNFSF10, TRADD, and PEA15, the inhibitor of caspase 8. The expression of the key genes activating autophagy is significantly increased (beclin 1; DEPP1; DAP; VPS18; VPS39, and autophagy regulator AMBRA1). The activation of these three processes in the B-cell tumor population indicates a profound effect of XMU-MP-1 on cell death in hematopoietic tumor cells. The treatment of Namalwa cells with XMU-MP-1 decreases their resistance to doxorubicin. The use of MST1/2 kinase inhibitors in the treatment of hematologic tumors may be extremely promising.
2025-07-02 | GSE279247 | GEO
Project description:ShhCre;Mst1/2flx/flx (Mst1/2 D/D) mice were generated to conditionally delete Mst1 and Mst2 from epithelial progenitors during lung morphogenesis. Lungs from E18.5 control and Mst1/2 D/D mice were mechanically and enzymatically dissociated to generate single cell suspension. Epcam(+) cells were isolated using magnetic microbeads. Microarray analysis of mRNAs isolated from Epcam(+) epithelial cells from E18.5 control and Mst1/2 D/D mice was performed to identify transcriptional changes following deletion of the mammalian Hippo kinases (Mst1 and Mst2) from the embryonic lung. The mammalian Hippo kinases, Mst1 and Mst2, were conditionally deleted in epithelial progenitors of the developing lung using ShhCre. Epcam(+) epithelial cells were isolated from the lungs of E18.5 control and Mst1/2 deleted mice. mRNA isolated from Epcam(+) epithelial cells was analyzed by microarray.
2015-01-01 | E-GEOD-61582 | biostudies-arrayexpress
Project description:We aim to the investigate the role of MST1/2 inhibitor XMU-MP-1 in prostate cancer progression. C4-2 cells were used as the model.
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Project description:We aim to the investigate the role of MST1/2 inhibitor XMU-MP-1 in kindy renal clear cell carcinoma (ccRCC) progression. 786-O cells were used as the model.
2022-02-28 | GSE197468 | GEO
Project description:ShhCre;Mst1/2flx/flx (Mst1/2 D/D) mice were generated to conditionally delete Mst1 and Mst2 from epithelial progenitors during lung morphogenesis. Lungs from E18.5 control and Mst1/2 D/D mice were mechanically and enzymatically dissociated to generate single cell suspension. Epcam(+) cells were isolated using magnetic microbeads. Microarray analysis of mRNAs isolated from Epcam(+) epithelial cells from E18.5 control and Mst1/2 D/D mice was performed to identify transcriptional changes following deletion of the mammalian Hippo kinases (Mst1 and Mst2) from the embryonic lung.
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Project description:Hippo pathway is evolutionarily well conserved. All core components of the pathway identified to date have one or more mammalian orthologs, including MST1/2 (Hippo), SAV1 (Salvador, also known as WW45), LATS1/2 (Warts), MOB1 (Mats), YAP1 and its paralog WWTR1 (also known as TAZ) (Yorkie), and TEAD1/2/3/4 (Scalloped). Ectopic over-expression of YAP1 in mouse liver led to develop hepatocellular carcinoma (HCC). HCC is the third most common cause of cancer-related death in the world, and accounts for an estimated 600,000 deaths annually. Lack of molecular classification and clinical heterogeneity of this malignant disease hampered the development of standardized treatment. To investigate roles of Hippo pathway in liver carcinogenesis, we generated liver-specific Mst1/2 -/- and Sav1 -/- mouse models and collected gene expression data from them. Our study provided new understanding on molecular characteristics of HCC. Sav1 and Mst1/2 Knockout models
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Project description:Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the PAX3-FOXO1 fusion gene. Despite its discovery over almost 20 years ago, PAX3-FOXO1 remains an enigmatic tumor driver. Previously, we reported that PAX3-FOXO1 supports aRMS initiation by enabling bypass of cellular senescence. Here, we show that bypass occurs in part by PAX3-FOXO1-mediated upregulation of RASSF4, a Ras-association domain family (RASSF) member, which then suppresses the evolutionarily conserved mammalian Hippo/Mst1 pathway. RASSF4 loss-of-function activates Hippo/Mst1 and inhibits downstream YAP, causing aRMS cell cycle arrest and senescence. This is the first evidence for an oncogenic role for RASSF4, and a novel mechanism for Hippo signaling suppression in human cancer. Human skeletal muscle myoblasts (HSMMs) were retrovirally transduced with either an empty vector (Vp, pK1) or PAX3-FOXO1 (PFp, pK1-PAX3-FOXO1) and selected on puromycin. Presenescent (presen) cells were harvested before the senescence checkpoint. Since cells expressing PAX3-FOXO1 can bypass the senescence checkpoint, postsenescent (postsen) cells expressing PAX3-FOXO1 were also harvested. the gene expression affected by the introduction of PAX3-FOXO1
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Project description:The Hippo Pathway has been found to play an important role in adrenal gland development and maintenance in mice. In this study, we further explored the role of the Hippo pathway in the adrenal gland using a transgenic mouse model where we knocked out the upstream kinases of the pathway, Mst1 and Mst2.
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Project description:Hippo kinases Mst1 and Mst2 act as molecular rheostats for the terminal maturation and effector differentiation programs of iNKT cells. Loss of Mst1 alone or with Mst2 impedes iNKT cell development, associated with defective IL-15-dependent cell survival
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Project description:The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR hetero-protein complexes. However, genetic analysis suggests that the availability of WWC1 is constrained by its interaction with the Hippo kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction. A proteome-wide analysis of kinase inhibition in SH-SY5Y neuroblastoma cell line using the kinobead assay identified the upstream kinases MST1/2 as two major targets of the small molecule inhibitor XMU-MP1 (hereafter, MSTi)and Luteolin.Upon pharmacological inhibition of MST1/2 in male mice and human brain organoids WWC1 dissociated from LATS1/2, resulting in increased abundance of WWC1 in AMPAR complexes. Moreover, MSTi enhanced synaptic transmission in mouse hippocampal brain slices, and improved cognition in healthy male mice and in male mouse models of Alzheimer’s disease and ageing. Thus, blocking WWC1-LATS1/2 binding might be explored for development as cognitive enhancers.
2024-05-03 | PXD050351 | Pride