MAP4K3 modulates cell death via the post-transcriptional regulation of BH3-only proteins

Lam, David; Dickens, David; Reid, Elizabeth; Loh, Samantha H. Y.; Moisoi, Nicoleta; Martins, L. Miguel

doi:10.1073/pnas.0900608106

Cited by 35 publications

(40 citation statements)

References 18 publications

(22 reference statements)

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“…One candidate for posttranscriptional regulation of mRNA for BAD is the newly described kinase, MAP4K3, that plays a role in DNA damage-induced cell death [41]. MAP4K3 functions by activating the mammalian target of rapamycin (mTOR) pathway.…”

Section: Discussionmentioning

confidence: 99%

Developmental Changes in Expression of Genes Involved in Regulation of Apoptosis in the Bovine Preimplantation Embryo1

Fear

Hansen

2011

Biology of Reproduction

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The early bovine preimplantation embryo is resistant to proapoptotic signals until around the 8- to 16-cell stage. We hypothesized that 2-cell embryos have higher amounts of antiapoptotic proteins and lower amounts of proapoptotic proteins when compared to embryos ≥16 cells. Steady-state concentrations of mRNA for the antiapoptotic genes BCL2 and HSPA1A were higher for MII oocytes, 2-cell embryos, and 2-cell embryos treated with alpha-amanitin as compared to ≥16-cell embryos. Steady-state concentrations of mRNA for the proapoptotic gene BAD increased in embryos ≥16 cells. There was no significant effect of stage of development on steady-state mRNA concentrations of BCL2L1, DFFA, or BAX. Using immunohistochemistry, it was found that BCL2 was present in greater relative concentrations for 2-cell embryos than for embryos ≥16 cells. These results were confirmed by Western blotting. Relative amounts of immunoreactive BAX detected by immunofluorescence were lower for 2-cell embryos than for embryos ≥16 cells. Using Western blotting, a high molecular weight (46 kDa) form of BAX was highest in ≥16-cell embryos, intermediate in 2-cell embryos, and lowest in MII oocytes. There were no effects of stage of development on relative amounts of immunoreactive BCL2L1, HSPA1A, or BAD, as determined by immunofluorescence. Treatment of embryos with alpha-amanitin from Day 0 to Day 5 or Day 4 to Day 5 after insemination reduced activation of group II caspases and terminal deoxynucleotidyl transferase dUTP nick end labeling after treatment with the proapoptotic signal C(2) ceramide at Day 5 after fertilization. Thus, transcription of BAX or other proteins is required for acquisition of the capacity for apoptosis. Results support the idea that changes in amounts of BCL2 family members are important for the inhibition of apoptosis in the 2-cell embryo and in the establishment of the capacity for apoptosis later in development.

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Section: Discussionmentioning

confidence: 99%

Developmental Changes in Expression of Genes Involved in Regulation of Apoptosis in the Bovine Preimplantation Embryo1

Fear

Hansen

2011

Biology of Reproduction

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“…They include MAP4K3 (FDR = 0.14, ranked 9th out of 7,115), a tumor suppressor kinase in the mitogenactivated protein kinase (MAPK) pathway which induces apoptosis [9][10][11]22], and EPM2A (FDR = 0.14, ranked 10th out of 7,115), another protein phosphatase that negatively regulates cell cycle progression [7,23]. From the ESC dataset, TRP53, a mouse ortholog of the human TP53 tumor suppressor gene [8,24], was ranked first out of the three positively selected genes identified.…”

Section: Mageck Allows Bi-directional Screening and Cell-type-specifimentioning

confidence: 99%

MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens

et al. 2014

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We propose the Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout (MAGeCK) method for prioritizing single-guide RNAs, genes and pathways in genome-scale CRISPR/Cas9 knockout screens. MAGeCK demonstrates better performance compared with existing methods, identifies both positively and negatively selected genes simultaneously, and reports robust results across different experimental conditions. Using public datasets, MAGeCK identified novel essential genes and pathways, including EGFR in vemurafenib-treated A375 cells harboring a BRAF mutation. MAGeCK also detected cell type-specific essential genes, including BCR and ABL1, in KBM7 cells bearing a BCR-ABL fusion, and IGF1R in HL-60 cells, which depends on the insulin signaling pathway for proliferation.

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“…MAP4K3 has been recently identified as a novel proapoptotic kinase that regulates BAX (BCL2 associated X protein) activation, and its expression was down-regulated in pancreatic cancer [9]. Amino acid sufficiency regulates MAP4K3 activity and mTOR (mammalian target of rapamycin) signaling by, together with PP2A (protein phosphatase 2), controlling the auto-phosphorylation status of amino acid S170 on the MAP4K3 A-loop [10].…”

Section: Gck-i Kinases Activate Mapk Pathwaymentioning

confidence: 99%

“…Activation of MST1 is regulated by homo-dimerization, autophosphorylation at sites T183 and T187, caspase cleavage, and by other protein factors including RASSF1 (Ras association domain family 1), RAPL (Regulator for cell adhesion and polarization enriched in lymphoid tissues), and Ras [22][23][24][25][26]. The two caspase cleavage sites at the sequences DEMD326S and TMTD349G can be selectively targeted by group I (3,6,7,9) and group II (6,7) caspases respectively to generate catalytic active enzymes of 36 and 40 kDa [24,26]. During TRAIL(TNF-related apoptosis inducing ligand)-induced apoptosis, MST1 functions as a bridge between caspase activation and MAPK activation, through which MAPK signaling is differentially regulated by distinct caspase cleavage of MST1 [27].…”

Section: Gck-ii Kinases Mediate Mammalian "Hippo" Pathwaymentioning

confidence: 99%

Multiple Functions of Mammalian Germinal Center Kinases

Yin¹,

Chen²,

Mao³

et al. 2012

CCB

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Germinal center kinases (GCKs) form a large part of the mammalian Ste20 kinase family. GCKs are involved in a variety of signaling pathways governing multiple biological processes including cell cycle, apoptosis, proliferation, cytoskeleton reorganization, cell polarity and migration, cell volume and ion transport. Dysregulation of GCKs has been linked to cell malfunction and human diseases. Despite the physiological and pathological importance of GCKs, the activation and regulatory mechanisms of their kinase activities are not fully understood. Moreover, GCK centered signaling network remains incomplete. This review highlights latest research progress on the biological functions and structures of GCKs by individual subfamilies, hoping to provoke insights into new ideas of GCK cell biology.

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MAP4K3 modulates cell death via the post-transcriptional regulation of BH3-only proteins

Cited by 35 publications

References 18 publications

Developmental Changes in Expression of Genes Involved in Regulation of Apoptosis in the Bovine Preimplantation Embryo1

Developmental Changes in Expression of Genes Involved in Regulation of Apoptosis in the Bovine Preimplantation Embryo1

MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens

Multiple Functions of Mammalian Germinal Center Kinases

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