LIVIVO - Search results -

Search results

Result 1 - 10 of total 49

Search options

Article ; Online: Too much death can kill you: inhibiting intrinsic apoptosis to treat disease.

Li, Kaiming / van Delft, Mark F / Dewson, Grant

2021 Volume 40, Issue 14, Page(s) e107341

Abstract: Apoptotic cell death is implicated in both physiological and pathological processes. Since many types of cancerous cells intrinsically evade apoptotic elimination, induction of apoptosis has become an attractive and often necessary cancer therapeutic ... ...

Abstract	Apoptotic cell death is implicated in both physiological and pathological processes. Since many types of cancerous cells intrinsically evade apoptotic elimination, induction of apoptosis has become an attractive and often necessary cancer therapeutic approach. Conversely, some cells are extremely sensitive to apoptotic stimuli leading to neurodegenerative disease and immune pathologies. However, due to several challenges, pharmacological inhibition of apoptosis is still only a recently emerging strategy to combat pathological cell loss. Here, we describe several key steps in the intrinsic (mitochondrial) apoptosis pathway that represent potential targets for inhibitors in disease contexts. We also discuss the mechanisms of action, advantages and limitations of small-molecule and peptide-based inhibitors that have been developed to date. These inhibitors serve as important research tools to dissect apoptotic signalling and may foster new treatments to reduce unwanted cell loss.
MeSH term(s)	Animals ; Apoptosis/physiology ; Humans ; Mitochondria/pathology ; Neoplasms/pathology ; Neurodegenerative Diseases/pathology ; Signal Transduction/physiology
Language	English
Publishing date	2021-05-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2020107341
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 1808: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 100: Show issues

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Details ▾

Article ; Online: Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins.

Huang, Allan Shuai / Chin, Hui San / Reljic, Boris / Djajawi, Tirta M / Tan, Iris K L / Gong, Jia-Nan / Stroud, David A / Huang, David C S / van Delft, Mark F / Dewson, Grant

Cell death and differentiation

2022 Volume 30, Issue 3, Page(s) 632–646

Abstract: Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to control this process. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it ... ...

Abstract	Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to control this process. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in diverse cell lines dependent on BAK conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an activated conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins and influence on pro-survival proteins. This study identifies a new mechanism by which MARCHF5 regulates apoptotic cell death by restraining BAK activating conformation change and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically.
MeSH term(s)	bcl-X Protein/metabolism ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; Ubiquitin-Protein Ligases ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Apoptosis/physiology ; Proto-Oncogene Proteins c-bcl-2/metabolism
Chemical Substances	bcl-X Protein ; bcl-2 Homologous Antagonist-Killer Protein ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2
Language	English
Publishing date	2022-09-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-022-01067-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 80: Show issues

Order via subito

Details ▾

Article ; Online: The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase.

Pierotti, Catia L / Jacobsen, Annette V / Grohmann, Christoph / Dempsey, Ruby K / Etemadi, Nima / Hildebrand, Joanne M / Fitzgibbon, Cheree / Young, Samuel N / Davies, Katherine A / Kersten, Wilhelmus J A / Silke, John / Lowes, Kym N / Jousset Sabroux, Hélène / Huang, David C S / van Delft, Mark F / Murphy, James M / Lessene, Guillaume

The Biochemical journal

2023 Volume 480, Issue 9, Page(s) 665–684

Abstract: Necroptosis is a mode of programmed, lytic cell death that is executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following activation by the upstream kinases, receptor-interacting serine/threonine protein kinase (RIPK)-1 and RIPK3. ... ...

Abstract	Necroptosis is a mode of programmed, lytic cell death that is executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following activation by the upstream kinases, receptor-interacting serine/threonine protein kinase (RIPK)-1 and RIPK3. Dysregulated necroptosis has been implicated in the pathophysiology of many human diseases, including inflammatory and degenerative conditions, infectious diseases and cancers, provoking interest in pharmacological targeting of the pathway. To identify small molecules impacting on the necroptotic machinery, we performed a phenotypic screen using a mouse cell line expressing an MLKL mutant that kills cells in the absence of upstream death or pathogen detector receptor activation. This screen identified the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinase inhibitor, ABT-869 (Linifanib), as a small molecule inhibitor of necroptosis. We applied a suite of cellular, biochemical and biophysical analyses to pinpoint the apical necroptotic kinase, RIPK1, as the target of ABT-869 inhibition. Our study adds to the repertoire of established protein kinase inhibitors that additionally target RIPK1 and raises the prospect that serendipitous targeting of necroptosis signalling may contribute to their clinical efficacy in some settings.
MeSH term(s)	Humans ; Tyrosine Kinase Inhibitors ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Necroptosis ; Vascular Endothelial Growth Factor A/metabolism ; Apoptosis ; Receptors, Vascular Endothelial Growth Factor/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
Chemical Substances	Tyrosine Kinase Inhibitors ; Protein Kinases (EC 2.7.-) ; Vascular Endothelial Growth Factor A ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; RIPK1 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2023-04-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20230035
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Uc I Zs.110: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: The Lck inhibitor, AMG-47a, blocks necroptosis and implicates RIPK1 in signalling downstream of MLKL.

Jacobsen, Annette V / Pierotti, Catia L / Lowes, Kym N / Au, Amanda E / Zhang, Ying / Etemadi, Nima / Fitzgibbon, Cheree / Kersten, Wilhelmus J A / Samson, André L / van Delft, Mark F / Huang, David C S / Sabroux, Hélène Jousset / Lessene, Guillaume / Silke, John / Murphy, James M

Cell death & disease

2022 Volume 13, Issue 4, Page(s) 291

Abstract: Necroptosis is a form of caspase-independent programmed cell death that arises from disruption of cell membranes by the mixed lineage kinase domain-like (MLKL) pseudokinase after its activation by the upstream kinases, receptor interacting protein kinase ...

Abstract	Necroptosis is a form of caspase-independent programmed cell death that arises from disruption of cell membranes by the mixed lineage kinase domain-like (MLKL) pseudokinase after its activation by the upstream kinases, receptor interacting protein kinase (RIPK)-1 and RIPK3, within a complex known as the necrosome. Dysregulated necroptosis has been implicated in numerous inflammatory pathologies. As such, new small molecule necroptosis inhibitors are of great interest, particularly ones that operate downstream of MLKL activation, where the pathway is less well defined. To better understand the mechanisms involved in necroptosis downstream of MLKL activation, and potentially uncover new targets for inhibition, we screened known kinase inhibitors against an activated mouse MLKL mutant, leading us to identify the lymphocyte-specific protein tyrosine kinase (Lck) inhibitor AMG-47a as an inhibitor of necroptosis. We show that AMG-47a interacts with both RIPK1 and RIPK3, that its ability to protect from cell death is dependent on the strength of the necroptotic stimulus, and that it blocks necroptosis most effectively in human cells. Moreover, in human cell lines, we demonstrate that AMG-47a can protect against cell death caused by forced dimerisation of MLKL truncation mutants in the absence of any upstream signalling, validating that it targets a process downstream of MLKL activation. Surprisingly, however, we also found that the cell death driven by activated MLKL in this model was completely dependent on the presence of RIPK1, and to a lesser extent RIPK3, although it was not affected by known inhibitors of these kinases. Together, these results suggest an additional role for RIPK1, or the necrosome, in mediating human necroptosis after MLKL is phosphorylated by RIPK3 and provide further insight into reported differences in the progression of necroptosis between mouse and human cells.
MeSH term(s)	Animals ; Apoptosis ; Cell Death ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ; Mice ; Necroptosis ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Signal Transduction
Chemical Substances	MLKL protein, mouse (EC 2.7.-) ; Protein Kinases (EC 2.7.-) ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (EC 2.7.10.2) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk1 protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2022-04-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-022-04740-w
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: MARCH5 requires MTCH2 to coordinate proteasomal turnover of the MCL1:NOXA complex.

Djajawi, Tirta Mario / Liu, Lei / Gong, Jia-Nan / Huang, Allan Shuai / Luo, Ming-Jie / Xu, Zhen / Okamoto, Toru / Call, Melissa J / Huang, David C S / van Delft, Mark F

Cell death and differentiation

2020 Volume 27, Issue 8, Page(s) 2484–2499

Abstract: ... E2 conjugating enzyme UBE2K, and the mitochondrial outer membrane protein MTCH2 co-operate to mark ...

Abstract	MCL1, a BCL2 relative, is critical for the survival of many cells. Its turnover is often tightly controlled through both ubiquitin-dependent and -independent mechanisms of proteasomal degradation. Several cell stress signals, including DNA damage and cell cycle arrest, are known to elicit distinct E3 ligases to ubiquitinate and degrade MCL1. Another trigger that drives MCL1 degradation is engagement by NOXA, one of its BH3-only protein ligands, but the mechanism responsible has remained unclear. From an unbiased genome-wide CRISPR-Cas9 screen, we discovered that the ubiquitin E3 ligase MARCH5, the ubiquitin E2 conjugating enzyme UBE2K, and the mitochondrial outer membrane protein MTCH2 co-operate to mark MCL1 for degradation by the proteasome-specifically when MCL1 is engaged by NOXA. This mechanism of degradation also required the MCL1 transmembrane domain and distinct MCL1 lysine residues to proceed, suggesting that the components likely act on the MCL1:NOXA complex by associating with it in a specific orientation within the mitochondrial outer membrane. MTCH2 has not previously been reported to regulate protein stability, but is known to influence the mitochondrial localization of certain key apoptosis regulators and to impact metabolism. We have now pinpointed an essential but previously unappreciated role for MTCH2 in turnover of the MCL1:NOXA complex by MARCH5, further strengthening its links to BCL2-regulated apoptosis.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Line, Tumor ; Cell Survival ; Lysine/metabolism ; Membrane Proteins/metabolism ; Mice ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Proteins/metabolism ; Myeloid Cell Leukemia Sequence 1 Protein/chemistry ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Peptide Elongation Factors/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Domains ; Proteolysis ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	MCL1 protein, human ; MIEF2 protein, human ; MTCH2 protein, human ; Membrane Proteins ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Proteins ; Myeloid Cell Leukemia Sequence 1 Protein ; PMAIP1 protein, human ; Peptide Elongation Factors ; Proto-Oncogene Proteins c-bcl-2 ; MARCHF5 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2020-02-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-020-0517-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 80: Show issues

Order via subito

Details ▾

Article ; Online: The transcription factor IRF4 represses proapoptotic BMF and BIM to licence multiple myeloma survival.

Fedele, Pasquale L / Liao, Yang / Gong, Jia-Nan / Yao, Yuan / van Delft, Mark F / Low, Michael S Y / Tai, Lin / Herold, Marco J / Jackson, Jacob T / Teh, Charis E / Tan, Tania / O'Reilly, Lorraine A / Tellier, Julie / Grigoriadis, George / Huang, David C S / Shi, Wei / Nutt, Stephen L / Willis, Simon N

Leukemia

2020 Volume 35, Issue 7, Page(s) 2114–2118

MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Apoptosis/genetics ; Apoptosis Regulatory Proteins/genetics ; Bcl-2-Like Protein 11/genetics ; Cell Line, Tumor ; Humans ; Interferon Regulatory Factors/genetics ; Multiple Myeloma/genetics ; Multiple Myeloma/mortality ; Survival Rate
Chemical Substances	Adaptor Proteins, Signal Transducing ; Apoptosis Regulatory Proteins ; BMF protein, human ; Bcl-2-Like Protein 11 ; Interferon Regulatory Factors ; interferon regulatory factor-4
Language	English
Publishing date	2020-11-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-020-01078-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 2295: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

Article ; Online: BAK/BAX-Mediated Apoptosis Is a Myc-Induced Roadblock to Reprogramming.

Kim, Esther J Y / Anko, Minna-Liisa / Flensberg, Christoffer / Majewski, Ian J / Geng, Fan-Suo / Firas, Jaber / Huang, David C S / van Delft, Mark F / Heath, Joan K

Stem cell reports

2018 Volume 10, Issue 2, Page(s) 331–338

Abstract: Despite intensive efforts to optimize the process, reprogramming differentiated cells to induced pluripotent stem cells (iPSCs) remains inefficient. The most common combination of transcription factors employed comprises OCT4, KLF4, SOX2, and MYC (OKSM). ...

Abstract	Despite intensive efforts to optimize the process, reprogramming differentiated cells to induced pluripotent stem cells (iPSCs) remains inefficient. The most common combination of transcription factors employed comprises OCT4, KLF4, SOX2, and MYC (OKSM). If MYC is omitted (OKS), reprogramming efficiency is reduced further. Cells must overcome several obstacles to reach the pluripotent state, one of which is apoptosis. To directly determine how extensively apoptosis limits reprogramming, we exploited mouse embryonic fibroblasts (MEFs) lacking the two essential mediators of apoptosis, BAK and BAX. Our results show that reprogramming is enhanced in MEFs deficient in BAK and BAX, but only when MYC is part of the reprogramming cocktail. Thus, the propensity for Myc overexpression to elicit apoptosis creates a significant roadblock to reprogramming under OKSM conditions. Our results suggest that blocking apoptosis during reprogramming may enhance the derivation of iPSCs for research and therapeutic purposes.
MeSH term(s)	Animals ; Apoptosis/genetics ; Cell Differentiation ; Cellular Reprogramming/genetics ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Gene Expression Regulation, Developmental ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/metabolism ; Mice ; Mouse Embryonic Stem Cells/cytology ; Mouse Embryonic Stem Cells/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; bcl-2 Homologous Antagonist-Killer Protein/genetics ; bcl-2-Associated X Protein/genetics
Chemical Substances	Bak1 protein, mouse ; Bax protein, mouse ; Proto-Oncogene Proteins c-myc ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-2-Associated X Protein
Language	English
Publishing date	2018-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2017.12.019
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway.

ACS chemical biology

2020 Volume 15, Issue 10, Page(s) 2702–2713

Abstract: Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. ... ...

Abstract	Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound
MeSH term(s)	Animals ; Cell Line, Tumor ; Female ; Humans ; Mice, Inbred C57BL ; Necroptosis/drug effects ; Phenylurea Compounds/metabolism ; Phenylurea Compounds/pharmacokinetics ; Phenylurea Compounds/therapeutic use ; Protein Binding ; Protein Kinase Inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/therapeutic use ; Protein Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Signal Transduction/drug effects ; Sulfonamides/metabolism ; Sulfonamides/pharmacokinetics ; Sulfonamides/therapeutic use ; Systemic Inflammatory Response Syndrome/drug therapy
Chemical Substances	Phenylurea Compounds ; Protein Kinase Inhibitors ; Sulfonamides ; MLKL protein, human (EC 2.7.-) ; MLKL protein, mouse (EC 2.7.-) ; Protein Kinases (EC 2.7.-) ; RIPK1 protein, human (EC 2.7.11.1) ; RIPK3 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk1 protein, mouse (EC 2.7.11.1) ; Ripk3 protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2020-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.0c00482
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: BAK/BAX-Mediated Apoptosis Is a Myc-Induced Roadblock to Reprogramming

Esther J.Y. Kim / Minna-Liisa Anko / Christoffer Flensberg / Ian J. Majewski / Fan-Suo Geng / Jaber Firas / David C.S. Huang / Mark F. van Delft / Joan K. Heath

Stem Cell Reports, Vol 10, Iss 2, Pp 331-

2018 Volume 338

Abstract: ... may enhance the derivation of iPSCs for research and therapeutic purposes. : In this article, Heath, van Delft ...

Abstract	Summary: Despite intensive efforts to optimize the process, reprogramming differentiated cells to induced pluripotent stem cells (iPSCs) remains inefficient. The most common combination of transcription factors employed comprises OCT4, KLF4, SOX2, and MYC (OKSM). If MYC is omitted (OKS), reprogramming efficiency is reduced further. Cells must overcome several obstacles to reach the pluripotent state, one of which is apoptosis. To directly determine how extensively apoptosis limits reprogramming, we exploited mouse embryonic fibroblasts (MEFs) lacking the two essential mediators of apoptosis, BAK and BAX. Our results show that reprogramming is enhanced in MEFs deficient in BAK and BAX, but only when MYC is part of the reprogramming cocktail. Thus, the propensity for Myc overexpression to elicit apoptosis creates a significant roadblock to reprogramming under OKSM conditions. Our results suggest that blocking apoptosis during reprogramming may enhance the derivation of iPSCs for research and therapeutic purposes. : In this article, Heath, van Delft, and colleagues show that mitochondrial apoptosis limits OKSM-mediated reprogramming of MEFs. Not only is reprogramming of MEFs lacking the two essential mediators of mitochondrial apoptosis, BAK and BAX, significantly enhanced in the presence of MYC, but reprogramming in these conditions does not compromise genome integrity. Keywords: mouse embryonic fibroblasts: reprogramming, induced pluripotent stem cells, mitochondrial apoptosis, BAK, BAX, MYC, p53
Keywords	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

Full text online

Full text

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article: How the Bcl-2 family of proteins interact to regulate apoptosis.

van Delft, Mark F / Huang, David C S

Cell research

2006 Volume 16, Issue 2, Page(s) 203–213

Abstract: Commitment of cells to apoptosis is governed largely by protein-protein interactions between members of the Bcl-2 protein family. Its three sub-families have distinct roles: the BH3-only proteins trigger apoptosis by binding via their BH3 domain to pro- ... ...

Abstract	Commitment of cells to apoptosis is governed largely by protein-protein interactions between members of the Bcl-2 protein family. Its three sub-families have distinct roles: the BH3-only proteins trigger apoptosis by binding via their BH3 domain to pro-survival relatives, while the pro-apoptotic Bax and Bak have an essential downstream role involving disruption of organellar membranes and induction of caspase activation. The BH3-only proteins act as damage sensors, held inert until their activation by stress signals. Once activated, they were thought to bind promiscuously to pro-survival protein targets but unexpected selectivity has recently emerged from analysis of their interactions. Some BH3-only proteins also bind to Bax and Bak. Whether Bax and Bak are activated directly by these BH3-only proteins, or indirectly as a consequence of BH3-only proteins neutralizing their pro-survival targets is the subject of intense debate. Regardless of this, a detailed understanding of the interactions between family members, which are often selective, has notable implications for designing anti-cancer drugs to target the Bcl-2 family.
MeSH term(s)	Animals ; Apoptosis/physiology ; Cell Survival ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins ; Protein Binding ; Proto-Oncogene Proteins c-bcl-2/metabolism ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins ; Proto-Oncogene Proteins c-bcl-2 ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-2-Associated X Protein
Language	English
Publishing date	2006-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1319303-x
ISSN	1748-7838 ; 1001-0602
ISSN (online)	1748-7838
ISSN	1001-0602
DOI	10.1038/sj.cr.7310028
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 5283: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

To top

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

Full text online

More links

Kategorien

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito