c-Jun NH<sub>2</sub>-Terminal Kinase Is Required for Lineage-Specific Differentiation but Not Stem Cell Self-Renewal

Xu, Ping; Davis, Roger J.

doi:10.1128/mcb.00795-09

Cited by 46 publications

(41 citation statements)

References 59 publications

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“…À=À Jnk2 À=À mES cells show severe defects in mesodermal differentiation [48]. Since SIRT1 À=À mES cells inhibited apoptosis in response to cellular ROS, and ROS is an important signal for lineage differentiation of ES cells, further investigation of SIRT1 target molecules during ES cell differentiation should be important for understanding lineage-specific differentiation.…”

Section: Jnk1mentioning

confidence: 99%

SIRT1 Deficiency Downregulates PTEN/JNK/FOXO1 Pathway to Block Reactive Oxygen Species-Induced Apoptosis in Mouse Embryonic Stem Cells

Chae

Broxmeyer

2011

Stem Cells and Development

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Silent mating type information regulation 2 homolog 1 (SIRT1) plays a critical role in reactive oxygen speciestriggered apoptosis in mouse embryonic stem (mES) cells. Here, we investigated a possible role for the PTEN=Akt=JNK pathway in the SIRT1-mediated apoptosis pathway in mES cells. Akt was activated by removal of anti-oxidant 2-mercaptoethanol in SIRT1À=À mES cells. Since PTEN is a negative regulator of Akt and its activity can be modulated by acetylation, we investigated if SIRT1 deacetylated PTEN to downregulate Akt to trigger apoptosis in anti-oxidant-free culture conditions. PTEN was hyperacetylated and excluded from the nucleus in SIRT1À=À mES cells, consistent with enhanced Akt activity. SIRT1 deficiency enhanced the acetylation=phos-phorylation level of FOXO1 and subsequently inhibited the nuclear localization of FOXO1. Cellular acetylation levels were enhanced by DNA-damaging agent, not by removal of anti-oxidant. c-Jun NH2-terminal kinase ( JNK) was activated by removal of anti-oxidant in SIRT1-dependent manner. Although p53 acetylation was stronger in SIRT1 À=À mES cells, DNA-damaging stress activated phosphorylation and enhanced cellular levels of p53 irrespective of SIRT1, whereas removal of anti-oxidant slightly activated p53 only with SIRT1. Expression levels of Bim and Puma were increased in anti-oxidant-free culture conditions in an SIRT1-dependent manner and treatment with JNK inhibitor blocked induction of Bim expression. DNA-damaging agent activated caspase3 regardless of SIRT1. Our data support an important role for SIRT1 in preparing the PTEN=JNK=FOXO1 pathway to respond to cellular reactive oxygen species.

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Section: Jnk1mentioning

confidence: 99%

SIRT1 Deficiency Downregulates PTEN/JNK/FOXO1 Pathway to Block Reactive Oxygen Species-Induced Apoptosis in Mouse Embryonic Stem Cells

Chae

Broxmeyer

2011

Stem Cells and Development

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“…Ttr is a target of AP1 transcription factor complexes, which contain the transcription factor c-Jun (Qian et al, 1995) and RHOU has been shown to influence AP-1 activity that is downstream of JNK (Zhang et al, 2011). Differentiation of EBs lacking JNK1 and JNK2 activity (Xu and Davis, 2010) or EBs in the presence of JNK inhibitor reduced the expression of some endodermal lineage markers (see Fig. S4 in the supplementary material).…”

Section: Research Articlementioning

confidence: 99%

Rhou maintains the epithelial architecture and facilitates differentiation of the foregut endoderm

et al. 2011

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SUMMARYRhou encodes a Cdc42-related atypical Rho GTPase that influences actin organization in cultured cells. In mouse embryos at earlysomite to early-organogenesis stages, Rhou is expressed in the columnar endoderm epithelium lining the lateral and ventral wall of the anterior intestinal portal. During foregut development, Rhou is downregulated in regions where the epithelium acquires a multilayered morphology heralding the budding of organ primordia. In embryos generated from Rhou knockdown embryonic stem (ES) cells, the embryonic foregut displays an abnormally flattened shape. The epithelial architecture of the endoderm is disrupted, the cells are depleted of microvilli and the phalloidin-stained F-actin content of their sub-apical cortical domain is reduced. Rhou-deficient cells in ES cell-derived embryos and embryoid bodies are less efficient in endoderm differentiation. Impaired endoderm differentiation of Rhou-deficient ES cells is accompanied by reduced expression of c-Jun/AP-1 target genes, consistent with a role for Rhou in regulating JNK activity. Downregulation of Rhou in individual endoderm cells results in a reduced ability of these cells to occupy the apical territory of the epithelium. Our findings highlight epithelial morphogenesis as a required intermediate step in the differentiation of endoderm progenitors. In vivo, Rhou activity maintains the epithelial architecture of the endoderm progenitors, and its downregulation accompanies the transition of the columnar epithelium in the embryonic foregut to a multilayered cell sheet during organ formation.

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“…Nevertheless, there are several tissues and experimental models where the actions of JNK1 and JNK2 are cooperative or synergistic. Examples include the development of skin keratinocytes (188), spiral ganglion neurons (189), or the differentiation of pluripotent embryonic cells, where both JNK1 and JNK2 were required for establishing mesodermal and epithelial lineages (190). UV-or arsenite-induced apoptosis of fibroblasts required both JNK1 and JNK2 (191,192).…”

Section: Comparison Of Jnk1 and Jnk2 Functions In Vivomentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

393

350

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SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

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c-Jun NH₂-Terminal Kinase Is Required for Lineage-Specific Differentiation but Not Stem Cell Self-Renewal

Cited by 46 publications

References 59 publications

SIRT1 Deficiency Downregulates PTEN/JNK/FOXO1 Pathway to Block Reactive Oxygen Species-Induced Apoptosis in Mouse Embryonic Stem Cells

SIRT1 Deficiency Downregulates PTEN/JNK/FOXO1 Pathway to Block Reactive Oxygen Species-Induced Apoptosis in Mouse Embryonic Stem Cells

Rhou maintains the epithelial architecture and facilitates differentiation of the foregut endoderm

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

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c-Jun NH2-Terminal Kinase Is Required for Lineage-Specific Differentiation but Not Stem Cell Self-Renewal

Cited by 46 publications

References 59 publications

SIRT1 Deficiency Downregulates PTEN/JNK/FOXO1 Pathway to Block Reactive Oxygen Species-Induced Apoptosis in Mouse Embryonic Stem Cells

SIRT1 Deficiency Downregulates PTEN/JNK/FOXO1 Pathway to Block Reactive Oxygen Species-Induced Apoptosis in Mouse Embryonic Stem Cells

Rhou maintains the epithelial architecture and facilitates differentiation of the foregut endoderm

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

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c-Jun NH₂-Terminal Kinase Is Required for Lineage-Specific Differentiation but Not Stem Cell Self-Renewal