MYC/MAX control ERK signaling and pluripotency by regulation of dual-specificity phosphatases 2 and 7

Chappell, James; Sun, Yuhua; Singh, Arashdeep; Dalton, Stephen

doi:10.1101/gad.211300.112

Cited by 72 publications

(74 citation statements)

References 25 publications

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“…The MYC/MAX network has also been shown to coordinate with BMP-4 signaling to activate phosphatases that repress mitogen-activated protein kinase (MAPK) signaling ( Fig. 1) (Hishida et al 2011;Li et al 2012;Chappell et al 2013). This is significant because activation of MAPK signaling by fibroblast growth factors External factors stimulate internal pathways, which cooperate to maintain PSCs.…”

Section: Myc Promotes the Maintenance Of Pluripotent Stem Cellsmentioning

confidence: 99%

“…Loss of MYC or MAX in PSCs leads to the down-regulation of ERK phosphatases, DUSP2 and DUSP7, stimulating MAPK signaling and resulting in differentiation (Chappell et al 2013). The observation that differentiation can be blocked by a small-molecule inhibition of MEK provides an explanation for how PSCs are maintained by MAPK/MEK inhibition in LIF-depleted media (Ying et al 2008).…”

Section: Myc and Pluripotent Stem Cellsmentioning

confidence: 99%

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Roles for MYC in the Establishment and Maintenance of Pluripotency

Chappell

Dalton

2013

Cold Spring Harbor Perspectives in Medicine

100

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MYC and MYCN have been directly implicated in the transcriptional regulation of several thousand genes in pluripotent stem cells and possibly contribute to the activity of all transcribed genes. Control of transcription by a pause-release mechanism, recruitment of positive and negative epigenetic regulators, and a general role in transcriptional amplification have all been implicated as part of the broad, overarching mechanism by which MYC controls stem cell biology. As would be anticipated from the regulation of so many genes, MYC is involved in a wide range of cellular processes including cell-cycle control, metabolism, signal transduction, self-renewal, maintenance of pluripotency, and control of cell fate decisions. MYC transcription factors also have clear roles in cell reprogramming and establishment of the pluripotent state. The mechanism by which MYC accomplishes this is now being explored and promises to uncover unexpected facets of general MYC regulation that are likely to be applicable to cancer biology. In this work we review our current understanding of how MYC contributes to the maintenance and establishment of pluripotent cells and how it contributes to early embryonic development. W ell before MYC was implicated in the establishment and maintenance of pluripotency, it was known as a potent oncogene with roles in transcriptional regulation of metabolism, differentiation, cell lifespan, cell cycle, and cell size control. These functions are all generally relevant to the maintenance and establishment of pluripotent stem cells. Despite this, however, defining the precise mechanism by which MYC functions has been problematic and has led to much confusion. The following discussion will focus on our current understanding of how MYC functions in early embryonic development, maintenance of stem cell identity, and in somatic cell reprogramming. MYC AND MYCN ARE FUNCTIONALLY REDUNDANT IN EARLY EMBRYONIC DEVELOPMENTThe MYC family of basic helix-loop-helix leucine zipper transcription factors consists of MYC, MYCN, and MYCL. DNA binding of MYC family members usually requires heterodimerization with MAX (Myc-associated factor X) through their respective leucine zipper do-

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Section: Myc Promotes the Maintenance Of Pluripotent Stem Cellsmentioning

confidence: 99%

Section: Myc and Pluripotent Stem Cellsmentioning

confidence: 99%

Roles for MYC in the Establishment and Maintenance of Pluripotency

Chappell

Dalton

2013

Cold Spring Harbor Perspectives in Medicine

100

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“…DUSP2, another regulator of cellular potency [67], was also elevated. Also elevated were BMP4, which induces primitive endoderm in monkey ESCs [68], and the hypoblast marker GATA4.…”

Section: Resultsmentioning

confidence: 99%

Effects of long-term endocrine disrupting compound exposure on Macaca mulatta embryonic stem cells

Midic

Vincent

VandeVoort

et al. 2016

Reproductive Toxicology

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Endocrine disrupting chemicals (EDCs) exert significant effects on health and physiology, many traceable to effects on stem cell programming underlying development. Understanding risk of low-level, chronic EDC exposure will be enhanced by knowledge of effects on stem cells. We exposed rhesus monkey embryonic stem cells to low levels of five EDCs [bisphenol A (BPA), atrazine (ATR), tributyltin (TBT), perfluorooctanoic acid (PFOA), and di-(2-ethylhexyl) phthalate (DEHP)] for 28 days, and evaluated effects on gene expression by RNAseq transcriptome profiling. We observed little effect of BPA, and small numbers of affected genes (≤119) with other EDCs. There was substantial overlap in effects across two, three, or four treatments. Ingenuity Pathway analysis indicated suppression of cell survival genes and genes downstream of several stress response mediators, activation of cell death genes, and modulations in several genes regulating pluripotency, differentiation, and germ layer development. Potential adverse effects of these changes on development are discussed.

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“…Isolated attenuation of Erk signaling – either by pharmacological MEK inhibition or by forced expression of Erk phosphatases – also facilitates self-renewal and prevents differentiation [215]. Myc/MAX complexes also suppress Erk activity by regulating the transcription of two members of the dual-specificity phosphatase (DUSP) family, which bind to and inactivate Erk1/2 by dephosphorylating residues required for its catalytic activity [216]. Ectopic DUSP2/7 expression severely delays differentiation, while loss of DUSP2/7 ectopically activates Erk, resulting in loss of pluripotency [216].…”

Section: Specific Protein Kinases and Associated Signaling Pathwaymentioning

confidence: 99%

“…Myc/MAX complexes also suppress Erk activity by regulating the transcription of two members of the dual-specificity phosphatase (DUSP) family, which bind to and inactivate Erk1/2 by dephosphorylating residues required for its catalytic activity [216]. Ectopic DUSP2/7 expression severely delays differentiation, while loss of DUSP2/7 ectopically activates Erk, resulting in loss of pluripotency [216]. FGFR signaling also exhibits a pro-differentiating effect in hESCs towards ectodermal and mesodermal cells [217] as well as neural lineages [218, 219].…”

Section: Specific Protein Kinases and Associated Signaling Pathwaymentioning

confidence: 99%

Protein Kinases and Associated Pathways in Pluripotent State and Lineage Differentiation

Shoni

Lui

Vavvas

et al. 2014

CSCR

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Protein kinases (PKs) mediate the reversible conversion of substrate proteins to phosphorylated forms, a key process in controlling intracellular signaling transduction cascades. Pluripotency is, among others, characterized by specifically expressed PKs forming a highly interconnected regulatory network that culminates in a finely-balanced molecular switch. Current high-throughput phosphoproteomic approaches have shed light on the specific regulatory PKs and their function in controlling pluripotent states. Pluripotent cell-derived endothelial and hematopoietic developments represent an example of the importance of pluripotency in cancer therapeutics and organ regeneration. This review attempts to provide the hitherto known kinome profile and the individual characterization of PK-related pathways that regulate pluripotency. Elucidating the underlying intrinsic and extrinsic signals may improve our understanding of the different pluripotent states, the maintenance or induction of pluripotency, and the ability to tailor lineage differentiation, with a particular focus on endothelial cell differentiation for anti-cancer treatment, cell-based tissue engineering, and regenerative medicine strategies.

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MYC/MAX control ERK signaling and pluripotency by regulation of dual-specificity phosphatases 2 and 7

Cited by 72 publications

References 25 publications

Roles for MYC in the Establishment and Maintenance of Pluripotency

Roles for MYC in the Establishment and Maintenance of Pluripotency

Effects of long-term endocrine disrupting compound exposure on Macaca mulatta embryonic stem cells

Protein Kinases and Associated Pathways in Pluripotent State and Lineage Differentiation

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