Myc in Stem Cell Behaviour: Insights from Drosophila

Quinn, Leonie M.; Secombe, Julie; Hime, Gary R.

doi:10.1007/978-94-007-6621-1_15

Cited by 15 publications

(13 citation statements)

References 123 publications

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“…c-MYC is one of the four Yamanaka factors (OCT3/4, SOX2, c-MYC, and KLF4) that are capable of reprogramming fibroblasts to induced pluripotent stem cells (27). C-Myc itself has been shown to play a significant role in selfrenewal of stem cells (28). Because it is well-known that c-MYC is subjected to ubiquitylation and degradation by two SCF E3 ubiquitin ligases, SCF FBXW7 (29) and SCF SKP2 (30), we determined whether MLN4924 can cause accumulation of c-MYC by inactivation of cullin neddylation (7).…”

Section: Ts Stimulatory Effect Of Mln4924 Is Mediated In Part By the mentioning

confidence: 99%

Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

Zhou

Tan

Nyati

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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MLN4924, also known as pevonedistat, is the first-in-class inhibitor of NEDD8-activating enzyme, which blocks the entire neddylation modification of proteins. Previous preclinical studies and current clinical trials have been exclusively focused on its anticancer property. Unexpectedly, we show here, to our knowledge for the first time, that MLN4924, when applied at nanomolar concentrations, significantly stimulates in vitro tumor sphere formation and in vivo tumorigenesis and differentiation of human cancer cells and mouse embryonic stem cells. These stimulatory effects are attributable to (i) c-MYC accumulation via blocking its degradation and (ii) continued activation of EGFR (epidermal growth factor receptor) and its downstream pathways, including PI3K/AKT/mammalian target of rapamycin and RAS/RAF/MEK/ERK, via inducing EGFR dimerization. Finally, MLN4924 accelerates EGF-mediated skin wound healing in mouse and stimulates cell migration in an in vitro culture setting. Taking these data together, our study reveals that neddylation modification could regulate stem cell proliferation and differentiation and that a low dose of MLN4924 might have a therapeutic value for stem cell therapy and tissue regeneration.MLN4924 | neddylation | EGFR | stem cell | wound healing I n cells, homeostasis is reached by a fine balance between the rates of protein synthesis and degradation. The process of protein degradation by the ubiquitin-proteasome system (UPS) involves two sequential steps: (i) ubiquitylation catalyzed by the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3) and (ii) degradation catalyzed by 26S proteasome (1). Abnormal UPS activity abrogates the homeostasis and is associated with many human diseases, including cancer (2, 3). Bortezomib, the first Food and Drug Administration-approved proteasome inhibitor for the treatment of multiple myeloma and mantle cell lymphoma (4), possesses significant cytotoxicity against normal cells due to its universal inhibition of the UPS (5). This stimulated an intensive search for inhibitors targeting the enzymes upstream of the proteasome for improved specificity.Cullin-RING ligases (CRLs), consisting of scaffold cullins, adaptor proteins, substrate-recognizing receptors, and RING finger proteins, are the largest family of E3 ubiquitin ligases and are responsible for the ubiquitylation of about 20% of all cellular proteins (6, 7). The activity of CRLs requires neddylation of the cullin proteins (8, 9), a ubiquitylation-like process, which is sequentially catalyzed by three enzymes: a NEDD8-activating enzyme (NAE or E1), NEDD8-conjugating enzyme (E2), and NEDD8 ligase (E3). Abnormal elevation of CRL activity has been found in multiple human cancers, which makes them favorable targets for cancer treatment (10, 11).MLN4924 was descried in 2009 as the first-in-class NAE inhibitor exclusively in the application for cancer treatment by inactivation of CRLs via blockage of cullin neddylation (7). Since the initial report, more than 150 p...

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Section: Ts Stimulatory Effect Of Mln4924 Is Mediated In Part By the mentioning

confidence: 99%

Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

Zhou

Tan

Nyati

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…A link between asymmetric cell division and dMyc (Drosophila Myc) has been inferred in Drosophila neuroblasts and germline stem cells [50], as dMyc is expressed in stem cells but not differentiated cells. During asymmetric cell division, Drosophila Brat suppresses dMyc expression post-transcriptionally in neuroblasts [31] and in germline stem cells [51].…”

Section: Noncanonical Signaling Pathway Influence On Asymmetric Cell mentioning

confidence: 99%

“…2A) [52], chromatin modification, and energy metabolism that promote cell division and stemness. Both Drosophila Myc and mammalian MYC bind to the promoter region of TORC1 target genes [50], suggesting a control over ribosome synthesis and Insulin/TOR metabolism axis driving selfrenewal. Another potential mechanism is that MYC represses a master regulator of endoderm differentiation, GATA6 [50] and drives proliferation.…”

Section: Noncanonical Signaling Pathway Influence On Asymmetric Cell mentioning

confidence: 99%

Cancer Stem Cell Division: When the Rules of Asymmetry Are Broken

Mukherjee

Kong

Brat³

2015

Stem Cells and Development

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Asymmetric division of stem cells is a highly conserved and tightly regulated process by which a single stem cell produces two daughter cells and simultaneously directs the differential fate of both: one retains its stem cell identity while the other becomes specialized and loses stem cell properties. Coordinating these events requires control over numerous intra-and extracellular biological processes and signaling networks. In the initial stages, critical events include the compartmentalization of fate determining proteins within the mother cell and their subsequent passage to the appropriate daughter cell. Disturbance of these events results in an altered dynamic of self-renewing and differentiation within the cell population, which is highly relevant to the growth and progression of cancer. Other critical events include proper asymmetric spindle assembly, extrinsic regulation through micro-environmental cues, and noncanonical signaling networks that impact cell division and fate determination. In this review, we discuss mechanisms that maintain the delicate balance of asymmetric cell division in normal tissues and describe the current understanding how some of these mechanisms are deregulated in cancer.The universe is asymmetric and I am persuaded that life, as it is known to us, is a direct result of the asymmetry of the universe or of its indirect consequences. The universe is asymmetric.-Louis Pasteur

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“…Consistent with this hypothesis, there is a partial overlap of target genes of c‐Myc and the Tip60 histone acetyl transferase in mouse embryonic stem cells (Takahashi & Yamanaka, ; Chappell & Dalton, ; Ravens et al , ). In mammals and Drosophila, Myc influences different stem cells in many, partly opposing ways (reviewed in Quinn et al , ) but the contribution of the Tip60 complex to Myc‐dependent stem cell functions is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Myc and the Tip60 chromatin remodeling complex control neuroblast maintenance and polarity in Drosophila

et al. 2018

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Stem cells establish cortical polarity and divide asymmetrically to simultaneously maintain themselves and generate differentiating offspring cells. Several chromatin modifiers have been identified as stemness factors in mammalian pluripotent stem cells, but whether these factors control stem cell polarity and asymmetric division has not been investigated so far. We addressed this question in neural stem cells called neuroblasts. We identified the Tip60 chromatin remodeling complex and its interaction partner Myc as regulators of genes required for neuroblast maintenance. Knockdown of Tip60 complex members results in loss of cortical polarity, symmetric neuroblast division, and premature differentiation through nuclear entry of the transcription factor Prospero. We found that aPKC is the key target gene of Myc and the Tip60 complex subunit Domino in regulating neuroblast polarity. Our transcriptome analysis further showed that Domino regulates the expression of mitotic spindle genes previously identified as direct Myc targets. Our findings reveal an evolutionarily conserved functional link between Myc, the Tip60 complex, and the molecular network controlling cell polarity and asymmetric cell division.

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Myc in Stem Cell Behaviour: Insights from Drosophila

Cited by 15 publications

References 123 publications

Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

Cancer Stem Cell Division: When the Rules of Asymmetry Are Broken

Myc and the Tip60 chromatin remodeling complex control neuroblast maintenance and polarity in Drosophila

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