ZNF423 Is Critically Required for Retinoic Acid-Induced Differentiation and Is a Marker of Neuroblastoma Outcome

Huang, Sidong; Laoukili, Jamila; Epping, Mirjam T.; Koster, Jan; Hölzel, Michael; Westerman, Bart A.; Nijkamp, Wouter; Hata, Akiko; Asgharzadeh, Shahab; Seeger, Robert C.; Versteeg, Rogier; Beijersbergen, Roderick L.; Bernards, René

doi:10.1016/j.ccr.2009.02.023

Cited by 131 publications

(141 citation statements)

References 45 publications

(72 reference statements)

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“…4D). Other studies have shown that loss of activation of RA target genes blocks RA-induced differentiation (20,21). It is therefore likely that the loss of activation of a subset of RA target genes contributes to RA resistance in MAML3-overexpressing cells.…”

Section: Discussionmentioning

confidence: 99%

“…Using loss-offunction genetic screens Huang and colleagues showed that knockdown of the zinc finger protein ZNF423 leads to the loss of activation of RA target genes. ZNF423 binds to the RAR/RXR complex and acts as a transcriptional coactivator (20). In another study, loss of the tumor suppressor NF1 was shown to determine responsiveness to RA.…”

Section: Introductionmentioning

confidence: 99%

“…One way cells can become resistant to RA-induced differentiation is by loss of RA target gene expression (20,21). To determine if ectopic MAML3 expression leads to the loss of RA-responsive gene expression, we integrated our ChIP-seq and transcriptome data.…”

Section: E Western Blot Analysis Of Maml3 Protein Levels In Gfp-infementioning

confidence: 99%

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Mastermind-Like 3 Controls Proliferation and Differentiation in Neuroblastoma

Heynen

Nevedomskaya

Palit

et al. 2016

Molecular Cancer Research

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Neuroblastoma cell lines can differentiate upon treatment with retinoic acid (RA), a finding that provided the basis for the clinical use of RA to treat neuroblastoma. However, resistance to RA is often observed, which limits its clinical utility. Using a gain-of-function genetic screen, we identified an unexpected link between RA signaling and mastermindlike 3 (MAML3), a known transcriptional coactivator for NOTCH. Our findings indicate that MAML3 expression leads to the loss of activation of a subset of RA target genes, which hampers RA-induced differentiation and promotes resistance to RA. The regulatory DNA elements of this subset of RA target genes show overlap in binding of MAML3 and the RA receptor, suggesting a direct role for MAML3 in the regulation of these genes. In addition, MAML3 has RA-independent functions, including the activation of IGF1R and downstream AKT signaling via upregulation of IGF2, resulting in increased proliferation. These results demonstrate an important mechanistic role for MAML3 in proliferation and RA-mediated differentiation.Implications: MAML3 coordinates transcription regulation with receptor tyrosine kinase pathway activation, shedding new light on why this gene is mutated in multiple cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mastermind-Like 3 Controls Proliferation and Differentiation in Neuroblastoma

Heynen

Nevedomskaya

Palit

et al. 2016

Molecular Cancer Research

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“…To gain insights into the regulation of cell proliferation by Ras proteins beyond the Raf/Mek/Erk cascade and to identify key elements that connect Ras signaling with the cell cycle machinery, we submitted mouse embryonic fibroblasts (MEFs) lacking all of the Ras proteins (Rasless cells) to an unbiased shRNA library "barcode" screen (10,11) (Fig. S1A).…”

Section: Resultsmentioning

confidence: 99%

“…1A). K-Raslox cells were transfected with the shRNA library and scored for cells capable of proliferating in the absence of Ras proteins (10,11) (Fig. S1A).…”

Section: Resultsmentioning

confidence: 99%

Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway

Drosten

Sum

Lechuga

et al. 2014

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

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The Ras family of small GTPases constitutes a central node in the transmission of mitogenic stimuli to the cell cycle machinery. The ultimate receptor of these mitogenic signals is the retinoblastoma (Rb) family of pocket proteins, whose inactivation is a required step to license cell proliferation. However, little is known regarding the molecular events that connect Ras signaling with the cell cycle. Here, we provide genetic evidence to illustrate that the p53/ p21 Cdk-interacting protein 1 (Cip1)/Rb axis is an essential component of the Ras signaling pathway. Indeed, knockdown of p53, p21Cip1, or Rb restores proliferative properties in cells arrested by ablation of the three Ras loci, H-, N-and K-Ras. Ras signaling selectively inactivates p53-mediated induction of p21Cip1 expression by inhibiting acetylation of specific lysine residues in the p53 DNA binding domain. Proliferation of cells lacking both Ras proteins and p53 can be prevented by reexpression of the human p53 ortholog, provided that it retains an active DNA binding domain and an intact lysine residue at position 164. These results unveil a previously unidentified role for p53 in preventing cell proliferation under unfavorable mitogenic conditions. Moreover, we provide evidence that cells lacking Ras and p53 proteins owe their proliferative properties to the unexpected retroactivation of the Raf/Mek/Erk cascade by a Ras-independent mechanism.T he RAS genes have been extensively studied due to their key role in mediating mitogenic signaling as well as their high prevalence in human cancers, including those cancers with poor survival rates, such as lung adenocarcinoma, colorectal carcinoma, and pancreatic ductal adenocarcinoma (1, 2). However, the mechanisms by which Ras proteins mediate mitogenic signaling in either normal or tumor cells remain obscure, especially beyond activation of the Raf/Mek/Erk cascade. Recent genetic studies have underscored the relevance of Ras proteins in cellular homeostasis by demonstrating that cells lacking the three Ras loci, H-Ras, N-Ras, and K-Ras (Rasless cells), are completely unable to proliferate (3, 4). Indeed, systemic ablation of these loci in adult mice causes rapid deterioration of multiple tissues, leading to their death in a few days.GTP-loaded Ras proteins promote activation of various downstream signal transduction pathways, mainly the Raf/Mek/Erk kinase cascade, the PI3K/Akt route, and the Ral guanine dissociation stimulator (RalGDS) pathway (1). Activation of other pathways, such as those pathways driven by the Rac family of small G proteins and phospholipase C, has also been illustrated (1). However, genetic interrogation of the pathways essential for cell proliferation has illustrated that only constitutive activation of the Raf, Mek, or Erk kinase can bypass the requirement for Ras proteins to sustain cell division, at least in vitro (3, 4). Indeed, constitutive activation of the PI3K/Akt and RalGDS pathways was incapable of inducing cell proliferation in the absence of Ras proteins. In agreement wit...

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CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming

Tao

Moreno‐Smith

Ibarra‐García‐Padilla

et al. 2021

Advanced Science

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Neuroblastoma (NB) arises from oncogenic disruption of neural crest (NC) differentiation. Treatment with retinoic acid (RA) to induce differentiation has improved survival in some NB patients, but not all patients respond, and most NBs eventually develop resistance to RA. Loss of the chromatin modifier chromatin assembly factor 1 subunit p150 (CHAF1A) promotes NB cell differentiation; however, the mechanism by which CHAF1A drives NB oncogenesis has remained unexplored. This study shows that CHAF1A gain-of-function supports cell malignancy, blocks neuronal differentiation in three models (zebrafish NC, human NC, and human NB), and promotes NB oncogenesis. Mechanistically, CHAF1A upregulates polyamine metabolism, which blocks neuronal differentiation and promotes cell cycle progression. Targeting polyamine synthesis promotes NB differentiation and enhances the anti-tumor activity of RA. The authors' results provide insight into the mechanisms that drive NB oncogenesis and suggest a rapidly translatable therapeutic approach (DFMO plus RA) to enhance the clinical efficacy of differentiation therapy in NB patients.

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ZNF423 Is Critically Required for Retinoic Acid-Induced Differentiation and Is a Marker of Neuroblastoma Outcome

Cited by 131 publications

References 45 publications

Mastermind-Like 3 Controls Proliferation and Differentiation in Neuroblastoma

Mastermind-Like 3 Controls Proliferation and Differentiation in Neuroblastoma

Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway

CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming

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