The long and the short of it: the MDM4 tail so far

Haupt, Sue; Mejía-Hernández, Javier Octavio; Vijayakumaran, Reshma; Keam, Simon P.; Haupt, Ygal

doi:10.1093/jmcb/mjz007

Cited by 57 publications

(65 citation statements)

References 134 publications

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“…Pbx1 plays a vital part in midbrain dopaminergic neuron development which has been reported to be impaired in PD 12 . Mdm4 has the capability to restrict the transcriptional activity of tumor suppressor p53 13 and p53 inhibitors are highly effective in protecting midbrain dopamine neurons and preserving motor function in PD mouse model 14 . Besides, alternative splicing dysregulation of Mdm4 can lead to the death of motor neurons 15 , which is one of the most prominent pathological features of PD.…”

Section: Resultsmentioning

confidence: 99%

Integrated profiling of single cell epigenomic and transcriptomic landscape of Parkinson’s disease mouse brain

Zhong

Tang

Zhu

et al. 2020

Preprint

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Parkinson's disease (PD) is a neurodegenerative disease leading to the impairment 24 of execution of movement. PD pathogenesis has been largely investigated, but either restricted 25 in bulk level or at certain cell types, which failed to capture cellular heterogeneity and intrinsic 26 interplays among distinct cell types. To overcome this, we applied single-nucleus RNA-seq 27 and single cell ATAC-seq on cerebellum, midbrain and striatum of PD mouse and matched 28 control. With 74,493 cells in total, we comprehensively depicted the dysfunctions under PD 29 pathology covering proteostasis, neuroinflammation, calcium homeostasis and extracellular 30 neurotransmitter homeostasis. Besides, by multi-omics approach, we identified putative 31 biomarkers for early stage of PD, based on the relationships between transcriptomic and 32 epigenetic profiles. We located certain cell types that primarily contribute to PD early 33 pathology, narrowing the gap between genotypes and phenotypes. Taken together, our study 34 provides a valuable resource to dissect the molecular mechanism of PD pathogenesis at single 35 cell level, which could facilitate the development of novel methods regarding diagnosis, 36 monitoring and practical therapies against PD at early stage. 37 38 39 Plenty of studies have made great progress in disentangling the link between -syn 52 oligomerization and neuron death, revealing pathways including proteostasis, mitochondrial 53 dysfunction, neuroinflammation and so on 4 . Nevertheless, the majority of previously studies 54 were conducted at tissue level. Wassouf's team performed RNA-seq on 6-month-old mice 55 overexpressing SNCA ( -syn encoding gene) and found that striatal gene expression profiles 56 3 were greatly disrupted, whose functions were primarily related to neuroinflammation and 57 synaptic plasticity 5 . Richard et. al. combined bulk and single-cell RNA-seq for iPSC-derived 58 dopamine neurons with a GBA mutation and identified HDAC4 as a potential therapeutic PD 59 target 6 . Given the fact that intricate interplay across and within cell types jointly contributes to 60 PD pathogenesis 7 , it is essential to interrogate cell-resolution information in order to unveil the 61 possible PD-related and PD-causing molecular circuits. Single cell sequencing technologies 62 have facilitated the researches in various fields, providing us an opportunity to capture subtler 63 changes that may be masked by bulk sequencing. 64 65Of note, due to synaptic plasticity, 80% of dopaminergic neurons in SN have been lost before 66 any diagnosable symptoms of PD occur 8 . Hence, this raises the necessity to dissect cellular 67 changes in the early stage of PD and identify corresponding markers, ultimately allowing the 68 development of novel early interventions. Nigrostriatal dopamine pathway malfunction 69 attributes largely to PD pathologies 9 . Besides, cerebellum is the pivot of motor coordination 70 but has been often overlooked in Parkinsonism. Therefore, with the aim to explore the 71 deregulation in early sta...

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Section: Resultsmentioning

confidence: 99%

Integrated profiling of single cell epigenomic and transcriptomic landscape of Parkinson’s disease mouse brain

Zhong

Tang

Zhu

et al. 2020

Preprint

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“…53 In future works, we intend to test such inhibitors in vitro (in cisplatin-resistant (T)GCT cell lines) and also explore the role of additional regulators of p53, like MDM4. 54…”

Section: Discussionmentioning

confidence: 99%

p53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome

et al. 2020

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Background Testicular germ cell tumors (TGCTs) are highly sensitive to platinum‐based chemotherapy, and wild‐type p53 seems to play a pivotal role in this susceptibility. On the other hand, overexpression of MDM2 seems to entail treatment resistance and unfavorable prognosis. Objectives We aimed to describe p53 and MDM2 immunoexpression in a well‐characterized cohort of primary and metastatic TGCTs and evaluate associations with clinicopathological and prognostic variables, including survival. Materials and methods 237 primary tumor samples and 12 metastases were evaluated for p53 and MDM2 immunoexpression using digital image analysis. Clinical records of all patients were reviewed for baseline clinical/pathologic characteristics and follow‐up. Results A significant positive correlation between p53 and MDM2 H‐scores was found (rs = 0.590, P < .0001). Non‐seminomas showed significantly higher expression levels of both p53 and MDM2 (P = .0002, P < .0001), which peaked in embryonal carcinomas and choriocarcinomas. Percentage of immunoexpressing cells and H‐score were significantly higher in chemo‐treated metastases compared with chemo‐naïve primary tumors for MDM2 (P ≤ .0001 for both), but not for p53 (P = .919 and P = .703, respectively). Cases with higher MDM2 immunoexpression showed a statistically significant trend for association with poorer prognosis (P = .043). Relapse/progression‐free survival at 12 months post‐diagnosis was lower in the “MDM2‐high” (≥P50) vs. the “MDM2‐low” (

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“…By centering on p53, the docking grid was created. In particular, a grid box size of 24×18×22 and centered at 0.514 (x), - 21.838 (y), and 8.047 (z) was set with spacing of 1.0 Å between the grid points.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…and Mdmx proteins [17]. The former is the first experimentally identified as a major endogenous inhibitor of p53 [18][19][20], and the latter, which is highly homologous with Mdm2, influences p53 transcriptional activity [14] and is a vital independent regulator of p53 [21]. Until now, however, the studies on smallmolecule Mdmx inhibitors have made slow progress.…”

Section: Introductionmentioning

confidence: 99%

Focused Library Generator: case of Mdmx inhibitors

Xia

Karpov

Popowicz

et al. 2019

J Comput Aided Mol Des

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We present a Focused Library Generator that is able to create from scratch new molecules with desired properties. After training the Generator on the ChEMBL database, transfer learning was used to switch the generator to producing new Mdmx inhibitors that are a promising class of anticancer drugs. Lilly medicinal chemistry filters, molecular docking, and a QSAR IC 50 model were used to refine the output of the Generator. Pharmacophore screening and molecular dynamics (MD) simulations were then used to further select putative ligands. Finally, we identified five promising hits with equivalent or even better predicted binding free energies and IC 50 values than known Mdmx inhibitors. The

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The long and the short of it: the MDM4 tail so far

Cited by 57 publications

References 134 publications

Integrated profiling of single cell epigenomic and transcriptomic landscape of Parkinson’s disease mouse brain

Integrated profiling of single cell epigenomic and transcriptomic landscape of Parkinson’s disease mouse brain

p53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome

Focused Library Generator: case of Mdmx inhibitors

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