CREB signaling activity correlates with differentiation and survival in medulloblastoma.
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ABSTRACT:
SUBMITTER: Armandari I
PROVIDER: S-EPMC8352923 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neuronal survival and morphological maturation depends on the action of the transcription factor calcium responsive element binding protein (CREB), which regulates expression of several target genes in an activity-dependent manner. However, it remains largely unknown whether CREB-mediated transcription could play a role at early stages of neuronal differentiation, prior to the establishment of functional synaptic contacts. Here, we show that CREB is phosphorylated at very early stages of neuronal differentiation in vivo and in vitro, even in the absence of depolarizing agents. Using genetic tools, we also show that inhibition of CREB-signaling affects neuronal growth and survival in vitro without affecting cell proliferation and neurogenesis. Expression of A-CREB or M-CREB, 2 dominant-negative inhibitors of CREB, decreases cell survival and the complexity of neuronal arborization. Similar changes are observed in neurons treated with protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitors, which also show decreased levels of pCREBSer133. Notably, expression of CREB-FY, a Tyr134Phe CREB mutant with a lower Km for phosphorylation, partly rescues the effects of PKA and CaMKII inhibition. Our data indicate that CREB-mediated signaling play important roles at early stages of cortical neuron differentiation, prior to the establishment of fully functional synaptic contacts.
| S-EPMC6248567 | biostudies-literature
Project description:Neurotrophins are a family of secreted proteins that act by binding to tropomyosin receptor kinase (Trk) or p75NTR receptors to regulate nervous system development and plasticity. Increasing evidence indicates that neurotrophins and their receptors in cancer cells play a role in tumor growth and resistance to treatment. In this review, we summarize evidence indicating that neurotrophin signaling influences medulloblastoma (MB), the most common type of malignant brain cancer afflicting children. We discuss the potential of neurotrophin receptors as new therapeutic targets for the treatment of MB. Overall, activation of TrkA and TrkC types of receptors seem to promote cell death, whereas TrkB might stimulate MB growth, and TrkB inhibition displays antitumor effects. Importantly, we show analyses of the gene expression profile of neurotrophins and their receptors in MB primary tumors, which indicate, among other findings, that higher levels of NTRK1 or NTRK2 are associated with reduced overall survival (OS) of patients with SHH MB tumors.
| S-EPMC7564905 | biostudies-literature
Project description:Circadian rhythmicity in mammals is under the control of a molecular pacemaker constituted of clock gene products organized in transcriptional autoregulatory loops. Phase resetting of the clock in response to light involves dynamic changes in the expression of several clock genes. The molecular pathways used by light to influence pacemaker-driven oscillation of clock genes remain poorly understood. We explored the functional integration of both light- and clock-responsive transcriptional regulation at the promoter level of the Period (Per) genes. Three Per genes exist in the mouse. Whereas mPer1 and mPer2 are light-inducible in clock neurons of the hypothalamic suprachiasmatic nucleus, mPer3 is not. We have studied the promoter structure of the three mPer genes and compared their regulation. All three mPer promoters contain E-boxes and respond to the CLOCK/brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein 1 (BMAL1) heterodimer. On the other hand, only mPer1 and mPer2 promoters contain bona fide cAMP-responsive elements (CREs) that bind CRE-binding protein (CREB) from suprachiasmatic nucleus protein extracts. The mPer1 promoter is responsive to synergistic activation of the cAMP and mitogen-activated protein kinase pathways, a physiological response that requires integrity of the CRE. In contrast, activation of mPer promoters by CLOCK/BMAL1 occurs regardless of an intact CRE. Altogether, these results constitute strong evidence that CREB acts as a pivotal endpoint of signaling pathways for the regulation of mPer genes. Our results reveal that signaling-dependent activation of mPer genes is distinct from the CLOCK/BMAL1-driven transcription required within the clock feedback loop.
| S-EPMC124335 | biostudies-literature
Project description:BackgroundCerebellar mutism syndrome (CMS) is a common complication following resection of posterior fossa tumors, most commonly after surgery for medulloblastoma. Medulloblastoma subgroups have historically been treated as a single entity when assessing CMS risk; however, recent studies highlighting their clinical heterogeneity suggest the need for subgroup-specific analysis. Here, we examine a large international multicenter cohort of molecularly characterized medulloblastoma patients to assess predictors of CMS.MethodsWe assembled a cohort of 370 molecularly characterized medulloblastoma subjects with available neuroimaging from 5 sites globally, including Great Ormond Street Hospital, Christian Medical College and Hospital, the Hospital for Sick Children, King Hussein Cancer Center, and Lucile Packard Children's Hospital. Age at diagnosis, sex, tumor volume, and CMS development were assessed in addition to molecular subgroup.ResultsOverall, 23.8% of patients developed CMS. CMS patients were younger (mean difference -2.05 years ± 0.50, P = 0.0218) and had larger tumors (mean difference 10.25 cm3 ± 4.60, P = 0.0010) that were more often midline (odds ratio [OR] = 5.72, P < 0.0001). In a multivariable analysis adjusting for age, sex, midline location, and tumor volume, Wingless (adjusted OR = 4.91, P = 0.0063), Group 3 (adjusted OR = 5.56, P = 0.0022), and Group 4 (adjusted OR = 8.57 P = 9.1 × 10-5) tumors were found to be independently associated with higher risk of CMS compared with sonic hedgehog tumors.ConclusionsMedulloblastoma subgroup is a very strong predictor of CMS development, independent of tumor volume and midline location. These findings have significant implications for management of both the tumor and CMS.
| S-EPMC7442348 | biostudies-literature
Project description:Long interspersed elements 1 (LINE-1 or L1) are retrotransposons that dominate the mouse genomic landscape, and are expressed in Embryonic Stem Cells (ESCs), germ cells, and during early development. Based on clear precedents in plants and fission yeast, we investigated in this study a role for RNAi and other RNA degradation pathways in the regulation of L1 expression and mobilization. We uncovered the existence of novel small (s)RNAs that map to active L1 elements. Some of these sRNAs have characteristics of cognate short-interfering RNA populations, while others display length heterogeneity that evokes a biogenesis through a RNA surveillance pathway, in a Dicer-independent manner. We additionally found that genetic ablation of Dicer and the sRNA effector protein AGO2 has complex and profound consequences on L1 transcription and mobilization in ESCs, indicating that endogenous RNA interference (RNAi) pathway indeed maintain genomic integrity against L1 proliferation. Finally, we investigated the implication of L1 retrotransposition during ESC differentiation and propose that the mobilization of L1 elements in Dicer mutant ESCs could partially explain the inability of these cells to differentiate. 2 samples examined: WT E14 and Dicer mutant mouse ESCs
2013-12-11 | E-GEOD-43110 | biostudies-arrayexpress
Project description:Tumor cells are characterized by unlimited proliferation and perturbed differentiation. Using single-cell RNA sequencing, we demonstrate that tumor cells in medulloblastoma (MB) retain their capacity to differentiate in a similar way as their normal originating cells, cerebellar granule neuron precursors. Once they differentiate, MB cells permanently lose their proliferative capacity and tumorigenic potential. Differentiated MB cells highly express NeuroD1, a helix-loop-helix transcription factor, and forced expression of NeuroD1 promotes the differentiation of MB cells. The expression of NeuroD1 in bulk MB cells is repressed by trimethylation of histone 3 lysine-27 (H3K27me3). Inhibition of the histone lysine methyltransferase EZH2 prevents H3K27 trimethylation, resulting in increased NeuroD1 expression and enhanced differentiation in MB cells, which consequently reduces tumor growth. These studies reveal the mechanisms underlying MB cell differentiation and provide rationales to treat MB (potentially other malignancies) by stimulating tumor cell differentiation.
| S-EPMC7357167 | biostudies-literature
Project description:BackgroundExtensive evidence implicates the Eph receptor family of tyrosine kinases and its ligand, ephrin, in glioma invasion, but it remains incompletely understood how these receptors affect chemotactic behavior of glioma. We sought to identify the Eph family members that correlate with patients' survival and to reveal the function of Eph in glioma invasion.MethodsClinical relevance of EphB genes was confirmed in a clinically annotated expression data set of 195 brain biopsy specimens. The function of EphB was analyzed in vitro and in vivo.ResultsLevels of mRNA of certain EphB members were significantly different in histological grades of glioma. According to Kaplan-Meier analysis, only the EphB1 level among 5 members of EphB emerged to be a powerful predictor of favorable survival in malignant glioma (n = 97, P = .0048), although the levels of EphB1 expression did not vary across the tumor grades. Immunoprecipitation showed that tyrosine phosphorylated EphB1 was not detected in all glioma cells tested. Forced overexpression and autophosphorylation of EphB1 in low expressor cell lines (U251, U87) did not affect cell migration or invasion in vitro, whereas EphB1 phosphorylation induced by ephrin-B2/Fc significantly decreased migration and invasion. Cells expressing ephrin-B2 showed noteworthy morphological changes consistent with migration induction; this alteration was negated by EphB1 overexpression. Concomitantly, overexpression of EphB1 abrogated the increased migration and invasion induced by ephrin-B2 in vitro and in vivo.ConclusionsThese data suggest that ligand-dependent EphB1 signaling negatively regulates glioma cell invasion, identifying EphB1 as a favorable prognostic factor in malignant glioma.
| S-EPMC3829595 | biostudies-literature
Project description:Radiotherapy remains the standard treatment for medulloblastoma (MB), and the radioresistance contributes to tumor recurrence and poor clinical outcomes. Nuclear DNA topoisomerase II-alpha (TOP2A) is a key catalytic enzyme that initiates DNA replication, and studies have shown that TOP2A is closely related to the therapeutic effects of radiation. In this study, we found that TOP2A was significantly upregulated in MB, and high expression of TOP2A related to poor prognosis of MB patients. Knockdown of TOP2A inhibited MB cell proliferation, migration, and invasion, whereas overexpression of TOP2A enhanced the proliferative and invasive ability of MB cells. Moreover, si-TOP2A transfection in combination with irradiation (IR) significantly reduced the tumorigenicity of MB cells, compared with those transfected with si-TOP2A alone. Cell survival curve analysis revealed that the survival fraction of MB cells was significantly reduced upon TOP2A downregulation and that si-TOP2A-transfected cells had decreased D0, Dq, and SF2 values, indicating that TOP2A knockdown suppresses the resistance to radiotherapy in MB cells. In addition, western blot analysis demonstrated that the activity of Wnt/β-catenin signaling pathway was inhibited after TOP2A downregulation alone or in combination with IR treatment, whereas overexpression of TOP2A exhibited the opposite effects. Gene set enrichment analysis also revealed that Wnt/β-catenin signaling pathway is enriched in TOP2A high-expression phenotypes. Collectively, these data indicate that high expression of TOP2A leads to poor prognosis of MB, and downregulation of TOP2A inhibits the malignant behaviour as well as the radioresistance of MB cells. The Wnt/β-catenin signaling pathway may be involved in the molecular mechanisms of TOP2A mediated reduced tumorigenicity and radioresistance of MB cells.
| S-EPMC9337862 | biostudies-literature
Project description:PurposeTumor infiltration by immunosuppressive myeloid cells or tumor-associated macrophages (TAMs) contributes to tumor progression and metastasis. In contrast to their adult counterparts, higher TAM signatures do not correlate with aggressive tumor behavior in pediatric brain tumors. While prominent TAM infiltrates exist before and after radiation, the degree to which irradiated macrophages and microglia support progression or leptomeningeal metastasis remains unclear. Patients with medulloblastoma often present with distant metastases and tumor recurrence is largely incurable, making them prime candidates for the study of novel approaches to prevent neuroaxis dissemination and recurrence.MethodsMacrophage depletion was achieved using CSF-1 receptor inhibitors (CSF-1Ri), BLZ945 and AFS98, with or without whole brain radiation in a variety of medulloblastoma models, including patient-derived xenografts bearing Group 3 medulloblastoma and a transgenic Sonic Hedgehog (Ptch1+/-, Trp53-/-) medulloblastoma model.ResultsEffective reduction of microglia, TAM, and spinal cord macrophage with CSF-1Ri resulted in negligible effects on the rate of local and spinal recurrences or survival following radiation. Results were comparable between medulloblastoma subgroups. While notably few tumor-infiltrating lymphocytes (TILs) were detected, average numbers of CD3+ TILs and FoxP3+ Tregs did not differ between groups following treatment and tumor aggressiveness by Ki67 proliferation index was unaltered.ConclusionIn the absence of other microenvironmental influences, medulloblastoma-educated macrophages do not operate as tumor-supportive cells or promote leptomeningeal recurrence in these models. Our data add to a growing body of literature describing a distinct immunophenotype amid the medulloblastoma microenvironment and highlight the importance of appropriate pediatric modeling prior to clinical translation.
| S-EPMC8248272 | biostudies-literature
Project description:Smad proteins are intracellular transducers for transforming growth factor-beta (TGF-beta) signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-beta and its regulated gene, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in the etiology and progression of neurodegenerative diseases and mood disorders. We previously reported that GSK-3beta protein depletion suppresses Smad3/4-dependent gene transcription and causes a reduction in PAI-1 expression. Here, we provide evidence that lithium, the drug for the treatment and prophylaxis of bipolar disorder, inhibits Smad-dependent signaling by regulating cAMP-protein kinase A (PKA), AKT-glycogen synthase kinase-3beta (GSK-3beta), and CRE-dependent signaling pathways in neuron-enriched cerebral cortical cultures of rats. We demonstrate that lithium-induced activation of these pathways inhibits Smad3/4-dependent gene transcription through an increase in pCREB(Ser133) protein levels, an enhanced interaction between pCREB(Ser133) and p300/CBP, which causes Smad3/4-p300/CBP complex disruption and transcriptional suppression of Smad3/4-dependent genes. Therapeutic implications of our findings are discussed.
| S-EPMC2276841 | biostudies-literature