ATF2 phosphorylation is essential for neuronal apoptosis, linking the DLK/LZK kinase cascade to JUN upregulation
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PROVIDER: PRJNA1188177 | ENA |
REPOSITORIES: ENA
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Project description:Apoptotic neuron death is a common feature of many neurodegenerative diseases. Perhaps surprisingly, the exact mechanisms by which neurons undergo apoptosis have yet to be elucidated. We conducted an unbiased whole genome screen in human neurons to discover genes required for apoptotic neuron death, and found ATF2, MAP3K12 and JUN among top hits. We demonstrate that ATF2 is a previously unappreciated master regulator of neuron death. ATF2 is phosphorylated downstream of MAP3K12 (dual leucine zipper kinase) and MAP3K13 (leucine zipper kinase) and its phosphorylation is essential for transcriptional upregulation of JUN. We show that JUN upregulation is essential for apoptosis – but not its phosphorylation. Contrary to previous assumptions, cJun phosphorylation is therefore simply a correlate of JUN upregulation. In this study, we identify phosphorylation of ATF2 as a key event in the mechanism of neuronal apoptosis, linking the MAP3K12/13 kinase cascade to transcriptional upregulation of JUN. Since targeting members of this signaling pathway to block neuronal death has proved difficult, ATF2 offers a novel and promising alternative.
2025-04-30 | GSE282354 | GEO
Project description:Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress
2010-06-05 | E-GEOD-1810 | biostudies-arrayexpress
Project description:Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress Keywords: other
2004-10-06 | GSE1810 | GEO
Project description:Injury to peripheral axons initiates a complex cascade of cellular responses, including cytoskeletal disassembly, axon transport disruption, and ultimately axon regeneration. Central to this process is the MAP triple kinase Dual-Leucine Zipper Kinase (DLK), activated by injury and other neuronal stressors. Here, we propose the existence of a homeostatic mechanism termed the Cytoskeletal Perturbation Response (CPR). We investigate this hypothesis by examining the response of cultured dorsal root ganglion (DRG) neurons to low dose nocodazole treatment, a cytoskeletal perturbing agent. To gain insights into DLK-dependent transcriptional changes following cytoskeletal insult, we performed bulk RNA sequencing on cultured neurons treated for 16 hours. Using a fully crossed two-factor design, we determined the interactive effect of DLK on nocodazole- dependent transcriptional changes. Our study demonstrates that cytoskeletal perturbation triggers DLK-dependent signaling cascades, leading to significant transcriptional changes. These changes involve transcription factors (Jun, Egr1, Atf3) and MAP kinase regulators (DUSPs), pointing to a regulatory network that attenuates DLK signaling. Taken together, our findings suggest that cytoskeletal perturbation activates a DLK-dependent homeostatic mechanism, the CPR, which orchestrates transcriptional changes and morphological adaptations to repair neuronal damage. The CPR bears similarities to established homeostatic responses, offering insights into the intricate processes that underlie axon regeneration and cellular repair.
2023-10-11 | GSE244883 | GEO
Project description:The conserved MAPKKK DLK plays many roles in neuronal development, axon injury, and neuronal stress responses. The outcomes of activating or inhibiting DLK signaling depend on cell-type and cellular contexts. Emerging evidence has implicated DLK signaling in several neurodegenerative diseases. However, our understanding of the DLK-dependent cellular network in the central nervous system remains limited. Here, we investigated roles of DLK in hippocampal glutamatergic neurons, using conditional knockout and overexpression mice. We find that dorsal CA1 and dentate gyrus neurons are particularly vulnerable to elevated DLK activity. We performed RiboTRAP-seq analysis and identified the DLK dependent translatome, majority of which are involved in neuronal developmental processes, neuronal stress responses, and synapse formation and function. Increasing DLK signaling is associated with disruptions of microtubules, potentially involving Stmn4. We also show that in primary hippocampal neurons DLK regulates neurite outgrowth, axon specification, and synapse formation. This study broadens our understanding of both conserved and cell-type specific effects of DLK signaling. The identification of translational targets of DLK in glutamatergic neurons has relevance to our understanding of neurodegenerative disease.
2025-01-16 | GSE266662 | GEO
Project description:To profile downstream gene-expression changes regulated by DLK, we profiled motoneurons in the lumbar spinal cord using RiboTag, following sciatic nerve crush in both control and Dlk conditional knockout (Dlk ΔMN) mice. We found that DLK regulates the expression of many secreted proteins, which have the potential to influence the behavior of other cells, including the immune system.
2024-01-22 | GSE213987 | GEO
Project description:Alzheimer’s disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK) were effective in alleviating wild-type human tau-induced neurodegeneration. In contrast, mutant P301L human tau was less toxic to neurons, despite causing comparable DNA damage. Axonal DLK activation induced by wild-type tau potentiated the impact of DNA damage response, resulting in overt neurotoxicity. In summary, we have established a cellular tauopathy model highly relevant to AD and identified a functional synergy between the MAPK-DLK axis and DNA damage response in the neuronal degenerative process.
2023-11-15 | GSE246259 | GEO
Project description:Characterized by striking metastatic propensity and chemoresistance, melanoma is among the most lethal cutaneous malignancies. The transcription factor ATF2 was shown to elicit oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, a mouse model engineered to express a transcriptionally inactive form of Atf2 (Atf2?8,9) was found to be sufficient to induce nevi formation and, when crossed with BrafV600E animals, to promote melanoma development. The cross of Atf2?8,9 with BrafV600E;Pten-/- mice augmented pigmentation, tumorigenicity, and metastasis. Similar to mouse Atf2?8,9, the human ATF2 splice variant 5 enhanced growth and migration capacity of cultured melanoma and immortalized melanocytes. Induced Melan-A, CXCL9, S100A8, CCR7 expression, seen in Atf2?8,9-driven tumors associate with their enhanced pigmentation, immune infiltration and propensity to metastasize. Notably, elevated ATF2SV5 expression in melanoma specimens coincided with poor prognosis. The gain-of-function activity elicited by the truncated ATF2 form offers unexpected insight into mechanisms underlying melanoma development and progression.
2016-05-02 | GSE81013 | GEO
Project description:Characterized by striking metastatic propensity and chemoresistance, melanoma is among the most lethal cutaneous malignancies. The transcription factor ATF2 was shown to elicit oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, a mouse model engineered to express a transcriptionally inactive form of Atf2 (Atf2?8,9) was found to be sufficient to induce nevi formation and, when crossed with BrafV600E animals, to promote melanoma development. The cross of Atf2?8,9 with BrafV600E;Pten-/- mice augmented pigmentation, tumorigenicity, and metastasis. Similar to mouse Atf2?8,9, the human ATF2 splice variant 5 enhanced growth and migration capacity of cultured melanoma and immortalized melanocytes. Induced Melan-A, CXCL9, S100A8, CCR7 expression, seen in Atf2?8,9-driven tumors associate with their enhanced pigmentation, immune infiltration and propensity to metastasize. Notably, elevated ATF2SV5 expression in melanoma specimens coincided with poor prognosis. The gain-of-function activity elicited by the truncated ATF2 form offers unexpected insight into mechanisms underlying melanoma development and progression.
2016-04-29 | GSE79917 | GEO
Project description:In order to identify transcriptional targets of ATF2, we used a recombinant adenovirus to express constitutively active ATF2 in murine hepatoblasts. Expression of GFP was the control condition. Total RNA was harvested from cells 8 hours post infection. Reverse transcription was performed using Ovation Pico WTA kit (NuGen, 3300-12). Labelling, Encore Biotin Module (NuGen, 4200-12) three replicates GFP control and C2ATF2
2013-11-10 | E-GEOD-50530 | biostudies-arrayexpress