Biology subjects

Yang, J.

Publications and source records attributed to Yang, J..

At least 451 records · Page 25Linked to original sources

bioRxiv2024

Aquatic risk calibration of tire wear particle in interaction with leaching time, high temperature and UV radiation based on reproductive toxicity to zooplankton

The aquatic toxicity of tire wear particles (TWPs) depends on the leaching of various components. The leaching process is time-dependent and influenced by various environmental factors, leading to fluctuation in leachate toxicity. In this study, we quantified the temporal dynamics of leachate toxicity using the dose-response model. Meanwhile, to simulate weathering conditions, TWPs were exposed to ultraviolet (UV) irradiation and elevated temperature. The results indicated that the leachate toxicity over time fitted a biphasic pattern, with an initial increase followed by a decrease, peaking at the 11th day. The toxicity fluctuation cannot be characterized by any single component, but rather leachate should be considered as an integral whole aligning with a typical hormesis dose-response curve. High temperature of road surface increased leachate toxicity by 66%, due to elevated concentrations of 67 identified organic compounds. UV irradiation, however, mitigated this effect, acting as antagonism. These findings underline the seasonal and spatial heterogeneity in leachate toxicity. Additionally, high temperature induced the volatilization of organic compounds within TWPs, highlighting an independent exposure pathway. The methodology developed in this study will provide foundation and standard for future research on the aquatic ecotoxicity of TWPs. Environmental ImplicationThe toxicity of leachate from ubiquitous tire wear particles (TWPs) to aquatic organisms has been confirmed in field and experimental studies. However, existing researches indirectly used TWPs quantity as sole proxy for leachate toxicity, neglecting its fluctuations over leaching duration and in situ environmental factors, potentially confounding toxic effects. Herein, this study quantifies these dynamics of leachate toxicity based on measurable biological response, aiming to establish a standard scale for further quantitative assessment of TWPs ecological risk.

ecology↗

bioRxiv2024

Dynamic Gamma Modulation of Hippocampal Place Cells Predominates Development of Theta Sequences

The experience-dependent spatial cognitive process requires sequential organization of hippocampal neural activities by theta rhythm, which develops to represent highly compressed information for rapid learning. However, how the theta sequences were developed in a finer time scale within theta cycles remains unclear. In this study, we found that sweep-ahead structure of theta sequences developing with exploration was predominantly dependent on a relatively large proportion of FG-cells, i.e. a subset of place cells dominantly phase-locked to fast gamma rhythms. These ensembles integrated compressed spatial information by cells consistently firing at precessing slow gamma phases within the theta cycle. Accordingly, the sweep-ahead structure of FG-cell sequences was positively correlated with the intensity of slow gamma phase precession, in particular during early development of theta sequences. These findings highlight the dynamic network-modulation by fast and slow gamma in the development of theta sequences which may further facilitate memory encoding and retrieval.

neuroscience↗

bioRxiv2024

Sensitive Fluorescent Biosensor Reveals Differential Subcellular Regulation of PKC

The protein kinase C (PKC) family of serine/threonine kinases, which consist of three distinctly regulated subfamilies, have long been established as critical for a variety of cellular functions. However, how PKC enzymes are regulated at different subcellular locations, particularly at emerging signaling hubs such as the ER, lysosome, and Par signaling complexes, is unclear. Here, we present a sensitive Excitation Ratiometric (ExRai) C Kinase Activity Reporter (ExRai-CKAR2) that enables the detection of minute changes in subcellular PKC activity. Using ExRai-CKAR2 in conjunction with an enhanced diacylglycerol (DAG) biosensor capable of detecting intracellular DAG dynamics, we uncover the differential regulation of PKC isoforms at distinct subcellular locations. We find that G-protein coupled receptor (GPCR) stimulation triggers sustained PKC activity at the ER and lysosomes, primarily mediated by Ca2+ sensitive conventional PKC (cPKC) and novel PKC (nPKC), respectively, with nPKC showing high basal activity due to elevated basal DAG levels on lysosome membranes. The high sensitivity of ExRai-CKAR2, targeted to either the cytosol or Par-complexes, further enabled us to detect previously inaccessible endogenous atypical PKC (aPKC) activity in 3D organoids. Taken together, ExRai-CKAR2 is a powerful tool for interrogating PKC regulation in response to physiological stimuli.

bioengineering↗

bioRxiv2024

KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3

Intellectual disability (ID) affects [~]2% of the general population and is often genetic in origin. ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is KAT6A, whose de novo heterozygous mutations cause KAT6A Syndrome (or Arboleda-Tham Syndrome), with ID as a common clinical feature. However, the underlying molecular mechanisms remain elusive. Here, we show that haploinsufficiency of Kat6a impairs learning and memory in mice, and specific deletion of Kat6a in excitatory neurons recapitulates the hippocampus-dependent memory deficits. Unexpectedly, KAT6A deficiency results in impaired synaptic structure and plasticity in hippocampal CA3, but not in CA1 region. Combining single-nucleus RNA-sequencing and chromatin analysis, we identify a CA3-enriched gene Rspo2, encoding a Wnt activator R-spondin 2, as a key transcriptional target of KAT6A. Moreover, deletion of Rspo2 in excitatory neurons phenocopies the loss of Kat6a, resulting in defective Wnt/{beta}-catenin signaling and synaptic plasticity in CA3, and abnormal cognitive behaviors in mice. Importantly, restoring RSPO2 expression in CA3 pyramidal neurons rescues the deficits in Wnt signaling and learning-associated behaviors in Kat6a mutant mice. Collectively, our results demonstrate that KAT6A plays a critical role in regulating synaptic plasticity and memory formation through RSPO2-mediated Wnt signaling in hippocampal CA3, shedding new light on the fundamental mechanisms of ID and providing potential therapeutic targets for the treatment of KAT6A Syndrome and related neurodevelopmental diseases.

neuroscience↗

bioRxiv2024

RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage-specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.

cancer biology↗

bioRxiv2024

LncRNA-Snhg3 Aggravates Hepatic Steatosis by Regulating PPARγ via SND1/H3K27me3

LncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNA Snhg3 in the development and progression of MASLD, along with the underlying mechanisms. The result showed that Snhg3 was significantly downregulated in the liver of high-fat diet-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of Snhg3 and overexpression of Snhg3 increased lipid accumulation in primary hepatocytes. Furthermore, hepatocyte-specific Snhg3 deficiency decreased body and liver weight, alleviated hepatic steatosis and promoted hepatic fatty acid metabolism in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, Snhg3 promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, Snhg3 decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the Ppar{gamma} promoter and enhancing Ppar{gamma} expression. The administration of PPAR{gamma} antagonist T0070907 improved Snhg3-aggravated hepatic steatosis. Our study revealed a new signaling pathway, Snhg3/SND1/H3K27me3/PPAR{gamma}, responsible for MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.

molecular biology↗

bioRxiv2024

CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development--either alone, or in the context of other genetic alterations--and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with Trp53 inactivation but negatively associated with Pten inactivation--akin to what is observed in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent Trp53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic Cdk12 and Trp53 loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably, Cdk12/Trp53 loss prostate tumors are sensitive to immune checkpoint blockade. Cdk12-null organoids (either with or without Trp53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treating CDK12-mutant mCRPC.

cancer biology↗

bioRxiv2024

Map based cloning of CT2 and the pilot functional exploration in abiotic stress

Heterotrimeric G-proteins are multifunctional modulators that participate in a wide range of growth and developmental processes in eukaryotic species, from yeast to plants and animals. Component detection and the study of G protein signaling in most plants, including maize, are in the initial stages. In this study, we characterized a maize mutant, ct2, that showed a compact architecture and reproductive organ-related phenotypic variation. The target gene CT2 was cloned using bulked segregant analysis and map-based cloning. Gene structure prediction and phylogenetic analysis indicated that CT2 is a canonical G protein belonging to the monocotyledonous group. Promoter analysis of CT2 and RNA sequencing revealed cis-acting regulatory elements and differentially expressed genes involved in JA signaling and stress tolerance. The transcription of CT2 was repressed by NaCl and PEG treatments, and ct2 mutation in the ct2 line compromised stress tolerance in maize. On the basis of our results, we proposed a schema diagram of CT2-regulated biological process and their feedback on CT2 transcription. This research provides clues for further studies of CT2 function in hormone signaling and stress tolerance, which is beneficial for maize breeding through the screening and application of beneficial alleles.

molecular biology↗

bioRxiv2024

Nine high-quality Anas genomes provide new insights into Anas evolution and domestication

The evolutionary origin and genetic architecture of domestic animals are becoming more tractable as the availability of more domestic species genomes. Evolutionary studies of wild and domestic organisms have yielded many fascinating discoveries, while the stories behind the species diversity of Anas or the domestication of duck were largely unknown. Here, we assembled eight chromosome-level Anas genomes. Together with our recently available Pekin duck genome, we investigated Anas phylogeny, genetic differentiation, and gene flow. Extensive phylogenetic inconsistencies were observed in Anas genomes, particularly two phylogeny conflicts between autosome and Z-chromosome. However, the Z chromosome was less impacted by introgression and more suitable to elucidate phylogenetic relationships than autosomes. From the Z-chromosome perspective, we found that the speciation of Anas platyrhynchos and Anas zonorhyncha accompanied with female-biased gene flow, and remodeled duck domestication history. Moreover, we constructed an Anas pan-genome and identified several differentiated SVs between domestic and wild ducks. These SVs might act as repressors/enhancers to regulate their neighboring genes (i.e., GHR and FER), which represented the promising "domestication genes". Additionally, Anas genomes were found being presented LTR retrotransposon bursts, which might largely contribute to functional shifts of genes involved in duck domestication (i.e., MITF and IGF2BP1). This study opens a new window to unravel avian speciation and domestication from Z chromosome.

genomics↗

bioRxiv2024

Multi-Scale Protein Language Model for Unified Molecular Modeling

Protein language models have demonstrated significant potential in the field of protein engineering. However, current protein language models primarily operate at the residue scale, which limits their ability to provide information at the atom level. This limitation prevents us from fully exploiting the capabilities of protein language models for applications involving both proteins and small molecules. In this paper, we propose ESM-AA (ESM All-Atom), a novel approach that enables atom-scale and residue-scale unified molecular modeling. ESM-AA achieves this by pretraining on multi-scale code-switch protein sequences and utilizing a multi-scale position encoding to capture relationships among residues and atoms. Experimental results indicate that ESM-AA surpasses previous methods in proteinmolecule tasks, demonstrating the full utilization of protein language models. Further investigations reveal that through unified molecular modeling, ESM-AA not only gains molecular knowledge but also retains its understanding of proteins.1

bioinformatics↗

bioRxiv2024

Bacteria in honeybee crops are decoupled from those in floral nectar and bee mouths

Bacteria in the honeybee gut are a well-recognized factor affecting bee health. However, the primary focus of this research has been the hindgut, while the crop, or honey stomach, is assumed to be dominated by environmentally acquired transient taxa that matter little to the bees. To evaluate this assumption, we examined bacterial taxa in the crop and mouth of Apis mellifera and A. cerana japonica foragers and in the nectar of Prunus mume flowers visited by the bees in the Minabe-Tanabe region of Japan. We found that in bacterial composition, the crop was distinct from both the mouth and the nectar, whereas mouth and nectar samples were indistinguishable. Furthermore, the crop remained similar in bacterial composition and diversity, while the mouth showed a sharp drop in alpha diversity and a large increase in beta diversity, from summer to winter. These results refute the conventional assumption, suggesting instead that the crop contains a conserved bacterial community largely distinct from environmental taxa. We also found that strains of a crop-associated species, Apilactobacillus kunkeei, could be season- and host species-specific. Together, these findings suggest that crop-associated bacterial communities should be studied further to better understand the relationship between honeybees and their gut bacteria.

ecology↗

bioRxiv2024

In silico identification of putative causal genetic variants

Understanding the causal genetic architecture of complex phenotypes will fuel future research into disease mechanisms and potential therapies. Here, we illustrate the power of a novel framework: it detects, starting from summary statistics, and across the entire genome, sets of variants that carry non-redundant information on the phenotypes and are therefore more likely to be causal in a biological sense. The approach, implemented in open-source software, is also computationally efficient, requiring less than 15 minutes on a single CPU to perform genome-wide analysis. Through extensive genome-wide simulation studies, we show that the method can substantially outperform existing methods in false discovery rate control, statistical power and various fine-mapping criteria. In applications to a meta-analysis of ten large-scale genetic studies of Alzheimers disease (AD), we identified 82 loci associated with AD, including 37 additional loci missed by conventional GWAS pipeline. Massively parallel reporter assays and CRISPR-Cas9 experiments have confirmed the functionality of the putative causal variants our method points to. Finally, we retrospectively analyzed summary statistics from 67 large-scale GWAS for a variety of phenotypes. Results reveal the methods capacity to robustly discover additional loci for polygenic traits and pinpoint potential causal variants underpinning each locus beyond conventional GWAS pipeline, contributing to a deeper understanding of complex genetic architectures in post-GWAS analyses.

genetics↗

bioRxiv2024

Molecular mechanism of Mad2 conformational conversion promoted by the Mad2-interaction motif of Cdc20

During mitosis, unattached kinetochores trigger the spindle assembly checkpoint by promoting assembly of the mitotic checkpoint complex, a heterotetramer comprising Mad2, Cdc20, BubR1 and Bub3. Critical to this process is the kinetochore-mediated catalysis of an intrinsically slow conformational conversion of Mad2 from an open (O-Mad2) inactive state to a closed (C-Mad2) active state bound to Cdc20. These Mad2 conformational changes involve substantial remodelling of the N-terminal {beta}1 strand and C-terminal {beta}7/{beta}8 hairpin. In vitro, the Mad2- interaction motif (MIM) of Cdc20 (Cdc20MIM) triggers rapid conversion of O- to C-Mad2, effectively removing the kinetic barrier for MCC assembly. How Cdc20MIM directly induces Mad2 conversion remains unclear. In this study we demonstrate that the Cdc20MIM-binding site is inaccessible in O-Mad2. Time-resolved NMR and molecular dynamics simulations show how Mad2 conversion involves sequential conformational changes of flexible structural elements in O-Mad2, orchestrated by Cdc20MIM. Conversion is initiated by the {beta}7/{beta}8 hairpin of O-Mad2 transiently unfolding to expose a nascent Cdc20MIM-binding site. Engagement of Cdc20MIM to this site promotes release of the {beta}1 strand. We propose that initial conformational changes of the {beta}7/{beta}8 hairpin allows binding of Cdc20MIM to a transient intermediate state of Mad2, thereby lowering the kinetic barrier to Mad2 conversion.

biochemistry↗

bioRxiv2024

Study of Impacts of Two Types of Cellular Aging on the Yeast Bud Morphogenesis

Understanding the mechanisms of cellular aging processes is crucial for attempting to extend organismal lifespan and for studying age-related degenerative diseases. Yeast cells divide through budding, providing a classical biological model for studying cellular aging. With their powerful genetics, relatively short lifespan and well-established signaling pathways also found in animals, yeast cells offer valuable insights into the aging process. Recent experiments suggested the existence of two aging modes in yeast characterized by nucleolar and mitochondrial declines, respectively. In this study, by analyzing experimental data it was shown that cells evolving into those two aging modes behave differently when they are young. While buds grow linearly in both modes, cells that consistently generate spherical buds throughout their lifespan demonstrate greater efficacy in controlling bud size and growth rate at young ages. A three-dimensional chemical-mechanical model was developed and used to suggest and test hypothesized mechanisms of bud morphogenesis during aging. Experimentally calibrated simulations showed that tubular bud shape in one aging mode could be generated by locally inserting new materials at the bud tip guided by the polarized Cdc42 signal during the early stage of budding. Furthermore, the aspect ratio of the tubular bud could be stabilized during the late stage, as observed in experiments, through a reduction on the new cell surface material insertion or an expansion of the polarization site. Thus model simulations suggest the maintenance of new cell surface material insertion or chemical signal polarization could be weakened due to cellular aging in yeast and other cell types. Significance StatementAging yeast exhibits two modes with different bud shapes. Experimental data analysis reveals that control of growth rate and bud size is more robust in cells aging in a spherical budding mode than in cells aging in a tubular budding mode. A computational model was developed and used in combination with experiments to test the hypothesized mechanisms underlying different types of budding in aging cells. Model simulations suggest that localized growth is sufficient to generate tubular budding and its aspect ratio can be stabilized through the regulation of chemical signals with an expanding polarization site or a decline on the new cell surface material insertion. Proposed mechanisms of morphological changes in aging yeast can be present in other cell types.

biophysics↗

bioRxiv2024

STCC: consensus clustering enhances spatial domain detection for spatial transcriptomics data

The rapid advance of spatially resolved transcriptomics technologies has yielded substantial spatial transcriptomics data. Deriving biological insights from these data poses non-trivial computational and analysis challenges, of which the most fundamental step is spatial domain detection (or spatial clustering). Although a number of tools for spatial domain detection have been proposed in recent years, their performance varies across datasets and experimental platforms. It is thus an important task to take full advantage of different tools to get a more accurate and stable result through consensus strategy. In this work, we developed STCC, a novel consensus clustering framework for spatial transcriptomics data that aggregates outcomes from state-of-the-art tools using a variety of consensus strategies, including Onehot-based, Average-based, Hypergraph-based and wNMF-based methods. Comprehensive assessments on simulated and real data from distinct experimental platforms show that consensus clustering significantly improves clustering accuracy over individual methods under varied input parameters. For normal tissue samples exhibiting clear layered structure, consensus clustering by integrating multiple baseline methods leads to improved results. Conversely, when analyzing tumor samples that display scattered cell type distribution patterns, integration of a single baseline method yields satisfactory performance. For consensus strategies, Average-based and Hypergraph-based approaches demonstrated optimal precision and stability. Overall, STCC provides a scalable and practical solution for spatial domain detection in spatial transcriptomic data, laying a solid foundation for future research and applications in spatial transcriptomics.

bioinformatics↗

bioRxiv2024

Loss of the APP regulator RHBDL4 preserves memory in an Alzheimer's disease mouse model.

Characteristic cerebral pathological changes of Alzheimers disease (AD) such as glucose hypometabolism or the accumulation of cleavage products of the amyloid precursor protein (APP), known as A{beta} peptides, lead to sustained endoplasmic reticulum (ER) stress and neurodegeneration. To preserve ER homeostasis, cells activate their unfolded protein response (UPR). The rhomboid-like-protease 4 (RHBDL4) is an enzyme that participates in the UPR by targeting proteins for proteasomal degradation. We demonstrated previously that RHBLD4 cleaves APP in HEK293T cells, leading to decreased total APP and A{beta}. More recently, we showed that RHBDL4 processes APP in mouse primary mixed cortical cultures as well. Here, we aim to examine the physiological relevance of RHBDL4 in the brain. We first found that brain samples from AD patients and an AD mouse model (APPtg) showed increased RHBDL4 mRNA and protein expression. To determine the effects of RHBDL4s absence on APP physiology in vivo, we crossed APPtg mice to a RHBDL4 knockout (R4-/-) model. RHBDL4 deficiency in APPtg mice led to increased total cerebral APP and amyloidogenic processing when compared to APPtg controls. Contrary to expectations, as assessed by cognitive tests, RHBDL4 absence rescued cognition in 5-month-old female APPtg mice. Informed by unbiased RNAseq data, we demonstrated in vitro and in vivo that RHBDL4 absence leads to greater levels of active {beta}-catenin due to decreased proteasomal clearance. Decreased {beta}-catenin activity is known to underlie cognitive defects in APPtg mice and AD. Our work suggests that RHBDL4s increased expression in AD, in addition to regulating APP levels, leads to aberrant degradation of {beta}-catenin, contributing to cognitive impairment.

animal behavior and cognition↗

bioRxiv2024

Gene Therapy Mediates Therapeutic Improvement in Cardiac Hypertrophy and Survival in a Murine Model of MYBPC3-Associated Cardiomyopathy

BackgroundHypertrophic cardiomyopathy (HCM) affects an estimated 600,000 people in the U.S. and is the leading cause of sudden cardiac arrest in those under 18. Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of HCM. The majority of MYBPC3 mutations causative for HCM result in truncations. The sarcomeric pathophysiology of the majority of HCM patients with MYBPC3 mutations appears to be due to haploinsufficiency, as the total amount of MYBPC3 protein incorporated into sarcomeres falls significantly below normal. MethodsA clear path for the treatment of haploinsufficiency is the restoration of the insufficient gene product; in this case wild-type MYBPC3. To achieve this, we engineered an AAV vector (TN-201) with superior properties for mediating cardiomyocyte-selective expression of MYBPC3 after systemic delivery. ResultsWe have demonstrated for the first time with AAV gene therapy the ability of both a mouse surrogate and TN-201, which encodes human MYBPC3 to reverse cardiac hypertrophy and systolic dysfunction and to improve diastolic dysfunction and survival in a symptomatic MYBPC3-deficient murine model of disease. Dose-ranging efficacy studies exhibited restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct. Further, we have established stable cardiac benefit for greater than one year post-injection, as well as reversal of cardiac dysfunction even in late-stage models of disease. ConclusionsOur data suggest that by restoring MYBPC3 to the sarcomere, TN-201 has the potential to slow and even reverse the course of the disease in patients with MYBPC3-associated HCM.

genetics↗

bioRxiv2024

CAMKV Kinase Signaling Is a Novel Therapeutic Avenue with Prognostic Relevance in Neuroblastoma

Neuroblastoma (NB) can be a highly aggressive malignancy in children. However, the precise mechanisms driving NB tumorigenesis remain elusive. This study revealed the critical role of CREB phosphorylation in NB cell proliferation. By employing a CRISPR-Cas9 knockout screen targeting calcium/calmodulin-dependent protein kinase (CaMK) family members, we identified the CaM kinase-like vesicle-associated (CAMKV) protein as a kinase that mediates direct phosphorylation of CREB to promote NB cell proliferation. CAMKV was found to be a transcriptional target of MYCN/MYC in NB cells. CAMKV knockout and knockdown effectively suppressed NB cell proliferation and tumor growth both in vitro and in vivo. Bioinformatic analysis revealed that high CAMKV expression is significantly correlated with poor patient survival. High-risk NB frequently had high CAMKV protein levels by Immunohistochemical staining. Integrated transcriptomic and proteomic analyses of CAMKV knockdown cells unveiled downstream targets involved in CAMKV-regulated phosphorylation and signaling pathways, many of which are linked to neural development and cancer progression. We identified small molecule inhibitors targeting CAMKV and further demonstrated the efficacy of one inhibitor in suppressing NB tumor growth and prolonging the survival of mice bearing xenografted tumors. These findings reveal a critical role for CAMKV kinase signaling in NB growth and identified CAMKV kinase as a potential therapeutic target and prognostic marker for patients with NB.

cancer biology↗