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1.
Nucleic Acids Res ; 52(12): 7225-7244, 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38709899

ABSTRACT

Emerging evidence indicates that arginine methylation promotes the stability of arginine-glycine-rich (RGG) motif-containing RNA-binding proteins (RBPs) and regulates gene expression. Here, we report that post-translational modification of FXR1 enhances the binding with mRNAs and is involved in cancer cell growth and proliferation. Independent point mutations in arginine residues of FXR1's nuclear export signal (R386 and R388) and RGG (R453, R455 and R459) domains prevent it from binding to RNAs that form G-quadruplex (G4) RNA structures. Disruption of G4-RNA structures by lithium chloride failed to bind with FXR1, indicating its preference for G4-RNA structure containing mRNAs. Furthermore, loss-of-function of PRMT5 inhibited FXR1 methylation both in vivo and in vitro, affecting FXR1 protein stability, inhibiting RNA-binding activity and cancer cell growth and proliferation. Finally, the enhanced crosslinking and immunoprecipitation (eCLIP) analyses reveal that FXR1 binds with the G4-enriched mRNA targets such as AHNAK, MAP1B, AHNAK2, HUWE1, DYNC1H1 and UBR4 and controls its mRNA expression in cancer cells. Our findings suggest that PRMT5-mediated FXR1 methylation is required for RNA/G4-RNA binding, which promotes gene expression in cancer cells. Thus, FXR1's structural characteristics and affinity for RNAs preferentially G4 regions provide new insights into the molecular mechanism of FXR1 in oral cancer cells.


Subject(s)
Arginine , Cell Proliferation , Protein-Arginine N-Methyltransferases , RNA-Binding Proteins , Humans , Protein-Arginine N-Methyltransferases/metabolism , Protein-Arginine N-Methyltransferases/genetics , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Arginine/metabolism , Arginine/genetics , Methylation , RNA, Messenger/metabolism , RNA, Messenger/genetics , Cell Line, Tumor , Protein Binding , G-Quadruplexes , Gene Expression Regulation, Neoplastic , Repressor Proteins/metabolism , Repressor Proteins/genetics , Repressor Proteins/chemistry , Protein Processing, Post-Translational , Neoplasms/genetics , Neoplasms/metabolism , HEK293 Cells , Protein Stability
2.
Mol Cell ; 62(6): 929-942, 2016 06 16.
Article in English | MEDLINE | ID: mdl-27237051

ABSTRACT

The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell-cycle progression. However, it remains largely elusive whether the hyper-phosphorylated, non-E2F1-interacting form of Rb has any physiological role. Here we report that hyper-phosphorylated Rb directly binds to and suppresses the function of mTORC2 but not mTORC1. Mechanistically, Rb, but not p107 or p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs. As such, inhibition of Rb phosphorylation by depleting cyclin D or using CDK4/6 inhibitors releases Rb-mediated mTORC2 suppression. This, in turn, leads to elevated Akt activation to confer resistance to chemotherapeutic drugs in Rb-proficient cells, which can be attenuated with Akt inhibitors. Therefore, our work provides a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Multiprotein Complexes/metabolism , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Retinoblastoma Protein/metabolism , TOR Serine-Threonine Kinases/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Proliferation/drug effects , Cyclin D/genetics , Cyclin D/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/metabolism , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Drug Synergism , Enzyme Activation , HCT116 Cells , HEK293 Cells , HeLa Cells , Humans , Mechanistic Target of Rapamycin Complex 2 , Mice , Molecular Targeted Therapy , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/pathology , Phosphorylation , Protein Binding , Protein Interaction Domains and Motifs , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Signal Transduction , Time Factors , Transfection
3.
Nature ; 545(7654): 365-369, 2017 05 18.
Article in English | MEDLINE | ID: mdl-28489822

ABSTRACT

The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways. mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORC1) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer. Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells. mTORC1 is activated by both nutrients and growth factors, whereas mTORC2 responds primarily to extracellular cues such as growth-factor-triggered activation of PI3K signalling. Although both mTOR and GßL (also known as MLST8) assemble into mTORC1 and mTORC2 (refs 11, 12, 13, 14, 15), it remains largely unclear what drives the dynamic assembly of these two functionally distinct complexes. Here we show, in humans and mice, that the K63-linked polyubiquitination status of GßL dictates the homeostasis of mTORC2 formation and activation. Mechanistically, the TRAF2 E3 ubiquitin ligase promotes K63-linked polyubiquitination of GßL, which disrupts its interaction with the unique mTORC2 component SIN1 (refs 12, 13, 14) to favour mTORC1 formation. By contrast, the OTUD7B deubiquitinase removes polyubiquitin chains from GßL to promote GßL interaction with SIN1, facilitating mTORC2 formation in response to various growth signals. Moreover, loss of critical ubiquitination residues in GßL, by either K305R/K313R mutations or a melanoma-associated GßL(ΔW297) truncation, leads to elevated mTORC2 formation, which facilitates tumorigenesis, in part by activating AKT oncogenic signalling. In support of a physiologically pivotal role for OTUD7B in the activation of mTORC2/AKT signalling, genetic deletion of Otud7b in mice suppresses Akt activation and Kras-driven lung tumorigenesis in vivo. Collectively, our study reveals a GßL-ubiquitination-dependent switch that fine-tunes the dynamic organization and activation of the mTORC2 kinase under both physiological and pathological conditions.


Subject(s)
Carcinogenesis , Endopeptidases/metabolism , Multiprotein Complexes/metabolism , Signal Transduction , TNF Receptor-Associated Factor 2/metabolism , TOR Serine-Threonine Kinases/metabolism , Ubiquitin/metabolism , Ubiquitination , Adaptor Proteins, Signal Transducing/chemistry , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Line , Endopeptidases/deficiency , Endopeptidases/genetics , Enzyme Activation , Female , Homeostasis , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , Mice , Multiprotein Complexes/biosynthesis , Multiprotein Complexes/chemistry , Phosphorylation , Polyubiquitin/metabolism , Protein Binding , Protein Subunits/chemistry , Protein Subunits/metabolism , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/biosynthesis , TOR Serine-Threonine Kinases/chemistry , mTOR Associated Protein, LST8 Homolog
4.
Mol Cell ; 59(6): 917-30, 2015 Sep 17.
Article in English | MEDLINE | ID: mdl-26344095

ABSTRACT

The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer.


Subject(s)
Nuclear Proteins/physiology , Prostatic Neoplasms/metabolism , Repressor Proteins/physiology , Trans-Activators/metabolism , Ubiquitination , Amino Acid Sequence , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Cell Movement , Cullin Proteins/metabolism , Disease Progression , Etoposide/pharmacology , HEK293 Cells , Humans , Male , Molecular Sequence Data , Neoplasm Invasiveness , Prostatic Neoplasms/pathology , Protein Interaction Domains and Motifs , Proteolysis , Transcriptional Regulator ERG , Tumor Suppressor Proteins/physiology
5.
Mol Cell ; 57(4): 648-661, 2015 Feb 19.
Article in English | MEDLINE | ID: mdl-25661488

ABSTRACT

Deficiency in repair of damaged DNA leads to genomic instability and is closely associated with tumorigenesis. Most DNA double-strand-breaks (DSBs) are repaired by two major mechanisms, homologous-recombination (HR) and non-homologous-end-joining (NHEJ). Although Akt has been reported to suppress HR, its role in NHEJ remains elusive. Here, we report that Akt phosphorylates XLF at Thr181 to trigger its dissociation from the DNA ligase IV/XRCC4 complex, and promotes its interaction with 14-3-3ß leading to XLF cytoplasmic retention, where cytosolic XLF is subsequently degraded by SCF(ß-TRCP) in a CKI-dependent manner. Physiologically, upon DNA damage, XLF-T181E expressing cells display impaired NHEJ and elevated cell death. Whereas a cancer-patient-derived XLF-R178Q mutant, deficient in XLF-T181 phosphorylation, exhibits an elevated tolerance of DNA damage. Together, our results reveal a pivotal role for Akt in suppressing NHEJ and highlight the tight connection between aberrant Akt hyper-activation and deficiency in timely DSB repair, leading to genomic instability and tumorigenesis.


Subject(s)
DNA End-Joining Repair/genetics , DNA Repair Enzymes/physiology , DNA-Binding Proteins/physiology , Proto-Oncogene Proteins c-akt/physiology , 14-3-3 Proteins/metabolism , Amino Acid Sequence , Carcinogenesis/genetics , Cytoplasm/metabolism , DNA Breaks, Double-Stranded , DNA Ligase ATP , DNA Ligases/metabolism , DNA Repair Enzymes/chemistry , DNA Repair Enzymes/genetics , DNA Repair Enzymes/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Genomic Instability , Humans , Molecular Sequence Data , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , SKP Cullin F-Box Protein Ligases/physiology , Sequence Alignment
6.
Proc Natl Acad Sci U S A ; 116(19): 9423-9432, 2019 05 07.
Article in English | MEDLINE | ID: mdl-31000600

ABSTRACT

The Hippo-YAP/TAZ signaling pathway plays a pivotal role in growth control during development and regeneration and its dysregulation is widely implicated in various cancers. To further understand the cellular and molecular mechanisms underlying Hippo signaling regulation, we have found that activities of core Hippo signaling components, large tumor suppressor (LATS) kinases and YAP/TAZ transcription factors, oscillate during mitotic cell cycle. We further identified that the anaphase-promoting complex/cyclosome (APC/C)Cdh1 E3 ubiquitin ligase complex, which plays a key role governing eukaryotic cell cycle progression, intrinsically regulates Hippo signaling activities. CDH1 recognizes LATS kinases to promote their degradation and, hence, YAP/TAZ regulation by LATS phosphorylation is under cell cycle control. As a result, YAP/TAZ activities peak in G1 phase. Furthermore, we show in Drosophila eye and wing development that Cdh1 is required in vivo to regulate the LATS homolog Warts with a conserved mechanism. Cdh1 reduction increased Warts levels, which resulted in reduction of the eye and wing sizes in a Yorkie dependent manner. Therefore, LATS degradation by APC/CCdh1 represents a previously unappreciated and evolutionarily conserved layer of Hippo signaling regulation.


Subject(s)
Anaphase-Promoting Complex-Cyclosome/metabolism , Antigens, CD/metabolism , Cadherins/metabolism , Cdh1 Proteins/metabolism , Drosophila Proteins/metabolism , G1 Phase/physiology , Intracellular Signaling Peptides and Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction/physiology , Anaphase-Promoting Complex-Cyclosome/genetics , Animals , Antigens, CD/genetics , Cadherins/genetics , Cdh1 Proteins/genetics , Drosophila Proteins/genetics , Drosophila melanogaster , HEK293 Cells , HeLa Cells , Hippo Signaling Pathway , Humans , Intracellular Signaling Peptides and Proteins/genetics , Protein Kinases/genetics , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/genetics
7.
Int J Mol Sci ; 23(17)2022 Aug 29.
Article in English | MEDLINE | ID: mdl-36077176

ABSTRACT

In response to DNA damage, cells have developed a sophisticated signaling pathway, consisting of DNA damage sensors, transducers, and effectors, to ensure efficient and proper repair of damaged DNA. During this process, posttranslational modifications (PTMs) are central events that modulate the recruitment, dissociation, and activation of DNA repair proteins at damage sites. Emerging evidence reveals that protein arginine methylation is one of the common PTMs and plays critical roles in DNA damage response. Protein arginine methyltransferases (PRMTs) either directly methylate DNA repair proteins or deposit methylation marks on histones to regulate their transcription, RNA splicing, protein stability, interaction with partners, enzymatic activities, and localization. In this review, we summarize the substrates and roles of each PRMTs in DNA damage response and discuss the synergistic anticancer effects of PRMTs and DNA damage pathway inhibitors, providing insight into the significance of arginine methylation in the maintenance of genome integrity and cancer therapies.


Subject(s)
Histones , Protein-Arginine N-Methyltransferases , Arginine/metabolism , DNA Damage , Histones/metabolism , Methylation , Protein Processing, Post-Translational , Protein-Arginine N-Methyltransferases/genetics , Protein-Arginine N-Methyltransferases/metabolism
8.
Int J Mol Sci ; 22(4)2021 Feb 11.
Article in English | MEDLINE | ID: mdl-33670113

ABSTRACT

The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth, proliferation, and metabolism by integrating various environmental inputs including growth factors, nutrients, and energy, among others. mTOR signaling has been demonstrated to control almost all fundamental cellular processes, such as nucleotide, protein and lipid synthesis, autophagy, and apoptosis. Over the past fifteen years, mapping the network of the mTOR pathway has dramatically advanced our understanding of its upstream and downstream signaling. Dysregulation of the mTOR pathway is frequently associated with a variety of human diseases, such as cancers, metabolic diseases, and cardiovascular and neurodegenerative disorders. Besides genetic alterations, aberrancies in post-translational modifications (PTMs) of the mTOR components are the major causes of the aberrant mTOR signaling in a number of pathologies. In this review, we summarize current understanding of PTMs-mediated regulation of mTOR signaling, and also update the progress on targeting the mTOR pathway and PTM-related enzymes for treatment of human diseases.


Subject(s)
Cardiovascular Diseases/metabolism , Metabolic Diseases/metabolism , Neoplasm Proteins/metabolism , Neoplasms/metabolism , Neurodegenerative Diseases/metabolism , Protein Processing, Post-Translational , TOR Serine-Threonine Kinases/metabolism , Cardiovascular Diseases/genetics , Cell Proliferation , Humans , Metabolic Diseases/genetics , Neoplasm Proteins/genetics , Neoplasms/genetics , Neurodegenerative Diseases/genetics , Signal Transduction , TOR Serine-Threonine Kinases/genetics
9.
Nature ; 508(7497): 541-5, 2014 Apr 24.
Article in English | MEDLINE | ID: mdl-24670654

ABSTRACT

Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance. Phosphorylation of Akt at S473 (ref. 5) and T308 (ref. 6) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.


Subject(s)
Cell Cycle/physiology , Proto-Oncogene Proteins c-akt/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Animals , Apoptosis/genetics , Cell Proliferation , Cyclin A2/metabolism , Cyclin-Dependent Kinase 2/metabolism , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Enzyme Activation , Male , Mechanistic Target of Rapamycin Complex 2 , Mice , Multiprotein Complexes/metabolism , Neoplasms/enzymology , Neoplasms/pathology , Olfactory Bulb/cytology , Olfactory Bulb/enzymology , Olfactory Bulb/metabolism , Oncogene Protein v-akt/chemistry , Oncogene Protein v-akt/metabolism , Phosphorylation , Phosphoserine/metabolism , Phosphothreonine/metabolism , TOR Serine-Threonine Kinases/metabolism
10.
Genes Dev ; 25(19): 2041-56, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21979917

ABSTRACT

Transcriptional R loops are anomalous RNA:DNA hybrids that have been detected in organisms from bacteria to humans. These structures have been shown in eukaryotes to result in DNA damage and rearrangements; however, the mechanisms underlying these effects have remained largely unknown. To investigate this, we first show that R-loop formation induces chromosomal DNA rearrangements and recombination in Escherichia coli, just as it does in eukaryotes. More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stability. Strikingly, we found that attenuation of replication strongly suppresses R-loop-mediated DNA rearrangements in both E. coli and HeLa cells. Our findings thus provide a direct demonstration that R-loop formation impairs DNA replication and that this is responsible for the deleterious effects of R loops on genome stability from bacteria to humans.


Subject(s)
DNA Replication/genetics , Genomic Instability , Animals , DNA/chemistry , DNA Damage/genetics , Escherichia coli/genetics , Evolution, Molecular , Gene Expression Regulation , Gene Rearrangement/genetics , HeLa Cells , Humans , Mice , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Nucleic Acid Conformation , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Ribonuclease H/metabolism , SOS Response, Genetics/genetics , Serine-Arginine Splicing Factors
11.
Proc Natl Acad Sci U S A ; 109(4): 1216-21, 2012 Jan 24.
Article in English | MEDLINE | ID: mdl-22232677

ABSTRACT

Somatic hypermutation (SHM) of Ig variable region (IgV) genes requires both IgV transcription and the enzyme activation-induced cytidine deaminase (AID). Identification of a cofactor responsible for the fact that IgV genes are much more sensitive to AID-induced mutagenesis than other genes is a key question in immunology. Here, we describe an essential role for a splice isoform of the prototypical serine/arginine-rich (SR) protein SRSF1, termed SRSF1-3, in AID-induced SHM in a DT40 chicken B-cell line. Unexpectedly, we found that SHM does not occur in a DT40 line lacking SRSF1-3 (DT40-ASF), although it is readily detectable in parental DT40 cells. Strikingly, overexpression of AID in DT40-ASF cells led to a large increase in nonspecific (off-target) mutations. In contrast, introduction of SRSF1-3, but not SRSF1, into these cells specifically restored SHM without increasing off-target mutations. Furthermore, we found that SRSF1-3 binds preferentially to the IgV gene and inhibits processing of the Ig transcript, providing a mechanism by which SRSF1-3 makes the IgV gene available for AID-dependent SHM. SRSF1 not only acts as an essential splicing factor but also regulates diverse aspects of mRNA metabolism and maintains genome stability. Our findings, thus, define an unexpected and important role for SRSF1, particularly for its splice variant, in enabling AID to function specifically on its natural substrate during SHM.


Subject(s)
Cytidine Deaminase/metabolism , Nuclear Proteins/metabolism , RNA-Binding Proteins/metabolism , Somatic Hypermutation, Immunoglobulin/immunology , Animals , B-Lymphocytes , Blotting, Western , Chickens , Chromatin Immunoprecipitation , DNA Primers/genetics , DNA, Complementary/biosynthesis , Mice , NIH 3T3 Cells , Nuclear Proteins/genetics , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA/isolation & purification , RNA-Binding Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , Serine-Arginine Splicing Factors
12.
Sci Rep ; 14(1): 22100, 2024 Sep 27.
Article in English | MEDLINE | ID: mdl-39333370

ABSTRACT

Using visual place recognition (VPR) technology to ascertain the geographical location of publicly available images is a pressing issue. Although most current VPR methods achieve favorable results under ideal conditions, their performance in complex environments, characterized by lighting variations, seasonal changes, and occlusions, is generally unsatisfactory. Therefore, obtaining efficient and robust image feature descriptors in complex environments is a pressing issue. In this study, we utilized the DINOv2 model as the backbone for trimming and fine-tuning to extract robust image features and employed a feature mix module to aggregate image features, resulting in globally robust and generalizable descriptors that enable high-precision VPR. We experimentally demonstrated that the proposed DINO-Mix outperforms the current state-of-the-art (SOTA) methods. Using test sets having lighting variations, seasonal changes, and occlusions such as Tokyo24/7, Nordland, and SF-XL-Testv1, our proposed architecture achieved Top-1 accuracy rates of 91.75%, 80.18%, and 82%, respectively, and exhibited an average accuracy improvement of 5.14%. In addition, we compared it with other SOTA methods using representative image retrieval case studies, and our architecture outperformed its competitors in terms of VPR performance. Furthermore, we visualized the attention maps of DINO-Mix and other methods to provide a more intuitive understanding of their respective strengths. These visualizations serve as compelling evidence of the superiority of the DINO-Mix framework in this domain.

13.
Sci Rep ; 14(1): 11756, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38783024

ABSTRACT

Visual place recognition (VPR) involves obtaining robust image descriptors to cope with differences in camera viewpoints and drastic external environment changes. Utilizing multiscale features improves the robustness of image descriptors; however, existing methods neither exploit the multiscale features generated during feature extraction nor consider the feature redundancy problem when fusing multiscale information when image descriptors are enhanced. We propose a novel encoding strategy-convolutional multilayer perceptron orthogonal fusion of multiscale features (ConvMLP-OFMS)-for VPR. A ConvMLP is used to obtain robust and generalized global image descriptors and the multiscale features generated during feature extraction are used to enhance the global descriptors to cope with changes in the environment and viewpoints. Additionally, an attention mechanism is used to eliminate noise and redundant information. Compared to traditional methods that use tensor splicing for feature fusion, we introduced matrix orthogonal decomposition to eliminate redundant information. Experiments demonstrated that the proposed architecture outperformed NetVLAD, CosPlace, ConvAP, and other methods. On the Pittsburgh and MSLS datasets, which contained significant viewpoint and illumination variations, our method achieved 92.5% and 86.5% Recall@1, respectively. We also achieved good performances-80.6% and 43.2%-on the SPED and NordLand datasets, respectively, which have more extreme illumination and appearance variations.

14.
Genome Instab Dis ; 4(4): 197-209, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37663901

ABSTRACT

DNA double-strand breaks (DSBs) are widely accepted to be the most deleterious form of DNA lesions that pose a severe threat to genome integrity. Two predominant pathways are responsible for repair of DSBs, homologous recombination (HR) and non-homologous end-joining (NHEJ). HR relies on a template to faithfully repair breaks, while NHEJ is a template-independent and error-prone repair mechanism. Multiple layers of regulation have been documented to dictate the balance between HR and NHEJ, such as cell cycle and post-translational modifications (PTMs). Arginine methylation is one of the most common PTMs, which is catalyzed by protein arginine methyltransferases (PRMTs). PRMT1 and PRMT5 are the predominate PRMTs that promote asymmetric dimethylarginine and symmetric dimethylarginine, respectively. They have emerged to be crucial regulators of DNA damage repair. In this review, we summarize current understanding and unaddressed questions of PRMT1 and PRMT5 in regulation of HR and NHEJ, providing insights into their roles in DSB repair pathway choice and the potential of targeting them for cancer therapy.

15.
Cancers (Basel) ; 15(9)2023 Apr 27.
Article in English | MEDLINE | ID: mdl-37173967

ABSTRACT

Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme generating symmetric dimethylarginine (sDMA) on numerous substrates, through which it regulates many cellular processes, such as transcription and DNA repair. Aberrant expression and activation of PRMT5 is frequently observed in various human cancers and associated with poor prognosis and survival. However, the regulatory mechanisms of PRMT5 remain poorly understood. Here, we report that TRAF6 serves as an upstream E3 ubiquitin ligase to promote PRMT5 ubiquitination and activation. We find that TRAF6 catalyzes K63-linked ubiquitination of PRMT5 and interacts with PRMT5 in a TRAF6-binding-motif-dependent manner. Moreover, we identify six lysine residues located at the N-terminus as the primarily ubiquitinated sites. Disruption of TRAF6-mediated ubiquitination decreases PRMT5 methyltransferase activity towards H4R3 in part by impairing PRMT5 interaction with its co-factor MEP50. As a result, mutating the TRAF6-binding motifs or the six lysine residues significantly suppresses cell proliferation and tumor growth. Lastly, we show that TRAF6 inhibitor enhances cellular sensitivity to PRMT5 inhibitor. Therefore, our study reveals a critical regulatory mechanism of PRMT5 in cancers.

16.
Mol Cancer Res ; 21(12): 1317-1328, 2023 12 01.
Article in English | MEDLINE | ID: mdl-37606694

ABSTRACT

Although androgen deprivation treatment often effectively decreases prostate cancer, incurable metastatic castration-resistant prostate cancer (CRPC) eventually occurs. It is important to understand how CRPC metastasis progresses, which is not clearly defined. The loss of PTEN, a phosphatase to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate in the PI3K pathway, occurs in up to 70% to 80% of CRPC. We generated a mouse androgen-independent prostate cancer cell line (PKO) from PTEN null and Hi-Myc transgenic mice in C57BL/6 background. We confirmed that this PKO cell line has an activated PI3K pathway and can metastasize into the femur and tibia of immunodeficient nude and immunocompetent C57BL/6 mice. In vitro, we found that androgen deprivation significantly enhanced PKO cell migration/invasion via the p110ß isoform-depended PAK1-MAPK activation. Inhibition of the p110ß-PAK1 axis significantly decreased prostate cancer cell migration/invasion. Of note, our analysis using clinical samples showed that PAK1 is more activated in CRPC than in advanced prostate cancer; high PAK1/phosphorylated-PAK1 levels are associated with decreased survival rates in patients with CRPC. All the information suggests that this cell line reflects the characteristics of CRPC cells and can be applied to dissect the mechanism of CRPC initiation and progression. This study also shows that PAK1 is a potential target for CRPC treatment. IMPLICATIONS: This study uses a newly generated PTEN null prostate cancer cell line to define a critical functional role of p110ß-PAK1 in CRPC migration/invasion. This study also shows that the p110ß-PAK1 axis can potentially be a therapeutic target in CRPC metastasis.


Subject(s)
Prostatic Neoplasms, Castration-Resistant , Animals , Humans , Male , Mice , Androgen Antagonists , Androgens/therapeutic use , Cell Line, Tumor , Mice, Inbred C57BL , Mice, Transgenic , p21-Activated Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Prostatic Neoplasms, Castration-Resistant/metabolism , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Receptors, Androgen/metabolism
17.
Sci Rep ; 13(1): 10752, 2023 07 03.
Article in English | MEDLINE | ID: mdl-37400460

ABSTRACT

Protein arginine methyltransferase 5 (PRMT5) catalyzes mono-methylation and symmetric di-methylation on arginine residues and has emerged as a potential antitumor target with inhibitors being tested in clinical trials. However, it remains unknown how the efficacy of PRMT5 inhibitors is regulated. Here we report that autophagy blockage enhances cellular sensitivity to PRMT5 inhibitor in triple negative breast cancer cells. Genetic ablation or pharmacological inhibition of PRMT5 triggers cytoprotective autophagy. Mechanistically, PRMT5 catalyzes monomethylation of ULK1 at R532 to suppress ULK1 activation, leading to attenuation of autophagy. As a result, ULK1 inhibition blocks PRMT5 deficiency-induced autophagy and sensitizes cells to PRMT5 inhibitor. Our study not only identifies autophagy as an inducible factor that dictates cellular sensitivity to PRMT5 inhibitor, but also unearths a critical molecular mechanism by which PRMT5 regulates autophagy through methylating ULK1, providing a rationale for the combination of PRMT5 and autophagy inhibitors in cancer therapy.


Subject(s)
Protein-Arginine N-Methyltransferases , Triple Negative Breast Neoplasms , Humans , Protein-Arginine N-Methyltransferases/metabolism , Methylation , Enzyme Inhibitors/pharmacology , Autophagy
18.
Cell Rep ; 42(4): 112316, 2023 04 25.
Article in English | MEDLINE | ID: mdl-36995937

ABSTRACT

The mammalian target of rapamycin complex1 (mTORC1) is a central regulator of metabolism and cell growth by sensing diverse environmental signals, including amino acids. The GATOR2 complex is a key component linking amino acid signals to mTORC1. Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical regulator of GATOR2. In response to amino acids, cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1 at S307 to promote PRMT1 translocation from nucleus to cytoplasm and lysosome, which in turn methylates WDR24, an essential component of GATOR2, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses hepatocellular carcinoma (HCC) cell proliferation and xenograft tumor growth. High PRMT1 protein expression is associated with elevated mTORC1 signaling in patients with HCC. Thus, our study dissects a phosphorylation- and arginine methylation-dependent regulatory mechanism of mTORC1 activation and tumor growth and provides a molecular basis to target this pathway for cancer therapy.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Amino Acids/metabolism , Cyclin-Dependent Kinase 5 , Mechanistic Target of Rapamycin Complex 1/metabolism , Protein-Arginine N-Methyltransferases/metabolism , Repressor Proteins/metabolism , TOR Serine-Threonine Kinases/metabolism
19.
Sci Signal ; 15(715): eabh2290, 2022 01 04.
Article in English | MEDLINE | ID: mdl-34982576

ABSTRACT

The kinase AKT (also known as protein kinase B) is a key regulator of cell proliferation, survival, and metabolism. In addition to being activated by growth factors, AKT is activated in response to DNA damage. Here, we found that the DNA damage response kinase DNA-PK sustains cell survival through a phosphorylation event that leads to increased AKT activity. In various cancer and noncancer cells in culture, DNA damage caused by ionizing radiation or topoisomerase inhibitors triggered DNA-PK­dependent phosphorylation of the mTOR complex 2 (mTORC2) subunit Sin1, which enabled its interaction with the guanine nucleotide exchange factor ECT2. Depleting Sin1 or ECT2 or disrupting the protein interaction or catalytic function of ECT2 attenuated DNA damage­induced AKT activation, thereby enhancing cellular sensitivity to DNA-damaging agents. Our findings elucidate a mechanism mediating DNA damage­induced AKT activation and cell survival.


Subject(s)
Proto-Oncogene Proteins c-akt , TOR Serine-Threonine Kinases , Adaptor Proteins, Signal Transducing/metabolism , DNA Damage , Mechanistic Target of Rapamycin Complex 2/genetics , Mechanistic Target of Rapamycin Complex 2/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism
20.
Sci Adv ; 8(49): eadd8928, 2022 12 09.
Article in English | MEDLINE | ID: mdl-36475791

ABSTRACT

BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4 functions on transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interacts with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 recruitment to acetylated histones/chromatin. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation-dependent regulatory mechanism of BRD4 and highlight targeting PRMT2/4 for better antitumor effect of BET inhibitors and DNA damaging agents.


Subject(s)
Neoplasms , Nuclear Proteins , Humans , Nuclear Proteins/genetics , Arginine , Transcription Factors/genetics , DNA Repair , DNA , Chromatin , Protein-Arginine N-Methyltransferases/genetics , Intracellular Signaling Peptides and Proteins , Cell Cycle Proteins/genetics
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