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1.
EMBO Rep ; 23(5): e54049, 2022 05 04.
Article in English | MEDLINE | ID: mdl-35253958

ABSTRACT

The healthy prostate is a relatively quiescent tissue. Yet, prostate epithelium overgrowth is a common condition during aging, associated with urinary dysfunction and tumorigenesis. For over thirty years, TGF-ß ligands have been known to induce cytostasis in a variety of epithelia, but the intracellular pathway mediating this signal in the prostate, and its relevance for quiescence, have remained elusive. Here, using mouse prostate organoids to model epithelial progenitors, we find that intra-epithelial non-canonical Activin A signaling inhibits cell proliferation in a Smad-independent manner. Mechanistically, Activin A triggers Tak1 and p38 ΜAPK activity, leading to p16 and p21 nuclear import. Spontaneous evasion from this quiescent state occurs upon prolonged culture, due to reduced Activin A secretion, a condition associated with DNA replication stress and aneuploidy. Organoids capable to escape quiescence in vitro are also able to implant with increased frequency into immunocompetent mice. This study demonstrates that non-canonical Activin A signaling safeguards epithelial quiescence in the healthy prostate, with potential implications for the understanding of cancer initiation, and the development of therapies targeting quiescent tumor progenitors.


Subject(s)
Activins , Prostate , Activins/metabolism , Animals , Male , Mice , Prostate/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism
2.
Cancer Lett ; 534: 215612, 2022 05 28.
Article in English | MEDLINE | ID: mdl-35259458

ABSTRACT

21q22.2-3 deletion is the most common copy number alteration in prostate cancer (PCa). The genomic rearrangement results in the androgen-dependent de novo expression of ETS-related gene (ERG) in prostate cancer cells, a condition promoting tumor progression to advanced stages of the disease. Interestingly, ERG expression characterizes 5-30% of tumor precursor lesions - High Grade Prostatic Intraepithelial Neoplasia (HGPIN) - where its role remains unclear. Here, by combining organoids technology with Click-chemistry coupled Mass Spectrometry, we demonstrate a prominent role of ERG in remodeling the protein secretome of prostate progenitors. Functionally, by lowering autocrine Wnt-4 signaling, ERG represses canonical Wnt pathway in prostate progenitors, and, in turn, promotes the accumulation of DNA double strand breaks via Gsk3ß-dependent degradation of the tumor suppressor Nkx3.1. On the other hand, by shaping extracellular paracrine signals, ERG strengthens the pro-oxidative transcriptional signature of inflammatory macrophages, which we demonstrate to infiltrate pre-malignant ERG positive prostate lesions. These findings highlight previously unrecognized functions of ERG in undermining adult prostate progenitor niche through cell autonomous and non-autonomous mechanisms. Overall, by supporting the survival and proliferation of prostate progenitors in the absence of growth stimuli and promoting the accumulation of DNA damage through destabilization of Nkx3.1, ERG could orchestrate the prelude to neoplastic transformation.


Subject(s)
Glycogen Synthase Kinase 3 beta , Homeodomain Proteins , Prostate , Prostatic Neoplasms , Transcription Factors , Transcriptional Regulator ERG , Animals , Genomic Instability , Glycogen Synthase Kinase 3 beta/genetics , Homeodomain Proteins/genetics , Male , Mice , Oncogene Proteins , Prostate/pathology , Prostatic Neoplasms/pathology , Trans-Activators/metabolism , Transcription Factors/genetics , Transcriptional Regulator ERG/genetics
3.
Cell Rep ; 36(11): 109694, 2021 09 14.
Article in English | MEDLINE | ID: mdl-34525372

ABSTRACT

Chromatin organization plays a crucial role in tissue homeostasis. Heterochromatin relaxation and consequent unscheduled mobilization of transposable elements (TEs) are emerging as key contributors of aging and aging-related pathologies, including Alzheimer's disease (AD) and cancer. However, the mechanisms governing heterochromatin maintenance or its relaxation in pathological conditions remain poorly understood. Here we show that PIN1, the only phosphorylation-specific cis/trans prolyl isomerase, whose loss is associated with premature aging and AD, is essential to preserve heterochromatin. We demonstrate that this PIN1 function is conserved from Drosophila to humans and prevents TE mobilization-dependent neurodegeneration and cognitive defects. Mechanistically, PIN1 maintains nuclear type-B Lamin structure and anchoring function for heterochromatin protein 1α (HP1α). This mechanism prevents nuclear envelope alterations and heterochromatin relaxation under mechanical stress, which is a key contributor to aging-related pathologies.


Subject(s)
Drosophila Proteins/metabolism , Heterochromatin/metabolism , Lamin Type B/metabolism , NIMA-Interacting Peptidylprolyl Isomerase/metabolism , Peptidylprolyl Isomerase/metabolism , Stress, Mechanical , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Animals , Cells, Cultured , Chromobox Protein Homolog 5/genetics , Chromobox Protein Homolog 5/metabolism , DNA Transposable Elements/genetics , Drosophila/metabolism , Drosophila Proteins/antagonists & inhibitors , Drosophila Proteins/genetics , Humans , Lamin Type B/chemistry , Mice , Mice, Inbred C57BL , NIMA-Interacting Peptidylprolyl Isomerase/antagonists & inhibitors , NIMA-Interacting Peptidylprolyl Isomerase/genetics , Neocortex/cytology , Neocortex/metabolism , Neurons/cytology , Neurons/metabolism , Nuclear Envelope/chemistry , Peptidylprolyl Isomerase/antagonists & inhibitors , Peptidylprolyl Isomerase/genetics , Phosphorylation , RNA Interference , RNA, Small Interfering/metabolism
4.
Cell Death Dis ; 11(12): 1039, 2020 12 07.
Article in English | MEDLINE | ID: mdl-33288740

ABSTRACT

Therapy resistance is a major roadblock in oncology. Exacerbation of molecular dysfunctions typical of cancer cells have proven effective in twisting oncogenic mechanisms to lethal conditions, thus offering new therapeutic avenues for cancer treatment. Here, we demonstrate that selective agonists of Transient Receptor Potential cation channel subfamily M member 8 (TRPM8), a cation channel characteristic of the prostate epithelium frequently overexpressed in advanced stage III/IV prostate cancers (PCa), sensitize therapy refractory models of PCa to radio, chemo or hormonal treatment. Overall, our study demonstrates that pharmacological-induced Ca2+ cytotoxicity is an actionable strategy to sensitize cancer cells to standard therapies.


Subject(s)
Calcium/toxicity , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Anilides/pharmacology , Apoptosis/drug effects , Cell Death/drug effects , Cell Line, Tumor , Humans , Ion Channel Gating/drug effects , Male , Menthol/analogs & derivatives , Menthol/pharmacology , Models, Biological , Neoplasm Staging , TRPM Cation Channels/metabolism , X-Rays
5.
Nat Commun ; 7: 11292, 2016 Apr 12.
Article in English | MEDLINE | ID: mdl-27068814

ABSTRACT

MALT1 channels proximal T-cell receptor (TCR) signalling to downstream signalling pathways. With MALT1A and MALT1B two conserved splice variants exist and we demonstrate here that MALT1 alternative splicing supports optimal T-cell activation. Inclusion of exon7 in MALT1A facilitates the recruitment of TRAF6, which augments MALT1 scaffolding function, but not protease activity. Naive CD4(+) T cells express almost exclusively MALT1B and MALT1A expression is induced by TCR stimulation. We identify hnRNP U as a suppressor of exon7 inclusion. Whereas selective depletion of MALT1A impairs T-cell signalling and activation, downregulation of hnRNP U enhances MALT1A expression and T-cell activation. Thus, TCR-induced alternative splicing augments MALT1 scaffolding to enhance downstream signalling and to promote optimal T-cell activation.


Subject(s)
Alternative Splicing/genetics , CD4-Positive T-Lymphocytes/immunology , Caspases/genetics , Lymphocyte Activation/immunology , Neoplasm Proteins/genetics , Signal Transduction , Animals , Caspases/metabolism , Down-Regulation , Enzyme Activation , Exons/genetics , HEK293 Cells , Heterogeneous-Nuclear Ribonucleoprotein U/metabolism , Humans , Interleukin-2/biosynthesis , JNK Mitogen-Activated Protein Kinases/metabolism , Jurkat Cells , Mice, Inbred C57BL , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein , NF-kappa B/metabolism , Neoplasm Proteins/metabolism , Receptors, Antigen, T-Cell/metabolism , TNF Receptor-Associated Factor 6/metabolism , Th17 Cells/immunology , Up-Regulation
6.
Sci Rep ; 6: 18934, 2016 Jan 07.
Article in English | MEDLINE | ID: mdl-26740240

ABSTRACT

The IκB kinase (IKK) complex acts as the gatekeeper of canonical NF-κB signaling, thereby regulating immunity, inflammation and cancer. It consists of the catalytic subunits IKKα and IKKß and the regulatory subunit NEMO/IKKγ. Here, we show that the ubiquitin binding domain (UBAN) in NEMO is essential for IKK/NF-κB activation in response to TNFα, but not IL-1ß stimulation. By screening a natural compound library we identified an anthraquinone derivative that acts as an inhibitor of NEMO-ubiquitin binding (iNUB). Using biochemical and NMR experiments we demonstrate that iNUB binds to NEMOUBAN and competes for interaction with methionine-1-linked linear ubiquitin chains. iNUB inhibited NF-κB activation upon UBAN-dependent TNFα and TCR/CD28, but not UBAN-independent IL-1ß stimulation. Moreover, iNUB was selectively killing lymphoma cells that are addicted to chronic B-cell receptor triggered IKK/NF-κB activation. Thus, iNUB disrupts the NEMO-ubiquitin protein-protein interaction interface and thereby inhibits physiological and pathological NF-κB signaling.


Subject(s)
Anthraquinones/pharmacology , Intracellular Signaling Peptides and Proteins/metabolism , NF-kappa B/metabolism , Signal Transduction/drug effects , Ubiquitin/metabolism , Animals , Drug Evaluation, Preclinical , HeLa Cells , Humans , Interleukin-1beta/physiology , Mice , Protein Binding , Protein Interaction Domains and Motifs , Tumor Necrosis Factor-alpha/physiology , Ubiquitination
7.
Eur J Immunol ; 45(6): 1614-20, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25787118

ABSTRACT

Replication-deficient recombinant adenoviruses are potent vectors for the efficient transient expression of exogenous genes in resting immune cells. However, most leukocytes are refractory to efficient adenoviral transduction as they lack expression of the coxsackie/adenovirus receptor (CAR). To circumvent this obstacle, we generated the R26/CAG-CARΔ1(StopF) (where R26 is ROSA26 and CAG is CMV early enhancer/chicken ß actin promoter) knock-in mouse line. This strain allows monitoring of in situ Cre recombinase activity through expression of CARΔ1. Simultaneously, CARΔ1 expression permits selective and highly efficient adenoviral transduction of immune cell populations, such as mast cells or T cells, directly ex vivo in bulk cultures without prior cell purification or activation. Furthermore, we show that CARΔ1 expression dramatically improves adenoviral infection of in vitro differentiated conventional and plasmacytoid dendritic cells (DCs), basophils, mast cells, as well as Hoxb8-immortalized hematopoietic progenitor cells. This novel dual function mouse strain will hence be a valuable tool to rapidly dissect the function of specific genes in leukocyte physiology.


Subject(s)
Adenoviridae/genetics , Gene Targeting , Genes, Reporter , Genetic Vectors/genetics , Homologous Recombination , Integrases/metabolism , Transduction, Genetic , Animals , Coxsackie and Adenovirus Receptor-Like Membrane Protein/genetics , Gene Expression , Gene Targeting/methods , Humans , Integrases/genetics , Leukocytes/immunology , Leukocytes/metabolism , Mice , Mice, Transgenic , Myeloid Cells/cytology , Myeloid Cells/immunology , Myeloid Cells/metabolism , Organ Specificity
9.
Immunity ; 38(4): 655-68, 2013 Apr 18.
Article in English | MEDLINE | ID: mdl-23583643

ABSTRACT

The Roquin-1 protein binds to messenger RNAs (mRNAs) and regulates gene expression posttranscriptionally. A single point mutation in Roquin-1, but not gene ablation, increases follicular helper T (Tfh) cell numbers and causes lupus-like autoimmune disease in mice. In T cells, we did not identify a unique role for the much lower expressed paralog Roquin-2. However, combined ablation of both genes induced accumulation of T cells with an effector and follicular helper phenotype. We showed that Roquin-1 and Roquin-2 proteins redundantly repressed the mRNA of inducible costimulator (Icos) and identified the Ox40 costimulatory receptor as another shared mRNA target. Combined acute deletion increased Ox40 signaling, as well as Irf4 expression, and imposed Tfh differentiation on CD4(+) T cells. These data imply that both proteins maintain tolerance by preventing inappropriate T cell activation and Tfh cell differentiation, and that Roquin-2 compensates in the absence of Roquin-1, but not in the presence of its mutated form.


Subject(s)
Inducible T-Cell Co-Stimulator Protein/metabolism , RNA, Messenger/metabolism , Receptors, OX40/metabolism , Repressor Proteins/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Ubiquitin-Protein Ligases/metabolism , Animals , CD4 Antigens/metabolism , Cell Differentiation/genetics , HEK293 Cells , Humans , Inducible T-Cell Co-Stimulator Protein/genetics , Lymphocyte Activation/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains , Protein Binding , Receptors, OX40/genetics , Repressor Proteins/genetics , Ubiquitin-Protein Ligases/genetics
10.
J Exp Med ; 208(9): 1749-56, 2011 Aug 29.
Article in English | MEDLINE | ID: mdl-21844204

ABSTRACT

The substitution of one amino acid in the Roquin protein by the sanroque mutation induces a dramatic autoimmune syndrome in mice. This is believed to occur through ectopic expression of inducible T cell co-stimulator (ICOS) and unrestrained differentiation of follicular T helper cells, which induce spontaneous germinal center reactions to self-antigens. In this study, we demonstrate that tissue-specific ablation of Roquin in T or B cells, in the entire hematopoietic system, or in epithelial cells of transplanted thymi did not cause autoimmunity. Loss of Roquin induced elevated expression of ICOS through T cell-intrinsic and -extrinsic mechanisms, which itself was not sufficient to break self-tolerance. Instead, ablation of Roquin in the hematopoietic system caused defined changes in immune homeostasis, including the expansion of macrophages, eosinophils, and T cell subsets, most dramatically CD8 effector-like T cells, through cell-autonomous and nonautonomous mechanisms. Germline Roquin deficiency led to perinatal lethality, which was partially rescued on the genetic background of an outbred strain. However, not even complete absence of Roquin resulted in overt self-reactivity, suggesting that the sanroque mutation induces autoimmunity through an as yet unknown mechanism.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/immunology , Autoimmunity , Gene Expression Regulation/immunology , Immunity, Cellular , Ubiquitin-Protein Ligases/immunology , Animals , Antigens, Differentiation, T-Lymphocyte/biosynthesis , Antigens, Differentiation, T-Lymphocyte/genetics , Autoantigens/immunology , Autoantigens/metabolism , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Eosinophils/immunology , Eosinophils/metabolism , Gene Expression Regulation/genetics , Germinal Center/immunology , Germinal Center/metabolism , Inducible T-Cell Co-Stimulator Protein , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Transgenic , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
11.
Blood ; 117(7): 2227-36, 2011 Feb 17.
Article in English | MEDLINE | ID: mdl-21088135

ABSTRACT

The ubiquitin-editing enzyme A20/TNFAIP3 is essential for controlling signals inducing the activation of nuclear factor-κB transcription factors. Polymorphisms and mutations in the TNFAIP3 gene are linked to various human autoimmune conditions, and inactivation of A20 is a frequent event in human B-cell lymphomas characterized by constitutive nuclear factor-κB activity. Through B cell-specific ablation in the mouse, we show here that A20 is required for the normal differentiation of the marginal zone B and B1 cell subsets. However, loss of A20 in B cells lowers their activation threshold and enhances proliferation and survival in a gene-dose-dependent fashion. Through the expression of proinflammatory cytokines, most notably interleukin-6, A20-deficient B cells trigger a progressive inflammatory reaction in naive mice characterized by the expansion of myeloid cells, effector-type T cells, and regulatory T cells. This culminates in old mice in an autoimmune syndrome characterized by splenomegaly, plasma cell hyperplasia, and the presence of class-switched, tissue-specific autoantibodies.


Subject(s)
B-Lymphocytes/immunology , B-Lymphocytes/pathology , Cysteine Endopeptidases/deficiency , Cysteine Endopeptidases/immunology , Intracellular Signaling Peptides and Proteins/deficiency , Intracellular Signaling Peptides and Proteins/immunology , Aging/immunology , Aging/pathology , Animals , Autoimmunity , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/pathology , Cell Differentiation , Cysteine Endopeptidases/genetics , Gene Dosage , Humans , In Vitro Techniques , Inflammation/etiology , Inflammation/immunology , Inflammation/pathology , Interleukin-6/biosynthesis , Intracellular Signaling Peptides and Proteins/genetics , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Cells/immunology , Myeloid Cells/pathology , NF-kappa B/metabolism , Signal Transduction/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology , Tumor Necrosis Factor alpha-Induced Protein 3 , Tumor Suppressor Proteins/deficiency , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/immunology
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