A5064610941- Advanced Breast Cancer Therapies
- Histone Deacetylase Inhibitors Research
- Cytokine Signaling Pathways and Interactions
- interferon and immune responses
- Epigenetics and DNA Methylation
- Cancer-related Molecular Pathways
- Protein Degradation and Inhibitors
- Estrogen and related hormone effects
- RNA modifications and cancer
- Retinoids in leukemia and cellular processes
- RNA and protein synthesis mechanisms
- Ubiquitin and proteasome pathways
- MicroRNA in disease regulation
- RNA Research and Splicing
- Cancer Genomics and Diagnostics
- Head and Neck Cancer Studies
- Telomeres, Telomerase, and Senescence
- Pancreatic and Hepatic Oncology Research
- PI3K/AKT/mTOR signaling in cancer
- Amino Acid Enzymes and Metabolism
- Ferroptosis and cancer prognosis
- Protein Tyrosine Phosphatases
- Diet, Metabolism, and Disease
- Cancer, Lipids, and Metabolism
- Oral and gingival health research
Université de Montréal
2016-2023
The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation JAK/STAT5 pathway, SOCS1 is required for and regulation cellular senescence. order to identify target genes acting during senescence response oncogenic STAT5A, we characterized transcriptome STAT5A-expressing cells after inhibition. We identified a set SOCS1-dependent that include several secreted proteins regulating oxidative metabolism ferroptosis. Exogenous was sufficient...
Promyelocytic leukemia (PML) plays a tumor suppressive role by inducing cellular senescence in response to oncogenic stress. However, cell lines fail engage complete upon PML activation. In this study, we investigated the mechanisms underlying resistance PML-induced senescence. Here, report that activation of cyclin-dependent kinases CDK4 and CDK6 are essential sufficient impair induced expression. Disrupting CDK function RNA interference or pharmacological inhibition restored cells...
Several regulators of SUMOylation have been previously linked to senescence but most targets this modification in senescent cells remain unidentified. Using a two-step purification modified SUMO3, we profiled the SUMO proteome site-specific manner. We identified 25 sites on 23 proteins that were significantly regulated during senescence. Of note, these PML nuclear body (PML-NB) associated, which correlates with increased number and size PML-NBs observed cells. Interestingly, sole E2 enzyme,...
Pancreatic adenocarcinomas (PDAC) often possess mutations in K-Ras that stimulate the ERK pathway. Aberrantly high activation triggers oncogene-induced senescence, which halts tumor progression. Here we report low-grade pancreatic intraepithelial neoplasia displays very levels of phospho-ERK consistent with a senescence response. However, advanced lesions have circumvented barrier exhibit lower levels. Restoring hyperactivation PDAC using activated RAF leads to ERK-dependent growth arrest...
Senescence is a tumor suppressor program characterized by stable growth arrest while maintaining cell viability. Senescence-associated ribogenesis defects (SARD) have been shown to regulate senescence through the ability of ribosomal protein S14 (RPS14 or uS11) bind and inhibit cyclin-dependent kinase 4 (CDK4). Here we report another that binds inhibits CDK4 in senescent cells: L22 (RPL22 eL22). Enforcing expression RPL22/eL22 sufficient induce an RB p53-dependent cellular phenotype human...
Expression of the suppressor cytokine signaling-1 (SOCS1) is inactivated in hematopoietic and solid cancers by promoter methylation, miRNA-mediated silencing, mutations. Paradoxically, SOCS1 also overexpressed many human cancers. We report here that ability to interact with p53 regulate cellular senescence depends on a structural motif includes tyrosine (Y)80 SH2 domain SOCS1. Mutations this are found at low frequency some cancers, substitution Y80 phosphomimetic residue inhibits p53-SOCS1...
Suppressor of cytokine signaling (SOCS) family members are upregulated following JAK-STAT pathway activation by cytokines. SOCS proteins recognized inhibitors playing roles in cell growth and differentiation. Moreover, SOCS1 SOCS3 have been shown to be involved tumor suppression through their ability interact with p53 leading the its transcriptional program showing implication regulation apoptosis, ferroptosis senescence. More recently, we demonstrated that SRC non-receptor tyrosine kinases...
MicroRNAs (miRNAs) are ribonucleic acids (RNAs) of ∼21 nucleotides that interfere with the translation messenger RNAs (mRNAs) and play significant roles in development diseases. In bilaterian animals, specificity miRNA targeting is determined by sequence complementarity involving seed. However, role remaining (non-seed) only vaguely defined, impacting negatively on our ability to efficiently use miRNAs exogenously control gene expression. Here, using reporter assays, we deciphered base pairs...
<div>Abstract<p>Promyelocytic leukemia (PML) plays a tumor suppressive role by inducing cellular senescence in response to oncogenic stress. However, cell lines fail engage complete upon PML activation. In this study, we investigated the mechanisms underlying resistance PML-induced senescence. Here, report that activation of cyclin-dependent kinases CDK4 and CDK6 are essential sufficient impair induced expression. Disrupting CDK function RNA interference or pharmacological...
<div>Abstract<p>Promyelocytic leukemia (PML) plays a tumor suppressive role by inducing cellular senescence in response to oncogenic stress. However, cell lines fail engage complete upon PML activation. In this study, we investigated the mechanisms underlying resistance PML-induced senescence. Here, report that activation of cyclin-dependent kinases CDK4 and CDK6 are essential sufficient impair induced expression. Disrupting CDK function RNA interference or pharmacological...
<p>Supplementary data contains additional methods and reagents figures. The figures contain the following information: Supplementary Figure 1 extends figure providing evidence that SOCS1 may interact with hydrophobic motifs present in many transcription factors. 2 supports showing mutations found human cancers affect SOCS1-p53 interacting motif 3 functional characterization of mutants p53 binding. 4 5 SOCS1, p53, YES1 expression levels DLBCL. a description patients' samples using to...
<p>Description of additional methods and procedures used in the study. Also includes Supplementary References.</p>
<p>Supplementary data contains additional methods and reagents figures. The figures contain the following information: Supplementary Figure 1 extends figure providing evidence that SOCS1 may interact with hydrophobic motifs present in many transcription factors. 2 supports showing mutations found human cancers affect SOCS1-p53 interacting motif 3 functional characterization of mutants p53 binding. 4 5 SOCS1, p53, YES1 expression levels DLBCL. a description patients' samples using to...
<div>Abstract<p>Expression of the suppressor cytokine signaling-1 (SOCS1) is inactivated in hematopoietic and solid cancers by promoter methylation, miRNA-mediated silencing, mutations. Paradoxically, SOCS1 also overexpressed many human cancers. We report here that ability to interact with p53 regulate cellular senescence depends on a structural motif includes tyrosine (Y)80 SH2 domain SOCS1. Mutations this are found at low frequency some cancers, substitution Y80 phosphomimetic...
<div>Abstract<p>Expression of the suppressor cytokine signaling-1 (SOCS1) is inactivated in hematopoietic and solid cancers by promoter methylation, miRNA-mediated silencing, mutations. Paradoxically, SOCS1 also overexpressed many human cancers. We report here that ability to interact with p53 regulate cellular senescence depends on a structural motif includes tyrosine (Y)80 SH2 domain SOCS1. Mutations this are found at low frequency some cancers, substitution Y80 phosphomimetic...
<p>Disabling RB bypasses PML-induced senescence in normal human fibroblasts (S1); Cyclin-dependent kinase inhibitors p21 and p16INK4A cooperate with PML to inhibit cancer cell proliferation (S2); CDK enhance PML-mediated growth arrest tumor lines (S3); Gene Set Enrichment Analysis (GSEA) showing homology our gene expression profiling (S4); (S5); Palbociclib or 5-Aza-dC sensitise cells irreversible (S6); palbociclib decreased DNMT1 levels a dose dependent manner (S7).</p>
<p>Legend for Supplementary Figures S1-S7.</p>
<p>Legend for Supplementary Figures S1-S7.</p>
<p>Description of additional methods and procedures used in the study. Also includes Supplementary References.</p>
<p>Disabling RB bypasses PML-induced senescence in normal human fibroblasts (S1); Cyclin-dependent kinase inhibitors p21 and p16INK4A cooperate with PML to inhibit cancer cell proliferation (S2); CDK enhance PML-mediated growth arrest tumor lines (S3); Gene Set Enrichment Analysis (GSEA) showing homology our gene expression profiling (S4); (S5); Palbociclib or 5-Aza-dC sensitise cells irreversible (S6); palbociclib decreased DNMT1 levels a dose dependent manner (S7).</p>
Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented cancer cells by poorly understood mechanisms. We report novel multi-enzymatic complex that reprograms NAD metabolism transferring reducing equivalents from NADH to NADP +. This hydride transfer (HTC) assembled Malate Dehydrogenase-1, Malic Enzyme-1 cytosolic Pyruvate Carboxylase. HTC enzymes are found phase-separated bodies the cytosol of can be vitro purified...