Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

TINCR lncRNA encodes a ubiquitin-like protein that activates CDC42, promotes epithelial differentiation and suppresses tumor growth

ABSTRACT: The human transcriptome contains thousands of small open reading frames (sORFs) that have been largely overlooked because of their small size. Some of these sORFs code for bioactive small proteins although none have been associated to the regulation of cell identity. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein with a SUMO interacting motif (SIM) that is expressed in many epithelia. pTINCR binds to SUMO and modifies global cell SUMOylation patterns. One of its main targets is CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and for epidermal differentiation. pTINCR increases CDC42 SUMOylation and promotes its activation in a SIM-dependent manner. pTINCR is necessary and sufficient for epithelial cell differentiation in vitro, and promotes epidermal differentiation in vivo. Consistent with its pro-differentiation role, pTINCR expression is lost in human cutaneous squamous cell carcinomas (cSCC), and its overexpression reduces cSCC growth in vitro and in vivo. Moreover, pTINCR is a target of the tumor suppressor p53, and the expression of pTINCR in epithelial cancers correlates with better prognosis. Our results identify pTINCR as a novel regulator of epithelial differentiation with tumor suppressor activity. More generally, our findings suggest that the proteome encoded by previously assumed non-coding RNAs can indeed be a source of new regulators of cell identity relevant for cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE175463 | GEO | 2022/09/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation

Project description:The human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for cancer.

2022-10-06 | PXD026181 | Pride

Identification of proximal SUMO-dependent interactors using SUMO-ID

Project description:To study the function of SUMOylation and SUMO-SIM interactions for particular substrates poses several challenges. SUMOylation occurs transiently and often in a small percentage of the total copy numbers of a given substrate. Modified proteins can be readily deSUMOylated and SUMO can be recycled and passed to other substrates. SUMO-SIM interactions are also difficult to analyze due to their weak affinity (Kd 1-100 µM). To overcome these technical issues, we developed SUMO-ID, a new strategy based on Split-TurboID to identify SUMO- interactors of specific substrates dependent on SUMO conjugation or interaction. Here we present SUMO-ID, a technology that merges proximity biotinylation by TurboID and protein-fragment complementation to find SUMO-dependent interactors. , the high sensitivity of SUMO-ID allowed to identify novel interactors of SUMOylated SALL1, a less characterized SUMO substrate.

2021-09-21 | PXD021923 | Pride

Polycomb Repressive Complex 1 subunit Cbx4 positively regulates effector responses in CD8 T cells

Project description:Cytotoxic T lymphocyte (CTL) differentiation is controlled by the crosstalk of various transcription factors and epigenetic modulators. Fully uncovering this process is fundamental to improving immunotherapy and designing novel therapeutic approaches. Here, we show that Polycomb Repressive Complex (PRC)1 subunit Chromobox (Cbx)4 favors effector CTL differentiation in murine model. Cbx4 deficiency in CTLs induced transcriptional signature and phenotype of memory cells, increasing the memory CTL population during acute viral infection. It has been previously shown that besides binding to H3K27me3 through its chromodomain, Cbx4 function as a SUMO E3 ligase in a SUMO interacting motifs (SIM)-dependent way. Overexpression of Cbx4 mutants in distinct domains showed that this protein regulates CTL differentiation primarily in a SIM-dependent way and partially through its chromodomain. Our data revealed a novel role of a Polycomb group protein Cbx4 controlling CTL differentiation and indicates the SUMOylation as a key molecular mechanism connected to chromatin modification in this process.

2023-07-10 | GSE236487 | GEO

HA-mSLX4 wild type and SIMdependent interactors

Project description:SUMOylation is known to play important roles in the DNA damage response, however, a role for SUMOylation in interstrand crosslink repair remains enigmatic. We report on the regulation of the SLX4 nuclease scaffold protein by SUMOylation. SLX4 contains three SUMO-Interaction Motifs (SIMs). Mutating all three SIMs abrogated the binding of SLX4 to SUMO-2 and covalent SLX4 SUMOylation. We attempt to identify which protein interaction are SIM dependent.

2015-03-02 | PXD001681 | Pride

Overexpression of Cbx4 wild type and of a Cbx4 sumoylation mutant in human epidermal stem cells

Project description:Human epidermal stem cells transit from a slow cycling to an actively proliferating state to contribute to homeostasis. Both stem cell states differ in their cell cycle profiles but must remain guarded from differentiation and senescence. Here we show that Cbx4, a Polycomb Repressive Complex-1 (PRC1)-associated protein, maintains human epidermal stem cells slow-cycling and undifferentiated, while protecting them from senescence. Interestingly, abrogating the polycomb activity of Cbx4 impairs its anti-senescent function without affecting stem cell differentiation, indicating that differentiation and senescence are independent processes in human epidermis. Conversely, Cbx4 inhibits stem cell activation and differentiation through its SUMO ligase activity. Global transcriptome and chromatin occupancy analyses indicate that Cbx4 regulates modulators of epidermal homeostasis and represses factors, such as Ezh2, Dnmt1, and Bmi1, to prevent the activate stem cell state. Our results suggest that distinct Polycomb complexes balance epidermal stem cell dormancy and activation, while continually preventing senescence and differentiation. Primary human keratinocytes were infected with control vector pBABE, Cbx4 wildtype and a Sumoylation mutant version of Cbx4 (the two Sumo Interaction Motifs were deleted), both fused to a Estrogen Receptor to render their activaty inducible by addition of 4OHT to the media. Cells were cultured for 5 days (after infection and selection) under 4OHT treatment, after which total RNA was collected.

2011-08-01 | E-GEOD-31094 | biostudies-arrayexpress

Genomic analyses of H1 cells induced by FOXO1

Project description:Insufficient understanding on cold adaptation technically restricts donor tissue banking. Here we identify FOXO1 as a conserved transcription factor for cell cold survival, relocating from cytosol to nucleus when temperature drops. FOXO1 small ubiquitin-like modifiers (SUMO) -interacting motif (SIM) antagonizes FOXO1-Importin-7 interaction regardless of temperature. At 37°C, SIM enhances FOXO1 interactions with SUMO E3 ligase RANBP2 and Exportin-1, FOXO1 hence cytoplasmic; at 4°C, FOXO1-Importin-7 interaction increases probably via RANBP2, making FOXO1 nuclear. These features enable fine-tuned FOXO1 regulations on chromatin folding and subsequent gene expression. Using these key factors as readouts, a ‘hibernation solution’ was developed, enabling long-term pancreatic islet cold storage and transplantation to cure diabetes. Henceforth, targeting FOXO1 SIM or the SUMO machinery may aid tissue/organ survival from long-term cold and other stresses.

2024-03-01 | GSE183998 | GEO

SUMOylation inhibition overcomes dexamethasone resistance in multiple myeloma

Project description:SUMOylation, a posttranslational modification, regulates proteins by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins. Here we use TAK-981, a selective SUMO-activating enzyme (SAE) inhibitor, to inhibit global SUMOylation in glucocorticoid sensitive and resistant multiple myeloma cell lines.

2021-12-31 | GSE163682 | GEO

Gene expression profiles in wild-type and SUMO knockdown mice after forebrain ischemia

Project description:Transient brain ischemia massively activates global SUMOylation. A large fraction of SUMO targets are nuclear proteins involved in gene expression. However, gene expression profile modulated by ischemia-induced SUMOylation has not been studied. Using a SUMO knockdown (SUMO-KD) mouse model and microarray technique, we investigated how SUMOylation modulated gene expression after brain ischemia. Wild-type and SUMO-KD mice were subjected to transient forebrain ischemia or sham surgery. The hippocampal CA1 subfield samples collected at 3 hours reperfusion were analyzed using Affymetrix microarrays.

2016-08-01 | E-GEOD-80681 | biostudies-arrayexpress

O-GlcNAcase SUMOylation studies identify the SUMO-code in chaperone-mediated autophagy

Project description:O-GlcNAcase (OGA) is the sole eraser for the intracellular O-linked N-acetylglucosamine (O-GlcNAc). OGA has many roles in diverse processes, such as cancer and embryonic stem cells, but its exact regulating mechanism is far from understood. Herein we studied small ubiquitin-like modifier (SUMO) modification of OGA, and found that OGA is SUMOylated at K358. SUMOylation targets OGA to the chaperone-mediated autophagy (CMA) pathway, which shunts client proteins to the lysosome for degradation. We demonstrate that SUMOylation increases the association between OGA and Heat shock cognate protein (HSC70), the CMA chaperone, and facilitates its further degradation. We further mapped a SUMO-interacting motif (SIM) (VLIFD, aa. 195-199) on HSC70. Surprisingly, HSC70-SIM is essential for affinity with other CMA clients, such as PKM2. We thus posit that the SIM of HSC70 binds SUMOylated clients in a lock-and-key fashion to confer substrate selectivity during CMA. To validate our hypothesis, we used label-free quantitative mass spectrometry to study the HSC70-SIM mutant interactome, and generated a proteome-wide SUMO-mediated CMA client pool. We then validated our model by studying YEATS domain containing 2 (YEATS2) from the protein pool, and demonstrated that YEATS2 is SUMOylated at K592, which also targets YEATS2 to CMA. Our work unveils the SUMO-SIM interaction as a fundamental mechanism that governs CMA substrate selectivity and identifies a potential CMA client proteome to deepen our understanding of its pathophysiological relevance.

2024-10-13 | PXD056772 |

NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation

Project description:Breast cancer is genetically heterogeneous, and recent studies have underlined a prominent contribution of epigenetics to the development of this disease. To uncover new synthetic lethalities with known breast cancer oncogenes, we screened an epigenome-focused short hairpin RNA library on a panel of engineered breast epithelial cell lines. Here we report a selective interaction between the NOTCH1 signaling pathway and the SUMOylation cascade. Knockdown of the E2-conjugating enzyme UBC9 (UBE2I) as well as inhibition of the E1-activating complex SAE1/UBA2 using ginkgolic acid impairs the growth of NOTCH1-activated breast epithelial cells. We show that upon inhibition of SUMOylation NOTCH1-activated cells proceed slower through the cell cycle and ultimately enter apoptosis. Mechanistically, activation of NOTCH1 signaling depletes the pool of unconjugated small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 leading to increased sensitivity to perturbation of the SUMOylation cascade. Depletion of unconjugated SUMO correlates with sensitivity to inhibition of SUMOylation also in patient-derived breast cancer cell lines with constitutive NOTCH pathway activation. Our investigation suggests that SUMOylation cascade inhibitors should be further explored as targeted treatment for NOTCH-driven breast cancer. We treated MCF10A and NOTCH1 cells with either DMSO or ginkgolic acid 30 uM for 3 days. Two replicates have been analysed for each condition.

2014-11-21 | E-GEOD-61727 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data