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

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lymph Node

SUBMITTER: Olga Boix

LAB HEAD: María Abad Méndez

PROVIDER: PXD026181 | Pride | 2022-10-06

REPOSITORIES: Pride

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

Project description: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.

2022-09-28 | GSE175463 | GEO

CDC42 controlled apical-basal polarity regulates intestinal stem cell to transit amplifying cell fate transition via YAP-EGF-mTOR signaling

Project description:Epithelial polarity is controlled by a polarity machinery including the Rho GTPase CDC42 and Scribble/PAR. By using intestinal stem cell (ISC)-specific deletion of CDC42 in Olfm4-IRES-eGFPCreERT2;CDC42flox/flox mice, we found that ISC-initiated CDC42 loss caused a drastic hyper-proliferation of transit amplifying (TA) cells and disrupted epithelial polarity. CDC42-null crypts displayed expanded TA cell and diminished ISC populations, accompanied by elevated hippo signaling via YAP/TAZ - Ereg and mTOR activation, independent from canonical Wnt signaling. YAP/TAZ conditional knockout restored the balance of ISC/TA cell populations and crypt proliferation but did not rescue the polarity in CDC42-null small intestine. mTOR or EGFR inhibitor treatment of CDC42 KO mice exhibited similar rescuing effects without affecting YAP/TAZ signaling. Inducible ablation of Scribble in intestinal epithelial cells mimics that of CDC42 KO defects including crypt hyperplasia and hippo signaling activation. Mammalian epithelial polarity regulates ISC and TA cell fate and proliferation via a hippo-Ereg-mTOR cascade.

2021-10-23 | GSE166736 | GEO

Roles of Cdc42 and Rac in Bergmann glia during cerebellar corticogenesis (WT_primary_astrocyte)

Project description:Bergmann glia (BG) are important in the inward type of radial migration of cerebellar granule neurons (CGNs). However, details regarding the functions of Cdc42 and Rac in BG for radial migration of CGN are unknown. To examine the roles of Cdc42 and Rac in BG during cerebellar corticogenesis, mice with a single deletion of Cdc42 or Rac1 and those with double deletions of Cdc42 and Rac1 under control of the glial fibrillary acidic protein (GFAP) promoter: GFAP-Cre;Cdc42flox/flox (Cdc42-KO), GFAP–Cre;Rac1flox/flox (Rac1-KO), and GFAP-Cre;Cdc42 flox/flox;Rac1flox/flox (Cdc42/Rac1-DKO) mice, were generated. Both Cdc42-KO and Rac1-KO mice, but more obviously Cdc42-KO mice, had disturbed alignment of BG in the Purkinje cell layer (PCL). We found that Cdc42-KO, but not Rac1-KO, induced impaired radial migration of CGNs in the late phase of radial migration, leading to retention of CGNs in the inferior half of the molecular layer (ML). Cdc42-KO, but not Rac1-KO, mice also showed aberrantly aligned Purkinje cells (PCs). These phenotypes were exacerbated in Cdc42/Rac1-DKO mice. Alignment of BG radial fibers in the ML and BG endfeet at the pial surface of the cerebellum evaluated by GFAP staining was disturbed and weak in Cdc42/Rac1-DKO mice, respectively. Our data indicate that that Cdc42 and Rac, but predominantly Cdc42, in BG play important roles during the late phase of radial migration of CGNs. We also report here that Cdc42 is involved in gliophilic migration of CGNs, in contrast to Rac, which is more closely connected to regulating neurophilic migration.

2018-01-01 | GSE106141 | GEO

Gene expression profiles of Treg cells lacking Cdc42 GTPase

Project description:Treg cells play an important role in immune tolerance and tumor immune evasion through suppression of effector T cells. Treg cell lineage instability may be harnessed to trigger anti-tumor T cell immunity. However, the mechanism underlying Treg cell stability remains poorly understand. By characterizing Treg cell-specific heterozygous and homozygous Cdc42 knockout mice, we found that Cdc42 is essential for Treg cell stability. By RNA sequencing of heterozygous and homozygous Cdc42 knockout Treg cells, we found that Cdc42 maintains Treg cell stability through suppression of carbonic anhydrase I (CAI) expression.

2021-08-12 | GSE181779 | GEO

Roles of Cdc42 and Rac in Bergmann glia during cerebellar corticogenesis (U87_CDC42RAC1-DKD)

2018-01-01 | GSE106142 | GEO

Gene expression changes in REH following CDC42 inhibition

Project description:ARHGEF4 expression is associated with t(12;21) acute lymphoblastic leukaemia (ALL). Our study investigated the substrate specificity of ARHGEF4, a member of the diffuse B-cell lymphoma (DBL) family of guanine nucleotide exchange factors (GEFs), in t(12;21) ALL REH cells. ARHGEF4 was found to activate the small guanine nucleotide binding protein (GTPase) CDC42. In order to determine the function of CDC42 in t(12;21) ALL cells, we performed RNAseq analysis on REH cells treated for 24 hours with DMSO vehicle control in comparison to 25uM ML141, a CDC42 inhibitor.

2020-06-20 | GSE152836 | GEO

Cdc42 controls DC-maturation - Cdc42-dependent actin dynamics controls maturation and secretory activity of dendritic cells

Project description:Cell division cycle 42 (Cdc42) is a member of the Rho GTPase family and has pivotal functions in actin organization, cell migration and proliferation. Cdc42 has been shown to regulate antigen (Ag)-uptake in immature dendritic cells (DC) and controls their migration from tissues to lymph nodes. Previous reports demonstrated that Cdc42 is inactivated upon DC-maturation to avoid continued Ag-acquisition. To further study the molecular mechanisms of DC-control by Cdc42, we used bone marrow-derived DCs from Cdc42-deficient mice. We show that Cdc42-deficient DCs are phenotypically mature without additional maturation stimuli, as they upregulate CD86 from intracellular storages to the cell surface. They also accumulate invariant chain (Ii)-MHC class II complexes at the cell surface, which cannot efficiently present peptide Ag for priming of Ag-specific CD4 T cells. Lack of Cdc42 in immature DCs does not allow MHC class II maturation, as lysosomal Cathepsins are lost into the supernatant and Ii-MHC class II complexes cannot mature. Therefore Cdc42-deficient DCs are "pseudomature" and lose most functional hallmarks of antigen-presenting cells. Our results propose that Cdc42 keeps DCs in an immature state, while downregulation of Cdc42-activity during maturation facilitates generation of CD86+MHCII+ mature DCs.

2015-10-12 | PXD001934 | Pride

Transport of influenza A virus neuraminidase to host cell surface and virus replication are regulated by ARHGAP21 and Cdc42

Project description:Influenza virus neuraminidase (NA), a type II transmembrane glycoprotein, is transported to the virus assembly site at the plasma membrane and is a major viral envelope component that plays a critical role in the release of progeny virions and in determination of host range restriction. Although signals/sequences in NA for translocation, sorting and raft association have been identified, little is known about the host factors that are involved in regulating the intracellular and cell surface transport of NA. In this report, we have investigated the involvement of Rho family GTPases in NA transport to the cell surface. We found that expression of constitutively active or inactive mutants of RhoA or Rac1 did not significantly affect the amount of NA that reached the cell surface. Interestingly, expression of constitutively active Cdc42 or depletion of the Cdc42-specific GAP, ARHGAP21, promoted the transport of NA to the plasma membranes. By contrast, cells expressing shRNA targrting Cdc42 or overexpressing ARHGAP21 exhibited a significant decrease in the amount of cell surface-localized NA. Furthermore, silencing of Cdc42 or ARHGAP21 had significant effects on influenza A virus replication. Together, our results reveal that ARHGAP21 and Cdc42-based signaling regulates the NA transport and thereby impacts virus replication. This microarray experiment was carried out to find out whether Cdc42 and ARHGAP21 expression levels in A549 cell were changed after WSN infection. Total RNAs were extracted from three different groups of A549 cells that had been infected with or without WSN for 10 h, using TRIzol reagent (Invitrogen, Carlsbad, CA). Samples were amplified and labeled using a NimbleGen One-Color DNA Labeling Kit.

2012-04-03 | E-GEOD-32878 | biostudies-arrayexpress

Cdc42 phosphorylation study - Cdc42 Regulates Neuronal Polarity during Cerebellar Axon Formation and Glial-Guided Migration

Project description:Govek et al. demonstrate conditional loss of Cdc42 in cerebellar granule cell progenitors (GCPs) perturbs GCP polarity and impairs axon patterning, glial-guided migration, and cerebellar foliation. Phospho-proteomic analysis identified polarity and cytoskeletal proteins as affected targets in Cdc42 deficient GCPs.

2018-10-22 | PXD008148 | Pride

Studies of target genes for signal transduction pathways (using a Ras1-, a Cdc42- and a Gap1-mutant) in the basidiomycete Schizophyllum commune.

Project description:Transcriptome changes associated with signal transduction mutants were analysed in order to identify targets of the distinct pathways of Ras1, Cdc42 and Gap1. Two monokaryons (12-43 and 4-39), a dikaryon (W22 x 12-43), a constitutive active Ras1 mutant (T2G12V, monokaryon), a Cdc42 mutant (G12V, monokaryon) and a M-bM-^HM-^Fgap1 x M-bM-^HM-^Fgap1 dikaryon (F15 x F28, deletion of Gap1) were analyzed for that purpose. With microarray analysis mRNA expression in different mutants of the basidiomycete S. commune was analyzed. Genes which show regulation in the comparison either of the two monokaryons 12-43 and 4-39 (for Ras2 and Cdc42 mutant) or the dikaryon W22 x 12-43 (for Gap1 x Gap1 dikaryon) have been eliminated from other comparisons as stage-specific (mono- or dikaryon) differences. Two biological replicate samples were analyzed for each condition.

2013-02-01 | E-GEOD-43965 | biostudies-arrayexpress

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