Aux/IAA proteins are well-known as key components of the nuclear auxin signaling pathway, repressing gene transcription when present and enabling gene activation upon their degradation. In this review, we explore the additional roles of Aux/IAA proteins in the known auxin perception pathways-the TIR1/AFBs nuclear as well as in the emerging cytoplasmic and apoplastic pathways. We summarize recent advances in understanding the regulation of Aux/IAA protein stability at the post-translational level, a critical factor in auxin-regulated transcriptional output. We further highlight the roles of auxin-nondegradable non-canonical Aux/IAAs in auxin-mediated transcription and their involvement in apoplastic auxin signalling. Additionally, we discuss the importance of Aux/IAAs for the adenylate cyclase activity of TIR1/AFB receptors and speculate on their involvement in the cytoplasmic auxin pathway. Using Arabidopsis root as a model, this work underscores the central role of Aux/IAA proteins in mediating auxin-driven developmental processes and environmental responses. Key questions for future research are proposed to further unravel the dynamic roles of Aux/IAAs in auxin signaling networks.

• MeSH
• Arabidopsis * metabolismus   genetika   MeSH
• F-box proteiny metabolismus   genetika   MeSH
• kořeny rostlin metabolismus   MeSH
• kyseliny indoloctové * metabolismus   MeSH
• proteiny huseníčku * metabolismus   genetika   MeSH
• receptory buněčného povrchu metabolismus   genetika   MeSH
• regulace genové exprese u rostlin MeSH
• regulátory růstu rostlin * metabolismus   MeSH
• rostlinné proteiny * metabolismus   genetika   MeSH
• signální transdukce MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• F-box proteiny MeSH
• kyseliny indoloctové * MeSH
• proteiny huseníčku * MeSH
• receptory buněčného povrchu MeSH
• regulátory růstu rostlin * MeSH
• rostlinné proteiny * MeSH

WBP1L is a broadly expressed transmembrane adaptor protein involved in regulating hematopoietic stem cell function and T cell development. It interacts with NEDD4-family E3 ubiquitin ligases and regulates important chemokine receptor CXCR4. Using tandem affinity purification coupled with mass spectrometry, we identified novel WBP1L interactions with the IFNγ receptor and the Cullin-RING ubiquitin ligases CRL1β-TrCP1/2. We found that WBP1L interaction with the IFNγ receptor serves to downregulate proximal IFNγ receptor signaling in female macrophages, while the interaction with CRL1β-TrCP1/2 ubiquitin ligases regulates WBP1L protein levels. Disrupting this interaction, as well as inhibiting proteasome activity or neddylation, increased WBP1L protein levels, demonstrating that CRL1β-TrCP1/2 ubiquitin ligases regulate WBP1L protein abundance. These data provide important insights into the mechanisms controlling WBP1L function.

• Klíčová slova
• Cullin-RING ubiquitin ligases, Interferon gamma receptor, Membrane adaptor proteins, NEDD4-Family ubiquitin ligases, WBP1L,
• MeSH
• adaptorové proteiny signální transdukční * metabolismus   MeSH
• HEK293 buňky MeSH
• hematopoéza * fyziologie   MeSH
• lidé MeSH
• makrofágy metabolismus   MeSH
• membránové proteiny * metabolismus   MeSH
• myši MeSH
• proteiny s repetitivními sekvencemi beta-transducinu * metabolismus   MeSH
• signální transdukce MeSH
• ubikvitinligasy * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční * MeSH
• membránové proteiny * MeSH
• proteiny s repetitivními sekvencemi beta-transducinu * MeSH
• ubikvitinligasy * MeSH

SKP1-CUL1-F-box protein (SCF) ubiquitin ligases are versatile protein complexes that mediate the ubiquitination of protein substrates. The direct substrate recognition relies on a large family of F-box-domain-containing subunits. One of these substrate receptors is FBXO38, which is encoded by a gene found mutated in families with early-onset distal motor neuronopathy. SCFFBXO38 ubiquitin ligase controls the stability of ZXDB, a nuclear factor associated with the centromeric chromatin protein CENP-B. Loss of FBXO38 in mice results in growth retardation and defects in spermatogenesis characterized by deregulation of the Sertoli cell transcription program and compromised centromere integrity. Moreover, it was reported that SCFFBXO38 mediates the degradation of PD-1, a key immune-checkpoint inhibitor in T cells. Here, we have re-addressed the link between SCFFBXO38 and PD-1 proteolysis. Our data do not support the notion that SCFFBXO38 directly or indirectly controls the abundance and stability of PD-1 in T cells.

• Klíčová slova
• Cullin, FBXO38, Immune Checkpoint, PD-1, Protein Degradation,
• MeSH
• antigeny CD279 * metabolismus   genetika   MeSH
• F-box proteiny * metabolismus   genetika   MeSH
• lidé MeSH
• myši MeSH
• proteinligasy komplexu SCF metabolismus   genetika   MeSH
• proteolýza MeSH
• T-lymfocyty metabolismus   MeSH
• ubikvitinace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD279 * MeSH
• F-box proteiny * MeSH
• Fbxo38 protein, mouse MeSH Prohlížeč
• Pdcd1 protein, mouse MeSH Prohlížeč
• proteinligasy komplexu SCF MeSH

BACKGROUND: Colorectal cancer is still the second leading cause of cancer-related deaths and thus biomarkers allowing prediction of the resistance of patients to therapy and estimating their prognosis are needed. We designed a panel of 558 genes with pharmacogenomics records related to 5-fluorouracil resistance, genes important for sensitivity to other frequently used drugs, major oncodrivers, and actionable genes. We performed a target enrichment sequencing of DNA from tumors and matched blood samples of patients, and compared the results with patient prognosis stratified by systemic adjuvant chemotherapy. RESULTS: The median number of detected variants per tumor sample was 18.5 with 4 classified as having a high predicted functional effect and 14.5 moderate effect. APC, TP53, and KRAS were the most frequent mutated genes (64%, 59%, and 42% of mutated samples, respectively) followed by FAT4 (23%), FBXW7, and PIK3CA (16% for both). Patients with advanced stage III had more frequently APC, TP53, or KRAS mutations than those in stages I or II. KRAS mutation counts followed an increasing trend with grade (G1 < G2 < G3). The response to adjuvant therapy was worse in carriers of frameshift mutations in APC or 12D variant in KRAS, but none of these oncodrivers had prognostic value. Carriage of somatic mutations in any of the genes ABCA13, ANK2, COL7A1, NAV3, or UNC80 had prognostic relevance for worse overall survival (OS) of all patients. In contrast, mutations in FLG, GLI3, or UNC80 were prognostic in the same direction for patients untreated, and mutations in COL6A3, LRP1B, NAV3, RYR1, RYR3, TCHH, or TENM4 for patients treated with adjuvant therapy. The first association was externally validated. From all germline variants with high or moderate predicted functional effects (median 326 per patient), > 5% frequency and positive Manhattan plot based on 3-year RFS, rs72753407 in NFACS, rs34621071 in ERBB4, and rs2444274 in RIF1 were significantly associated with RFS, OS or both. CONCLUSIONS: The present study identified several putative somatic and germline genetic events with prognostic potential for colorectal cancer that should undergo functional characterization.

• Klíčová slova
• Carcinoma, Colorectal, Drug, Oncodriver, Pharmacogene, Prognosis, Resistance, Sequencing,
• MeSH
• chemorezistence genetika   MeSH
• dospělí MeSH
• F-Box a WD repetice obsahující protein 7 genetika   MeSH
• farmakogenetika metody   MeSH
• fluoruracil terapeutické užití   MeSH
• fosfatidylinositol-3-kinasy třídy I MeSH
• kolorektální nádory * genetika   farmakoterapie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace genetika   MeSH
• nádorové biomarkery genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• prognóza MeSH
• protein familiární adenomatózní polypózy genetika   MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• APC protein, human MeSH Prohlížeč
• F-Box a WD repetice obsahující protein 7 MeSH
• fluoruracil MeSH
• fosfatidylinositol-3-kinasy třídy I MeSH
• KRAS protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• nádorový supresorový protein p53 MeSH
• PIK3CA protein, human MeSH Prohlížeč
• protein familiární adenomatózní polypózy MeSH
• protoonkogenní proteiny p21(ras) MeSH
• TP53 protein, human MeSH Prohlížeč

The phytohormone auxin triggers root growth inhibition within seconds via a non-transcriptional pathway. Among members of the TIR1/AFB auxin receptor family, AFB1 has a primary role in this rapid response. However, the unique features that confer this specific function have not been identified. Here we show that the N-terminal region of AFB1, including the F-box domain and residues that contribute to auxin binding, is essential and sufficient for its specific role in the rapid response. Substitution of the N-terminal region of AFB1 with that of TIR1 disrupts its distinct cytoplasm-enriched localization and activity in rapid root growth inhibition by auxin. Importantly, the N-terminal region of AFB1 is indispensable for auxin-triggered calcium influx, which is a prerequisite for rapid root growth inhibition. Furthermore, AFB1 negatively regulates lateral root formation and transcription of auxin-induced genes, suggesting that it plays an inhibitory role in canonical auxin signaling. These results suggest that AFB1 may buffer the transcriptional auxin response, whereas it regulates rapid changes in cell growth that contribute to root gravitropism.

• Klíčová slova
• Arabidopsis, auxin signaling, calcium, gravitropism, lateral root,
• MeSH
• Arabidopsis * metabolismus   MeSH
• cytosol metabolismus   MeSH
• F-box proteiny * metabolismus   MeSH
• kořeny rostlin metabolismus   MeSH
• kyseliny indoloctové farmakologie   metabolismus   MeSH
• proteiny huseníčku * metabolismus   MeSH
• receptory buněčného povrchu genetika   metabolismus   MeSH
• regulace genové exprese u rostlin MeSH
• regulátory růstu rostlin metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• F-box proteiny * MeSH
• kyseliny indoloctové MeSH
• proteiny huseníčku * MeSH
• receptory buněčného povrchu MeSH
• regulátory růstu rostlin MeSH

Long non-coding RNAs (lncRNAs) are crucial in chronic liver diseases, but the specific molecular mechanism of lncRNAs in alcoholic fatty liver (AFL) remains unclear. In this study, we investigated the in-depth regulatory mechanism of mTOR affected by AIRN non-protein coding RNA (lncRNA-AIRN) in the development of AFL. LncRNA-AIRN was highly expressed in the liver tissues of AFL C57BL/6mice and oleic acid+alcohol (O+A)treated AML-12cells by using quantitative real-timePCR. RNA pull-down and RNA immunoprecipitation experiments demonstrated that there was an interaction between lncRNA-AIRN and mTOR, and that interference with lncRNA-AIRN could promote the mTOR protein level. Results ofcycloheximide-chase assay showed that the proteinlevel of mTOR was decreased with the treatment time after the knockdown of lncRNA-AIRN. Furthermore, the knockdown of lncRNA-AIRN reducedmTOR protein level by promoting the E3 ubiquitin ligase FBXW7-mediated ubiquitination.The lncRNA-AIRN/mTORaxis was involved in the regulation of the mitophagy of O+A treated hepatocytes, which was confirmed by the cell transfection and the MTT assay.SPSS 16.0 was used for analyzing data. The difference between the two groups was analyzed by performing Student's t-test, and ANOVA was used to analyze the difference when more than two groups. P values < 0.05 were considered to be significantly different.Our findings demonstrated that the knockdown of lncRNA-AIRN influencedmitophagy in AFL by promoting mTOR ubiquitination.

• MeSH
• alkoholická steatóza jater enzymologie   genetika   patologie   MeSH
• buněčné linie MeSH
• down regulace MeSH
• F-Box a WD repetice obsahující protein 7 metabolismus   MeSH
• hepatocyty enzymologie   patologie   MeSH
• jaterní mitochondrie enzymologie   genetika   patologie   MeSH
• játra enzymologie   patologie   MeSH
• mitofagie * MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• RNA dlouhá nekódující genetika   metabolismus   MeSH
• signální transdukce MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• ubikvitinace MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Air non-coding RNA, mouse MeSH Prohlížeč
• F-Box a WD repetice obsahující protein 7 MeSH
• Fbxw7 protein, mouse MeSH Prohlížeč
• mTOR protein, mouse MeSH Prohlížeč
• RNA dlouhá nekódující MeSH
• TOR serin-threoninkinasy MeSH

The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G > A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by prominent motor dysfunction.

• MeSH
• dítě MeSH
• dystonie etiologie   genetika   patofyziologie   MeSH
• F-box proteiny genetika   MeSH
• lidé MeSH
• mozková obrna komplikace   genetika   patofyziologie   MeSH
• nádorové supresorové proteiny genetika   MeSH
• svalová spasticita etiologie   genetika   patofyziologie   MeSH
• syndrom MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• F-box proteiny MeSH
• FBXO31 protein, human MeSH Prohlížeč
• nádorové supresorové proteiny MeSH

A precisely balanced activity of canonical Wnt signaling is essential for a number of biological processes and its perturbation leads to developmental defects or diseases. Here, we demonstrate that alternative isoforms of the KDM2A and KDM2B lysine demethylases have the ability to negatively regulate canonical Wnt signaling. These KDM2A and KDM2B isoforms (KDM2A-SF and KDM2B-SF) lack the N-terminal demethylase domain, but they still have the ability to bind to CpG islands in promoters and to interact with their protein partners via their other functional domains. We have observed that KDM2A-SF and KDM2B-SF bind to the promoters of axin 2 and cyclin D1, two canonical Wnt signaling target genes, and repress their activity. Moreover, KDM2A-SF and KDM2B-SF are both able to strongly repress a Wnt-responsive luciferase reporter. The transcriptional repression mediated by KDM2A-SF and KDM2B-SF, but also by KDM2A-LF, is dependent on their DNA binding domain, while the N-terminal demethylase domain is dispensable for this process. Surprisingly, KDM2B-LF is unable to repress both the endogenous promoters and the luciferase reporter. Finally, we show that both KDM2A-SF and KDM2B-SF are able to interact with TCF7L1, one of the transcriptional mediators of canonical Wnt signaling. KDM2A-SF and KDM2B-SF are thus likely to negatively affect the transcription of canonical Wnt signaling target genes by binding to their promoters and by interacting with TCF7L1 and other co-repressors.

• MeSH
• CpG ostrůvky MeSH
• cyklin D1 genetika   metabolismus   MeSH
• doména Jumonji s histondemethylasami genetika   metabolismus   MeSH
• F-box proteiny genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• lysin genetika   metabolismus   MeSH
• promotorové oblasti (genetika) * MeSH
• protein - isoformy MeSH
• protein 1 podobný transkripčnímu faktoru 7 genetika   metabolismus   MeSH
• regulace genové exprese * MeSH
• signální dráha Wnt * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CCND1 protein, human MeSH Prohlížeč
• cyklin D1 MeSH
• doména Jumonji s histondemethylasami MeSH
• F-box proteiny MeSH
• KDM2A protein, human MeSH Prohlížeč
• lysin MeSH
• protein - isoformy MeSH
• protein 1 podobný transkripčnímu faktoru 7 MeSH
• TCF7L1 protein, human MeSH Prohlížeč

Plant survival depends on vascular tissues, which originate in a self-organizing manner as strands of cells co-directionally transporting the plant hormone auxin. The latter phenomenon (also known as auxin canalization) is classically hypothesized to be regulated by auxin itself via the effect of this hormone on the polarity of its own intercellular transport. Correlative observations supported this concept, but molecular insights remain limited. In the current study, we established an experimental system based on the model Arabidopsis thaliana, which exhibits auxin transport channels and formation of vasculature strands in response to local auxin application. Our methodology permits the genetic analysis of auxin canalization under controllable experimental conditions. By utilizing this opportunity, we confirmed the dependence of auxin canalization on a PIN-dependent auxin transport and nuclear, TIR1/AFB-mediated auxin signaling. We also show that leaf venation and auxin-mediated PIN repolarization in the root require TIR1/AFB signaling. Further studies based on this experimental system are likely to yield better understanding of the mechanisms underlying auxin transport polarization in other developmental contexts.

• Klíčová slova
• Arabidopsis thaliana, PIN1, TIR1/AFB, auxin, auxin canalization, cell polarity,
• MeSH
• Arabidopsis * genetika   metabolismus   MeSH
• F-box proteiny * genetika   MeSH
• kyseliny indoloctové MeSH
• proteiny huseníčku * genetika   metabolismus   MeSH
• receptory buněčného povrchu genetika   metabolismus   MeSH
• regulace genové exprese u rostlin MeSH
• regulátory růstu rostlin MeSH
• signální transdukce MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• F-box proteiny * MeSH
• kyseliny indoloctové MeSH
• proteiny huseníčku * MeSH
• receptory buněčného povrchu MeSH
• regulátory růstu rostlin MeSH
• TIR1 protein, Arabidopsis MeSH Prohlížeč

In Arabidopsis thaliana, canonical auxin-dependent gene regulation is mediated by 23 transcription factors from the AUXIN RESPONSE FACTOR (ARF) family that interact with auxin/indole acetic acid repressors (Aux/IAAs), which themselves form co-receptor complexes with one of six TRANSPORT INHIBITOR1/AUXIN-SIGNALLING F-BOX (TIR1/AFB) proteins. Different combinations of co-receptors drive specific sensing outputs, allowing auxin to control a myriad of processes. ARF6 and ARF8 are positive regulators of adventitious root initiation upstream of jasmonate, but the exact auxin co-receptor complexes controlling the transcriptional activity of these proteins has remained unknown. Here, using loss-of-function mutants we show that three Aux/IAA genes, IAA6, IAA9, and IAA17, act additively in the control of adventitious root (AR) initiation. These three IAA proteins interact with ARF6 and/or ARF8 and likely repress their activity in AR development. We show that TIR1 and AFB2 are positive regulators of AR formation and TIR1 plays a dual role in the control of jasmonic acid (JA) biosynthesis and conjugation, as several JA biosynthesis genes are up-regulated in the tir1-1 mutant. These results lead us to propose that in the presence of auxin, TIR1 and AFB2 form specific sensing complexes with IAA6, IAA9, and/or IAA17 to modulate JA homeostasis and control AR initiation.

• Klíčová slova
• Arabidopsis, AuxIAA, TIR1/AFB, adventitious roots, jasmonate,
• MeSH
• Arabidopsis cytologie   genetika   růst a vývoj   metabolismus   MeSH
• F-box proteiny metabolismus   MeSH
• hypokotyl metabolismus   MeSH
• kořeny rostlin růst a vývoj   MeSH
• kyseliny indoloctové metabolismus   MeSH
• proteiny huseníčku metabolismus   MeSH
• receptory buněčného povrchu metabolismus   MeSH
• regulace genové exprese u rostlin MeSH
• signální transdukce * MeSH
• stabilita proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AFB2 protein, Arabidopsis MeSH Prohlížeč
• F-box proteiny MeSH
• indoleacetic acid MeSH Prohlížeč
• kyseliny indoloctové MeSH
• proteiny huseníčku MeSH
• receptory buněčného povrchu MeSH
• TIR1 protein, Arabidopsis MeSH Prohlížeč