Cloning and Characterization of DULP, a Novel Ubiquitin-Like Molecule from Human Dendritic Cells

Liu, Guo Yan; Liu, Shu Xun; Li, Ping; Tang, Ling; Yao, Han; An, Hua Zhang; Li, Jiang Yan; Dai, Xian Kun; Li, Nan; Cao, Xue Tao; Yu, Yi

doi:10.1038/cmi.2009.4

Cited by 6 publications

(6 citation statements)

References 130 publications

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“…The complete comprehension of how these events are regulated is crucial for the identification of those defects responsible for the development of many diseases, from inflammatory diseases to cancer. Our previous reports showed that the protein HOPS plays a central role in different cellular functions, including maintenance of genomic stability, correct proliferation and progression through the cell cycle 1 , 10 , 14 , 28 , 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Instead, IL-6 could be responsible of the increased expression of HOPS during liver regeneration, possibly through a mechanism involving the binding of the transcription factor C/EBPβ to the promoter of HOPS and the activation of its transcription 8 , 9 . HOPS has a role in mitotic spindle assembly and centrosome duplication and is involved in the control of cell cycle progression 10 – 12 . Moreover, it was found to participate in the ERAD pathway, where it plays an important role in the control of sterol-accelerated ubiquitination and degradation of the cholesterol biosynthetic enzyme HMG-CoA reductase 13 .…”

Section: Introductionmentioning

confidence: 99%

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HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6

et al. 2020

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HOPS/Tmub1 is a ubiquitously expressed transmembrane ubiquitin-like protein that shuttles between nucleus and cytoplasm during cell cycle progression. HOPS causes cell cycle arrest in G0/G1 phase, an event associated to stabilization of p19Arf, an important tumor suppressor protein. Moreover, HOPS plays an important role in driving centrosomal assembly and maintenance, mitotic spindle proper organization, and ultimately a correct cell division. Recently, HOPS has been described as an important regulator of p53, which acts as modifier, stabilizing p53 half-life and playing a key role in p53 mediating apoptosis after DNA damage. NF-κB is a transcription factor with a central role in many cellular events, including inflammation and apoptosis. Our experiments demonstrate that the transcriptional activity of the p65/RelA NF-κB subunit is regulated by HOPS. Importantly, Hops−/− cells have remarkable alterations of pro-inflammatory responses. Specifically, we found that HOPS enhances NF-κB activation leading to increase transcription of inflammatory mediators, through the reduction of IκBα stability. Notably, this effect is mediated by a direct HOPS binding to the E3 ubiquitin ligase TRAF6, which lessens TRAF6 stability ultimately leading increased IKK complex activation. These findings uncover a previously unidentified function of HOPS/Tmub1 as a novel modulator of TRAF6, regulating inflammatory responses driven by activation of the NF-κB signaling pathway. The comprehension on how HOPS/Tmub1 takes part to the inflammatory processes in vivo and whether this function is important in the control of proliferation and tumorigenesis could establish the basis for the development of novel pharmacological strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6

et al. 2020

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“…In 2009, Liu et al. 7 mentioned that Tmub1 can induce apoptosis in 293T cells, but the specific role and the underlying mechanisms are yet to be revealed. In our preliminary studies, we found that Tmub1 may interact with an apoptosis-related protein, p63, indicating a possible relationship between Tmub1, p63, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Tmub1 Suppresses Hepatocellular Carcinoma by Promoting the Ubiquitination of ΔNp63 Isoforms

Zhang

Chen

et al. 2020

Molecular Therapy - Oncolytics

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Transmembrane and ubiquitin-like domain-containing 1 (Tmub1) inhibits hepatocyte proliferation during liver regeneration, but its role in hepatocellular carcinoma (HCC) has yet to be revealed. In this study, we show that the levels of Tmub1 were significantly lower in HCC tissues and cells than they were in adjacent tissues and normal hepatic cells, and the low levels of Tmub1 indicated a poor prognosis in HCC patients. Xenograft growth assay revealed that Tmub1 represses HCC growth in vivo . In addition, Tmub1 formed a protein complex with apoptosis-associated protein tumor protein 63 (p63), especially with the ΔN isoforms (ΔNp63α, β, and γ). Further loss- and gain-of-function analyses indicated that Tmub1 promotes apoptosis of Hep3B and MHCC-LM3 cells. Tmub1 decreased the protein expression of ΔNp63, and the pro-apoptotic effect of Tmub1 can be reversed by ΔNp63 isoforms (α, β, and γ). Additionally, we report that Tmub1 promotes the ubiquitination and degradation of ΔNp63 proteins. Finally, we confirmed in HCC tissues that Tmub1 is negatively correlated with ΔNp63 and positively correlated with the level of apoptosis. Taken together, Tmub1 suppresses HCC by enhancing the ubiquitination and degradation of ΔNp63 isoforms to induce HCC cell apoptosis. These findings provide a potential strategy for the management of HCC.

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“…Tmub1 encodes for a protein, HOPS/DULP, containing transmembrane domains and a ubiquitin-like domain (UBL) [1] , [2] . Ubiquitin can be employed to modify proteins by either single or multiple ubiquitin conjugation to mark them for proteasomal destruction, endocytosis and binding to other proteins [3] – [5] .…”

Section: Introductionmentioning

confidence: 99%

Transmembrane and Ubiquitin-Like Domain Containing 1 (Tmub1) Regulates Locomotor Activity and Wakefulness in Mice and Interacts with CAMLG

et al. 2010

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Tmub1 (C7orf21/HOPS) encodes a protein containing a ubiquitin-like domain. Tmub1 is highly expressed in the nervous system. To study its physiological function, we generated mice with Tmub1 deleted by homologous recombination. The knockout mice were grossly normal and viable. In a comprehensive behavioral testing battery, the only knockout phenotype displayed was a strong increase in home cage locomotor activity during the dark phase (subjective day) of the light∶dark (L∶D) cycle. There were no changes in activity during the light period. There were no changes in locomotor activity observed in other assays, e.g. novel open-field. The increase in dark phase locomotor activity persisted during a seven day D∶D (complete darkness) challenge, and remained largely confined to the normally dark period. Telemetric recording in freely moving subjects for one 24 hr L∶D cycle, revealed the same increase in locomotor activity in the dark phase. In addition, EEG analysis showed that the knockout mice exhibited increased waking and decreased NREM & REM times during the dark phase, but the EEG was otherwise normal. Using lacZ as a reporter we found Tmub1 expression prominent in a few brain structures including the thalamus, a region known to drive wakefulness and arousal via its projections to the cortex. We identified calcium modulating cyclophilin ligand CAMLG/CAML as a binding partner by a yeast two-hybrid screen of a brain library. The interaction of Tmub1 and CAMLG was confirmed by co-immunoprecipitation assays in HEK cells. The two proteins were also found to be co-localized to the cytoplasm when expressed in HEK cells. Both Tmub1 and CAMLG have been recently described in the regulation of membrane trafficking of specific receptors. Taken together our results implicate Tmub1 in the regulation of locomotor activity and wakefulness and suggest that Tmub1 binds to and functions together with CAMLG.

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Cloning and Characterization of DULP, a Novel Ubiquitin-Like Molecule from Human Dendritic Cells

Cited by 6 publications

References 130 publications

HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6

HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6

Tmub1 Suppresses Hepatocellular Carcinoma by Promoting the Ubiquitination of ΔNp63 Isoforms

Transmembrane and Ubiquitin-Like Domain Containing 1 (Tmub1) Regulates Locomotor Activity and Wakefulness in Mice and Interacts with CAMLG

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