A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

Pakay, Julian L.; Diesch, Jeannine; Gilan, Omer; Yip, Yan Yan; Sayan, Emre; Kölch, Walter; Mariadason, John M.; Hannan, Ross D.; Tulchinsky, Eugene; Dhillon, Amardeep S.

doi:10.1038/onc.2011.375

Cited by 29 publications

(23 citation statements)

References 50 publications

(55 reference statements)

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“…Also, we found the 26S protease regulatory proteins including PSMC1, PSMC2, and PSMC3 (also known as Tat-binding Protein 1, TBP1) to interact with SIRT7 ( Figure 2D ), which we then confirmed by co-immunoprecipitation ( Figure 2E and Supplementary Figure 2C ). These proteins have been previously reported to mediate ubiquitination-independent degradation 32, 33 which is consistent with our data. To identify which of these proteins were responsible for modulating SIRT7 degradation, we performed siRNA-mediated knockdown of TBP1, PSMC1, and PSMC2 and monitored the rate of degradation of SIRT7 after 5-FU incubation.…”

Section: Resultssupporting

confidence: 94%

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Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer

Tang¹,

Lu²,

Zhang³

et al. 2017

Theranostics

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5-Fluorouracil (5-FU) combined with radiotherapy is a common treatment strategy to treat human cancers, but the underlying mechanisms of this combination treatment remain unclear. Here, we report that NAD+-dependent deacetylase sirtuin-7 (SIRT7) protein levels were decreased due to 5-FU exposure rendering colorectal cancer cells sensitive to radiation. We found that SIRT7 downregulation was mediated via a Tat-binding Protein 1 (TBP1) proteasome-dependent pathway. Specifically, TBP1 was dephosphorylated at tyrosine 381 upon 5-FU treatment, which enhanced its direct interaction with SIRT7 and targeted it for degradation. Depletion of SIRT7 in cultured colorectal cancer cells induced radiosensitivity triggering cell death. Interestingly, decreased levels of SIRT7 mediated by 5-FU correlated well with improved therapeutic effect in patients with rectal cancer and with inhibited tumor growth in immune-compromised mice post-irradiation. Taken together, these data suggest that 5-FU induces radiosensitivity via SIRT7 degradation to favor a cell death pathway in targeted cancer cells. Thus, downregulation of SIRT7 could be a promising pharmacologic strategy to increase the effectiveness of chemoradiation therapy in cancer patients.

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Section: Resultssupporting

confidence: 94%

“…TBP1 also mediates protein degradation via a ubiquitin-independent pathway. Fos-related antigen-1 (Fra-1) is a member of the activator protein-1 transcription factor superfamily, and its turnover does not require ubiquitination but is destabilized via a TBP1 ubiquitin-independent pathway 33.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer

Tang¹,

Lu²,

Zhang³

et al. 2017

Theranostics

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“…5B, LT treatment also caused a time-dependent reduction in Fra-1 protein levels. Erk1/2 stabilizes Fra-1 by phosphorylating its two serine residues at the C terminus (Ser-252 and Ser-265) (29). We next generated a constitutively active Fra-1 mutant with substitution of Ser-252 and Ser-265 with Asp (Fra-12D), which mimics cells, which were treated with CHX for 3 h in the presence or absence of LT for the last 1 h. Cells were subsequently washed with PBS twice and then incubated with MG132 for 0 -3 h. The intensities of protein bands were quantified using the Image Studio software of the Odyssey system and normalized by the amounts of ␤-actin; relative amounts are shown below each lane.…”

Section: Lt Inactivation Of Mkk1/2-erk1/2 Promotes C-jun Protein Degrmentioning

confidence: 99%

Anthrax lethal toxin rapidly reduces c-Jun levels by inhibiting c-Jun gene transcription and promoting c-Jun protein degradation

Ouyang

Guo

Fang

et al. 2017

Journal of Biological Chemistry

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Anthrax is a life-threatening disease caused by infection with , which expresses lethal factor and the receptor-binding protective antigen. These two proteins combine to form anthrax lethal toxin (LT), whose proximal targets are mitogen-activated kinase kinases (MKKs). However, the downstream mediators of LT toxicity remain elusive. Here we report that LT exposure rapidly reduces the levels of c-Jun, a key regulator of cell proliferation and survival. Blockade of proteasome-dependent protein degradation with the 26S proteasome inhibitor MG132 largely restored c-Jun protein levels, suggesting that LT promotes degradation of c-Jun protein. Using the MKK1/2 inhibitor U0126, we further show that MKK1/2-Erk1/2 pathway inactivation similarly reduces c-Jun protein, which was also restored by MG132 pre-exposure. Interestingly, c-Jun protein rebounded to normal levels 4 h following U0126 exposure but not after LT exposure. The restoration of c-Jun in U0126-exposed cells was associated with increased c-Jun mRNA levels and was blocked by inactivation of the JNK1/2 signaling pathway. These results indicate that LT reduces c-Jun both by promoting c-Jun protein degradation via inactivation of MKK1/2-Erk1/2 signaling and by blocking c-Jun gene transcription via inactivation of MKK4-JNK1/2 signaling. In line with the known functions of c-Jun, LT also inhibited cell proliferation. Ectopic expression of LT-resistant MKK2 and MKK4 variants partially restored Erk1/2 and JNK1/2 signaling in LT-exposed cells, enabling the cells to maintain relatively normal c-Jun protein levels and cell proliferation. Taken together, these findings indicate that LT reduces c-Jun protein levels via two distinct mechanisms, thereby inhibiting critical cell functions, including cellular proliferation.

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“…Исследуя транскрипционный фактор Fra-1, сверхэкспрессия которого наблюдается при многих видах рака и напрямую связана с ростом и миграцией опухолевых клеток, Pakay и соавт., используя различные культуры клеток, методы генной инженерии, коиммунопреципитационный анализ, масс-спектрометрию, доказали, что метаболизм белка Fra-1, подвергающегося убиквитин-независимой деградации, опосредован следующими процессами: ассоциация Fra-1 с субъединицей TBP-1 регуляторной 19S субчастицы протеасомы и регуляция С-концевого дегрона белка с помощью сигнального пути RAS-ERK (от английского extracellular signal-regulated kinase) [110]. Rpn10-связывающих белков.…”

Section: разнообразие внутриклеточных белков подвергающихся убиквитиunclassified

Ubiquitin-independent protein degradation in proteasomes

Buneeva

Медведев

2018

BIOMED KHIM

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Proteasomes are large supramolecular protein complexes present in all prokaryotic and eukaryotic cells, where they perform targeted degradation of intracellular proteins. Until recently, it was generally accepted that prior proteolytic degradation in proteasomes the proteins had to be targeted by ubiquitination: the ATP-dependent addition of (typically four sequential) residues of the low-molecular ubiquitin protein, involving the ubiquitin-activating enzyme, ubiquitin-conjugating enzyme and ubiquitin ligase. The cytoplasm and nucleoplasm proteins labeled in this way are then digested in 26S proteasomes. However, in recent years it has become increasingly clear that using this route the cell eliminates only a part of unwanted proteins. Many proteins can be cleaved by the 20S proteasome in an ATP-independent manner and without previous ubiquitination. Ubiquitin-independent protein degradation in proteasomes is a relatively new area of studies of the role of the ubiquitin-proteasome system. However, recent data obtained in this direction already correct existing concepts about proteasomal degradation of proteins and its regulation. Ubiquitin-independent proteasome degradation needs the main structural precondition in proteins: the presence of unstructured regions in the amino acid sequences that provide interaction with the proteasome. Taking into consideration that in humans almost half of all genes encode proteins that contain a certain proportion of intrinsically disordered regions, it appears that the list of proteins undergoing ubiquitin-independent degradation will demonstrate further increase. Since 26S of proteasomes account for only 30% of the total proteasome content in mammalian cells, most of the proteasomes exist in the form of 20S complexes. The latter suggests that ubiquitin-independent proteolysis performed by the 20S proteasome is a natural process of removing damaged proteins from the cell and maintaining a constant level of intrinsically disordered proteins. In this case, the functional overload of proteasomes in aging and/or other types of pathological processes, if it is not accompanied by triggering more radical mechanisms for the elimination of damaged proteins, organelles and whole cells, has the most serious consequences for the whole organism.

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A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

Cited by 29 publications

References 50 publications

Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer

Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer

Anthrax lethal toxin rapidly reduces c-Jun levels by inhibiting c-Jun gene transcription and promoting c-Jun protein degradation

Ubiquitin-independent protein degradation in proteasomes

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