Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4A DCAF1 to promote colon cancer development

2016 ◽  
Vol 375 (2) ◽  
pp. 209-220 ◽  
Author(s):  
Weiguo Ren ◽  
Shourong Shen ◽  
Zhenqiang Sun ◽  
Peng Shu ◽  
Xiaohua Shen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Ubiquitin Ligase ◽  
Proteasomal Degradation ◽  
Cancer Development ◽  
Stat3 Pathway ◽  
Ubiquitin Ligase Complex

scholarly journals p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex

2017 ◽  
Vol 37 (8) ◽  
Author(s):  
Shasha Tao ◽  
Pengfei Liu ◽  
Gang Luo ◽  
Montserrat Rojo de la Vega ◽  
Heping Chen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Complexes ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Client Proteins

ABSTRACT Activation of the stress-responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targeted to the proteasome for degradation (the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation was previously unknown. p97 is a ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system (UPS). In this study, we show that p97 negatively regulates NRF2 through the canonical pathway by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric cofactor UFD1/NPL4 and the UBA-UBX-containing protein UBXN7, for efficient proteasomal degradation. Given the role of NRF2 in chemoresistance and the surging interest in p97 inhibitors to treat cancers, our results indicate that dual p97/NRF2 inhibitors may offer a more potent and long-term avenue of p97-targeted treatment.

scholarly journals A stalled retrotranslocation complex reveals physical linkage between substrate recognition and proteasomal degradation during ER-associated degradation

2013 ◽  
Vol 24 (11) ◽  
pp. 1765-1775 ◽  
Author(s):  
Kunio Nakatsukasa ◽  
Jeffrey L. Brodsky ◽  
Takumi Kamura
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Ubiquitin Ligase ◽  
Substrate Recognition ◽  
Proteasomal Degradation ◽  
26S Proteasome ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Ubiquitin Ligase Complex ◽  
Physical Linkage ◽  
Tightly Coupled

During endoplasmic reticulum–associated degradation (ERAD), misfolded lumenal and membrane proteins in the ER are recognized by the transmembrane Hrd1 ubiquitin ligase complex and retrotranslocated to the cytosol for ubiquitination and degradation. Although substrates are believed to be delivered to the proteasome only after the ATPase Cdc48p/p97 acts, there is limited knowledge about how the Hrd1 complex coordinates with Cdc48p/p97 and the proteasome to orchestrate substrate recognition and degradation. Here we provide evidence that inactivation of Cdc48p/p97 stalls retrotranslocation and triggers formation of a complex that contains the 26S proteasome, Cdc48p/p97, ubiquitinated substrates, select components of the Hrd1 complex, and the lumenal recognition factor, Yos9p. We propose that the actions of Cdc48p/p97 and the proteasome are tightly coupled during ERAD. Our data also support a model in which the Hrd1 complex links substrate recognition and degradation on opposite sides of the ER membrane.

scholarly journals Kelch-like protein 5-mediated ubiquitination of lysine 183 promotes proteasomal degradation of sphingosine kinase 1

2019 ◽  
Vol 476 (21) ◽  
pp. 3211-3226 ◽  
Author(s):  
Jason A. Powell ◽  
Melissa R. Pitman ◽  
Julia R. Zebol ◽  
Paul A.B. Moretti ◽  
Heidi A. Neubauer ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Conformational Changes ◽  
Protein Turnover ◽  
Expression System ◽  
Proteasome Inhibitors ◽  
Sphingosine Kinase ◽  
Proteasomal Degradation ◽  
Dominant Negative ◽  
Sphingosine Kinase 1 ◽  
Ubiquitin Ligase Complex

Sphingosine kinase 1 (SK1) is a signalling enzyme that catalyses the phosphorylation of sphingosine to generate the bioactive lipid sphingosine 1-phosphate (S1P). A number of SK1 inhibitors and chemotherapeutics can induce the degradation of SK1, with the loss of this pro-survival enzyme shown to significantly contribute to the anti-cancer properties of these agents. Here we define the mechanistic basis for this degradation of SK1 in response to SK1 inhibitors, chemotherapeutics, and in natural protein turnover. Using an inducible SK1 expression system that enables the degradation of pre-formed SK1 to be assessed independent of transcriptional or translational effects, we found that SK1 was degraded primarily by the proteasome since several proteasome inhibitors blocked SK1 degradation, while lysosome, cathepsin B or pan caspase inhibitors had no effect. Importantly, we demonstrate that this proteasomal degradation of SK1 was enabled by its ubiquitination at Lys183 that appears facilitated by SK1 inhibitor-induced conformational changes in the structure of SK1 around this residue. Furthermore, using yeast two-hybrid screening, we identified Kelch-like protein 5 (KLHL5) as an important protein adaptor linking SK1 to the cullin 3 (Cul3) ubiquitin ligase complex. Notably, knockdown of KLHL5 or Cul3, use of a cullin inhibitor or a dominant-negative Cul3 all attenuated SK1 degradation. Collectively this data demonstrates the KLHL5/Cul3-based E3 ubiquitin ligase complex is important for regulation of SK1 protein stability via Lys183 ubiquitination, in response to SK1 inhibitors, chemotherapy and for normal SK1 protein turnover.

scholarly journals Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Omar M. Khan ◽  
Jorge Almagro ◽  
Jessica K. Nelson ◽  
Stuart Horswell ◽  
Vesela Encheva ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Proteasomal Degradation ◽  
Tumour Suppressor ◽  
Negative Regulator ◽  
Protein Accumulation ◽  
Protein Levels ◽  
Ubiquitin Ligase Complex ◽  
Library Screen ◽  
Shrna Library

AbstractThe tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCFFBW7-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCFFBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.

A combination of omega-3 fatty acids and a butyrate-producing fiber mitigates colon cancer development

2006 ◽  
Author(s):  
Dr. Joanne R. Lupton ◽  
Dr. Nancy D. Turner ◽  
Dr. Leslie Braby ◽  
Dr. John Ford ◽  
Dr. Raymond J. Carroll ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Colon Cancer ◽  
Cancer Development ◽  
Omega 3 Fatty Acids ◽  
Omega 3

Tu1985 Loss of Integrin β6 (ITGB6) Protects From Colon Cancer Development In Vivo

2015 ◽  
Vol 148 (4) ◽  
pp. S-953
Author(s):  
Susan Bengs ◽  
Marianne R. Spalinger ◽  
Stephanie Kasper ◽  
Silvia Lang ◽  
Isabelle Frey-Wagner ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Development
Sign in / Sign up

Export Citation Format

Share Document