Diminished proteasomal degradation results in accumulation of Gfi1 protein in monocytes

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 100-108 ◽  
Author(s):  
Jurgen A. F. Marteijn ◽  
Laurens T. van der Meer ◽  
Liesbeth Van Emst ◽  
Theo de Witte ◽  
Joop H. Jansen ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Myeloid Differentiation ◽  
Mrna Levels ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Monocytic Cell ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Monocytic Lineage

Abstract Gfi1 is a transcriptional repressor essential during myeloid differentiation. Gfi1−/− mice exhibit a block in myeloid differentiation resulting in the accumulation of an immature myelo-monocytic cell population and the complete absence of mature neutrophils. Even though mRNA levels of Gfi1 appear to be very low in monocytes, Gfi1 might play a role in the monocytic lineage as Gfi1−/− mice exhibit diminished monocyte-derived dendritic cells and disturbed cytokine production by macrophages in response to LPS. We show here that Gfi1 protein levels are mainly regulated by the ubiquitin-proteasome system. Upon forced monocytic differentiation of U937 cells, Gfi1 mRNA levels dropped but protein levels increased due to diminished proteasomal turnover. Similarly, Gfi1 mRNA levels are low in primary monocytes whereas the protein is clearly detectable. Conversely, Gfi1 mRNA levels are high in granulocytes but the protein is swiftly degraded by the proteasome in these cells. Chromatin immunoprecipitation experiments showed that Gfi1 binds to the promoter of several granulocyte-specific genes in primary monocytes, including C/EBPα, neutrophil elastase, and Gfi1 itself. The binding of the repressor Gfi1 to these promoters correlated with low expression of these genes in monocytes compared with granulocytes. Our data fit a model in which Gfi1 protein levels are induced in primary monocytes, due to diminished proteasomal degradation, to repress genes that play a role in granulocytic differentiation.

Gfi1 Protein Levels Are Upregulated upon Myeloid Differentiation Due to Diminished Proteasomal Degradation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2710-2710
Author(s):  
Jurgen A.F. Marteijn ◽  
Laurens T. van der Meer ◽  
Theo de Witte ◽  
Joop H. Jansen ◽  
Bert van der Reijden
Keyword(s):  
Proteasome Inhibitors ◽  
Myeloid Cells ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Myeloid Differentiation ◽  
Mrna Levels ◽  
Monocytic Differentiation ◽  
Hematopoietic Stem ◽  
Protein Levels

Abstract Granulocytes and monocytes play an essential role in the innate immune system and the inflammatory system. The generation of these differentiated myeloid cells from hematopoietic stem cells is a tightly regulated process in which transcription factors play an essential role. One of these transcription factors is Growth factor independence 1 (Gfi1). Gfi1 was originally identified as a proviral insertion site in murine leukemia models. Subsequently, it was shown that Gfi1 is essential for the self-renewal and long term reconstituting potential of hematopoietic stem cells and that it regulates T-cell development. In addition, Gfi1 knockout mice are severely neutropenic and exhibit a block in myeloid differentiation resulting in the accumulation of an atypical immature myelo-monocytic cell population. The observed defect in granulocytic differentiation in Gfi1 null mice is in line with Gfi1 point mutations described in patients suffering from severe congenital neutropenia. To further investigate the role of Gfi1 in myelopoiesis, we measured Gfi1 expression during both granulocytic and monocytic differentiation of HL60, NB4 and U937 cells. Upon differentiation of these cells with PMA or retinoic acid Gfi1 mRNA levels declined more than 3-fold. Interestingly, at the same time Gfi1 protein levels increased significantly suggesting that Gfi1 protein expression was regulated in a post-transcriptional manner. Since the ubiquitin proteasome system is one of the main pathways that control protein stability we tested whether Gfi1 was regulated by this system. Proteasome inhibition resulted in an accumulation of cellular Gfi1 protein levels. Moreover, ubiquitination experiments showed that Gfi1 is ubiquitinated and that proteasome inhibition resulted in an accumulation of ubiquitinated Gfi1 species indicating that ubiquitinated Gfi1 is targeted for 26S proteasomal degradation. To study Gfi1 degradation during myelopoiesis we developed a Gfi1 protein degradation assay. This showed that in vitro translated Gfi1 was quickly degraded in lysates from immature myeloid cells in a proteasome-dependent manner since the proteasome inhibitors MG132 and Velcade clearly blocked Gfi1 degradation. Importantly, Gfi1 was not degraded in lysates from differentiated myeloid cells. This suggests that the Gfi1 protein is no longer subject to proteasomal degradation upon terminal myeloid differentiation. To further study this, we treated undifferentiated U937 cells with proteasome inhibitors and observed a clear accumulation of endogenous Gfi1 protein levels, while endogenous protein levels in differentiated U937 did not further increase upon proteasome inhibition. Based on these results we conclude that Gfi1 is upregulated upon myeloid differentiation due to diminished proteasomal degradation despite diminished mRNA levels. Because total proteasome activity was comparable in immature and mature myeloid cells these data strongly suggest that an E3 ubiquitin ligase is responsible for the specific differential degradation. To determine Gfi1 protein stability in primary cells, we performed the degradation experiments with freshly isolated human hematopoietic subsets. This revealed a rapid degradation in immature CD34+ cells and a clear delayed degradation in CD14+ monocytes. Together these data indicate that the ubiquitin proteasome system is a key regulator of Gfi1 protein expression and that Gfi1 may play a role during both terminal granulocytic and monocytic differentiation.

Gfi1 ubiquitination and proteasomal degradation is inhibited by the ubiquitin ligase Triad1

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3128-3135 ◽  
Author(s):  
Jurgen A. F. Marteijn ◽  
Laurens T. van der Meer ◽  
Liesbeth van Emst ◽  
Simon van Reijmersdal ◽  
Willemijn Wissink ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Binding Domain ◽  
U937 Cells ◽  
Dna Binding Domain ◽  
Protein Levels ◽  
Ubiquitin Ligase Activity ◽  
Ubiquitin Proteasome

Abstract Growth factor independence 1 (Gfi1) is a transcriptional repressor essential for the function and development of many different hematopoietic lineages. The Gfi1 protein expression is regulated by the ubiquitin-proteasome system. In granulocytes, Gfi1 is rapidly degraded by the proteasome, while it is more stable in monocytes. How the ubiquitination and degradation of Gfi1 is regulated is unclear. Here, we show that the ubiquitin ligase Triad1 interacts with the DNA-binding domain of Gfi1. Unexpectedly, we found that Triad1 inhibited Gfi1 ubiquitination, resulting in a prolonged half-life. Down-regulation of endogenous Triad1 by siRNAs resulted in increased Gfi1 ubiquitination. In U937 cells, Triad1 caused an increase in endogenous Gfi1 protein levels and slowed cell proliferation in a similar manner when Gfi1 itself was expressed. A Triad1 mutant that lacks the Gfi1-binding domain did not affect Gfi1 levels and proliferation. Because neither proteasome-ubiquitin nor Triad1 ubiquitin ligase activity was required for the inhibition of Gfi1 ubiquitination, these data suggest that Triad1 competes for Gfi1 binding with as yet to be identified E3 ubiquitin ligases that do mark Gfi1 for proteasomal degradation. The finetuning of Gfi1 protein levels regulated by Triad1 defines an unexpected role for this protein in hematopoiesis.

scholarly journals All-trans retinoic acid reverses phorbol ester resistance in a human myeloid leukemia cell line

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 490-496 ◽  
Author(s):  
KD Yang ◽  
T Mizobuchi ◽  
SM Kharbanda ◽  
R Datta ◽  
E Huberman ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Line ◽  
Leukemia Cell Line ◽  
Nonspecific Esterase ◽  
Mrna Levels ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Protein Levels ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Treatment of human HL-60 leukemic cells with 12-O-tetradecanoylphorbol- 13-acetate (TPA) is associated with activation of protein kinase C (PKC) and induction of monocytic differentiation. An HL-60 variant cell line, termed HL-525, derived from long-term exposure to TPA (Homma et al, Proc Natl Acad Sci USA 83: 7316, 1986) is resistant to TPA-induced differentiation and displays decreased PKC beta expression compared with the HL-60 parent line. However, this variant exhibits features of granulocytic differentiation, including nitroblue tetrazolium reduction, when exposed to all-trans retinoic acid (ATRA). Whereas treatment of HL-525 cells with ATRA or TPA alone had no effect on features of monocytic differentiation, these agents in combination resulted in cellular adhesion, nonspecific esterase staining, and induction of the c-fms (monocyte growth factor receptor) gene. In order to measure PKC expression associated with the reversal of TPA resistance by ATRA, we exposed HL-525 cells to ATRA and analyzed PKC- mRNA and protein levels. Exposure of HL-525 cells to ATRA for 3 days resulted in induction of PKC beta transcripts, whereas there was little change in PKC alpha mRNA levels. ATRA treatment was also associated with an increase in PKC activity and an induction of cytosolic PKC beta protein levels. These findings are consistent with the hypothesis that ATRA reverses TPA resistance in HL-525 cells by enhancing the expression of PKC.

scholarly journals All-trans retinoic acid reverses phorbol ester resistance in a human myeloid leukemia cell line

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 490-496 ◽  
Author(s):  
KD Yang ◽  
T Mizobuchi ◽  
SM Kharbanda ◽  
R Datta ◽  
E Huberman ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Line ◽  
Leukemia Cell Line ◽  
Nonspecific Esterase ◽  
Mrna Levels ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Protein Levels ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Treatment of human HL-60 leukemic cells with 12-O-tetradecanoylphorbol- 13-acetate (TPA) is associated with activation of protein kinase C (PKC) and induction of monocytic differentiation. An HL-60 variant cell line, termed HL-525, derived from long-term exposure to TPA (Homma et al, Proc Natl Acad Sci USA 83: 7316, 1986) is resistant to TPA-induced differentiation and displays decreased PKC beta expression compared with the HL-60 parent line. However, this variant exhibits features of granulocytic differentiation, including nitroblue tetrazolium reduction, when exposed to all-trans retinoic acid (ATRA). Whereas treatment of HL-525 cells with ATRA or TPA alone had no effect on features of monocytic differentiation, these agents in combination resulted in cellular adhesion, nonspecific esterase staining, and induction of the c-fms (monocyte growth factor receptor) gene. In order to measure PKC expression associated with the reversal of TPA resistance by ATRA, we exposed HL-525 cells to ATRA and analyzed PKC- mRNA and protein levels. Exposure of HL-525 cells to ATRA for 3 days resulted in induction of PKC beta transcripts, whereas there was little change in PKC alpha mRNA levels. ATRA treatment was also associated with an increase in PKC activity and an induction of cytosolic PKC beta protein levels. These findings are consistent with the hypothesis that ATRA reverses TPA resistance in HL-525 cells by enhancing the expression of PKC.

scholarly journals TcpC inhibits toll-like receptor signaling pathway by serving as an E3 ubiquitin ligase that promotes degradation of myeloid differentiation factor 88

2021 ◽  
Vol 17 (3) ◽  
pp. e1009481
Author(s):  
Jia-qi Fang ◽  
Qian Ou ◽  
Jun Pan ◽  
Jie Fang ◽  
Da-yong Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ubiquitin Ligase ◽  
Bacterial Pathogens ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Mrna Levels ◽  
Tlr Signaling ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Myeloid Differentiation Factor

TcpC is a virulence factor of uropathogenic E. coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase.

Abstract 131: PDE1 Inhibition Improves Cardiac Protein Quality Control

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Hanming Zhang ◽  
Xuejun "XJ" Wang
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Mrna Levels ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Bona Fide

Protein quality control (PQC) functions to minimize the level and toxicity of misfolded proteins in the cell. PQC relies on molecular chaperones and the targeted degradation of misfolded proteins. The latter is currently known to require the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP). Virtually all cardiovascular diseases end up heart failure (HF), the leading cause of death of our society. UPS function insufficiency is implicated in the genesis of a large subset of HF, making cardiac PQC enhancement via promoting UPS and ALP function a promising therapeutic strategy to treat HF. Previously, we have demonstrated that stimulating protein kinase G (PKG) genetically or via inhibition of the type 5 phosphodiesterase (PDE5) improves UPS performance, facilitates the removal of misfolded proteins in cardiomyocytes and slows down the progression of cardiac proteinopathy in a transgenic mouse model (CryAB R120G ). PKA has also been shown to enhance proteasomal function. Our preliminary studies reveal that myocardial protein levels of PDE1A, which suppresses both PKG and PKA, are remarkably elevated in the CryAB R120G mice. Hence we hypothesize that PDE1 inhibition (PDE1I) stimulates cardiac proteasomes via PKG and PKA activation and thereby protects against cardiac proteotoxicity. To test our hypothesis, we took advantage of a proven surrogate UPS substrate (GFPu or GFPdgn) as well as a bona fide misfolded protein (CryAB R120G ) that is known to induce cardiac proteinopathy in human and mice. In cultured cardiomyocytes, PDE1 inhibitor LSN2790158 dose- and time-dependently decreased GFPu. Cycloheximide (CHX) chase assays further confirmed that PDE1I shortened the half-life of GFPu, indicative of improved UPS performance. Furthermore, PDE1I promoted the degradation of CryAB R120G . Our in vivo findings revealed that GFPdgn mice treated with LSN2790158 (3mg/kg, i.p.) displayed a significant reduction of myocardial GFPdgn protein but not mRNA levels. Taken together, our data strongly indicate that PDE1I improves cardiac UPS performance and PDE1 represents a potential target to treat cardiac diseases with elevated proteotoxicity.

scholarly journals Ccr4 is a novel shuttle factor required for ubiquitin-dependent proteolysis by the 26S proteasome

2020 ◽  
Author(s):  
Ganapathi Kandasamy ◽  
Ashis Kumar Pradhan ◽  
R Palanimurugan
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Rna Degradation ◽  
26S Proteasome ◽  
Cellular Proteins ◽  
Cellular Homeostasis ◽  
Substrate Degradation ◽  
Ubiquitin Proteasome

AbstractDegradation of short-lived and abnormal proteins are essential for normal cellular homeostasis. In eukaryotes, such unstable cellular proteins are selectively degraded by the ubiquitin proteasome system (UPS). Furthermore, abnormalities in protein degradation by the UPS have been linked to several human diseases. Ccr4 protein is a known component of the Ccr4-Not complex, which has established roles in transcription, mRNA de-adenylation and RNA degradation etc. Excitingly in this study, we show that Ccr4 protein has a novel function as a shuttle factor that promotes ubiquitin-dependent degradation of short-lived proteins by the 26S proteasome. Using a substrate of the well-studied ubiquitin fusion degradation (UFD) pathway, we found that its UPS-mediated degradation was severely impaired upon deletion of CCR4 in Saccharomyces cerevisiae. Additionally, we show that Ccr4 binds to cellular ubiquitin conjugates and the proteasome. In contrast to Ccr4, most other subunits of the Ccr4-Not complex proteins are dispensable for UFD substrate degradation. From our findings we conclude that Ccr4 functions in the UPS as a shuttle factor targeting ubiquitylated substrates for proteasomal degradation.

scholarly journals c-sis but not c-fos gene expression is lineage specific in human myeloid cells

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 488-493
Author(s):  
E Sariban ◽  
T Mitchell ◽  
A Rambaldi ◽  
DW Kufe
Keyword(s):  
Gene Expression ◽  
Leukemic Cells ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Drug Induced ◽  
Monocytic Cells ◽  
Hexamethylene Bisacetamide ◽  
Gene Transcripts ◽  
Myelomonocytic Leukemia ◽  
Monocytic Lineage

Expression of both the c-fos and c-sis protooncogenes during myeloid differentiation has been detected in cells of the monocytic lineage. Since an increase in c-fos transcripts was not detected during dimethylsulfoxide induced HL-60 granulocytic differentiation, it was suggested that within the myeloid series c-fos gene expression might be lineage specific. In the present study, we have determined whether expression of the c-fos and c-sis genes is indeed specific for the monocytic pathway or rather common to both the granulocyte and monocyte pathways. C-fos and c-sis gene expression was analyzed in freshly isolated human granulocytes and monocytes, in human HL-60 promyelocytic leukemia cells induced to differentiate along the granulocytic or monocytic pathway, in myeloblasts from five patients with the M1 or M2 subtype of acute myeloblastic leukemia (AML) and in blasts from six patients with M4 myelomonocytic leukemia. The level of c-fos mRNA was fifteen times higher in granulocytes as compared with monocytes. An increase in c-fos expression was also found in HL-60 cells differentiated along the granulocytic pathway after exposure to hypoxanthine, hexamethylene bisacetamide, and the combination of retinoic acid and dibutyryl adenosine 3′5′ cyclic monophosphate. Three of 5 M1 and M2 leukemic myeloblast preparations depleted of lymphoid and monocytic cells and all six M4 leukemic cells expressed c-fos transcripts. In contrast, c-sis gene transcripts were detectable in monocytes and during drug induced monocytic differentiation of the HL- 60 cells but not in granulocytes during granulocytic differentiation of the HL-60 cells or in AML samples. Thus, in the myeloid series, c-sis gene expression is lineage specific while expression of the c-fos gene is found in both lineages and may be related to metabolic pathways common to both granulocytes and monocytes.

Posttranscriptional stabilization of c-fms mRNA by a labile protein during human monocytic differentiation

1989 ◽  
Vol 9 (2) ◽  
pp. 769-775
Author(s):  
B Weber ◽  
J Horiguchi ◽  
R Luebbers ◽  
M Sherman ◽  
D Kufe
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Half Life ◽  
Mrna Levels ◽  
Human Monocytes ◽  
Monocytic Differentiation ◽  
Transmembrane Glycoprotein ◽  
Inhibition Of Protein Synthesis ◽  
Monocytic Lineage ◽  
Posttranscriptional Level

The c-fms proto-oncogene encodes a transmembrane glycoprotein that is closely related or identical to the receptor for the monocyte colony-stimulating factor CSF-1. The present studies examined the mechanisms responsible for the regulation of c-fms gene expression during human monocytic differentiation. Levels of c-fms mRNA were undetectable in HL-60 promyelocytic leukemia cells, while 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced monocytic differentiation of these cells was associated with the appearance of these transcripts. Run-on transcription assays demonstrated that the c-fms gene was transcriptionally active in uninduced HL-60 cells and that the rate of transcription was unchanged after TPA treatment. These findings suggested that c-fms mRNA levels in HL-60 cells are controlled by posttranscriptional mechanisms. The half-life of c-fms transcripts in TPA-induced HL-60 cells was found to be at least 6 h, while inhibition of protein synthesis with cycloheximide (CHX) decreased this half-life to 4 h. Moreover, inhibition of protein synthesis was associated with decreases in c-fms mRNA levels and a block in the induction of c-fms transcripts by TPA. These findings indicated that the c-fms transcript is stabilized by a labile protein. In contrast to HL-60 cells, c-fms mRNA is constitutively expressed in resting human monocytes and is down-regulated by treatment of these cells with TPA. Run-on assays demonstrated that TPA-induced downregulation of c-fms mRNA levels in monocytes occurred at the posttranscriptional level. Moreover, the results demonstrate that levels of c-fms mRNA are regulated posttranscriptionally by a labile protein. In this regard, the half-life of the c-fms transcript was 6.1 h in monocytes, while treatment of these cells with CHX decreased the half-life to 30 min. Furthermore, this effect of CHX occurred in the absence of changes in the rate of c-fms gene transcription. Together, these findings indicate that c-fms gene expression is regulated at a posttranscriptional level both in HL-60 cells induced to differentiate along the monocytic lineage and in human monocytes. The findings also indicate that levels of c-fms mRNA are regulated by the synthesis of a labile protein which is involved in stabilization of the c-fms transcript.

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.

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