Targeting F Box Protein Fbxo3 To Control Cytokine-Driven Inflammation

Mallampalli, Rama K.; Coon, Tiffany A.; Glasser, Jennifer R.; Wang, Claire; Dunn, Sarah R.; Weathington, Nathaniel M.; Zhao, Jing; Zou, Chunbin; Zhao, Yutong; Chen, Bill B.

doi:10.4049/jimmunol.1300456

Cited by 58 publications

(78 citation statements)

References 45 publications

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“…Another small molecule screening approach revealed the compound SCF-I2, which allosterically blocks activity of the yeast F-box protein Cdc4, but not its human ortholog FBXW7 (45). BC-1215, a small molecule inhibitor of F-box protein Fbxo3, was recently synthesized to block SCF E3 ligase degradation of another F-box (Fbxl2), which in turn degrades the TNF receptor-associated factor (TRAF) adaptor proteins; thus, BC-1215 decreases TRAF proteins and blunts NF-κB activation and inflammation through the TNF signaling axis (46,47). Because Fbxl2 also targets proteins within the cell cycle (48,49), drugs targeting the Fbxo3/Fbxl2 axis may also be anti-neoplastic.…”

Section: Therapeuticsmentioning

confidence: 99%

Emerging therapies targeting the ubiquitin proteasome system in cancer

Weathington¹,

Mallampalli²

2014

J. Clin. Invest.

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The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics. IntroductionA new era in myeloma therapy. At the turn of the millennium, targeted molecular therapeutics against hematologic malignancies initiated a shift in our perspective on treatment, prognosis, and survival for patients with some of the most aggressive and fatal neoplasms. Bortezomib (branded and marketed as Velcade by Millennium Pharmaceuticals) entered the armamentarium of new antiproliferative therapies with approval in May 2003 for the hematologic malignancy multiple myeloma (MM), in which B cellderived plasma cells clonally proliferate and produce large quantities of monoclonal antibody. MM can be a devastating disease, with renal failure, blood hyperviscosity, and bone marrow invasion seen clinically. Before 2000, there were few life-prolonging therapies for the disease. Bortezomib blocks the proteolytic activity of the 26S proteasome, a cellular structure whose role in cell metabolism has now been meticulously characterized; indeed, bortezomib is the first agent available for use in humans that inhibits the activity of this system. Bortezomib quickly proved effective in refractory MM (1), and its inclusion in initial MM treatment was superior to the conventional cytotoxic chemotherapy regimen alone (2).During this time thalidomide, an agent that produced deformities in infants of mothers prescribed the drug during pregnancy, further suppressed myeloma plasma cell proliferation when added to the regimen. A decade of careful clinical trials since these first breakthrough observations has revealed that therapeutic combinations including bortezomib with thalidomide or related compounds (collectively called immunomodulatory drugs, or IMiDs) and steroids confer a very favorable prognosis compared with historic therapy, greatly prolonging the median survival time from diagnosis over this period (3). When this therapy is implemented in conjunction with autologous bone marrow stem cell transplant, recent clinical trials show a three-year progression-free survival of 60% and overall survival of 90% for patients eligible for stem cell transplant (4), compared with only 48% three-year relative survival for patients diagnosed in 1999 (5). Multiple clinical trials for this new generation of MM molecular therapies are underway, with median survival projected by some to exceed 10 years in the post-bortezomib...

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Section: Therapeuticsmentioning

confidence: 99%

Emerging therapies targeting the ubiquitin proteasome system in cancer

Weathington¹,

Mallampalli²

2014

J. Clin. Invest.

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110

100

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“…In addition to its effects on AIRE, this SCF FBXO3 complex has been reported to increase proinflammatory responses by eliminating FBXL2, which inhibits TRAF proteins (31,32). A more recent study found an association between FBXO3 and SMURF1, which is a Nedd4 family member (34).…”

Section: Discussionmentioning

confidence: 99%

“…FBXL2 also ubiquitylates, degrades, and inhibits tumor necrosis factor receptor-associated factors (TRAFs). By removing it, FBXO3 increases TRAF signaling (31,32). FBXO3 also ubiquitylates and degrades homeodomain-interacting protein kinase 2 (HIPK2) and P300 (33).…”

Section: Aire Interacts With Fbxo3mentioning

confidence: 99%

FBXO3 Protein Promotes Ubiquitylation and Transcriptional Activity of AIRE (Autoimmune Regulator)

Shao

Žumer

Fujinaga

et al. 2016

Journal of Biological Chemistry

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The autoimmune regulator (AIRE) is a transcription factor which is expressed in medullary thymic epithelial cells. It directs the expression of otherwise tissue-specific antigens, which leads to the elimination of autoreactive T cells during development. AIRE is modified post-translationally by phosphorylation and ubiquitylation. In this report we connected these modifications. AIRE, which is phosphorylated on two specific residues near its N terminus, then binds to the F-box protein 3 (FBXO3) E3 ubiquitin ligase. In turn, this SCF FBXO3 (SKP1-CUL1-F box) complex ubiquitylates AIRE, increases its binding to the positive transcription elongation factor b (P-TEFb), and potentiates its transcriptional activity. Because P-TEFb is required for the transition from initiation to elongation of transcription, this interaction ensures proper expression of AIRE-responsive tissue-specific antigens in the thymus.

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“…We had previously used a similar approach to design the inhibitors for the proinflammatory protein FBXO3 Mallampalli et al, 2013). Because , and total cell count were measured.…”

Section: And L) Fiel1mentioning

confidence: 99%