The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis

Abstract MCL1 is an important antiapoptotic member of the BCL-2 family that is distinguishable from other family members based on its relatively short half-life. Emerging studies have revealed the crucial role of MCL1 in the chemoresistance of cancer cells. The antiapoptotic function of MCL1 makes it a popular therapeutic target, although specific inhibitors have begun to emerge only recently. Notably, emerging studies have reported that several E3 ligases and deubiquitinases modulate MCL1 stability, providing an alternate means of targeting MCL1 activity. In addition, the emergence and development of proteolysis-targeting chimeras, the function of which is based on ubiquitination-mediated degradation, has shown great potential. In this review, we provide an overview of the studies investigating the ubiquitination and deubiquitination of MCL1, summarize the latest evidence regarding the development of therapeutic strategies targeting MCL1 in cancer treatment, and discuss the promising future of targeting MCL1 via the ubiquitin–proteasome system in clinical practice.

Download Full-text

Strategies for the identification of ubiquitin ligase inhibitors

Biochemical Society Transactions ◽

10.1042/bst0380132 ◽

2010 ◽

Vol 38 (1) ◽

pp. 132-136 ◽

Cited By ~ 25

Author(s):

Seth J. Goldenberg ◽

Jeffrey G. Marblestone ◽

Michael R. Mattern ◽

Benjamin Nicholson

Keyword(s):

Ubiquitin Ligase ◽

Therapeutic Target ◽

Therapeutic Strategy ◽

Ubiquitin Proteasome System ◽

Advantages And Disadvantages ◽

Wide Range ◽

Attractive Therapeutic Target ◽

Ubiquitin Proteasome ◽

Effective Therapeutic Strategy ◽

Protein Ligases

Dysregulation of the UPS (ubiquitin–proteasome system) has been implicated in a wide range of pathologies including cancer, neurodegeneration and viral infection. Inhibiting the proteasome has been shown to be an effective therapeutic strategy in humans; however, toxicity with this target remains high. E3s (Ub–protein ligases) represent an alternative attractive therapeutic target in the UPS. In this paper, we will discuss current platforms that report on E3 ligase activity and can detect E3 inhibitors, and underline the advantages and disadvantages of each approach.

Download Full-text

Serum CXCL16 Concentrations Correlate with the Extent of Skin Sclerosis in Patients with Systemic Sclerosis

The Journal of Rheumatology ◽

10.3899/jrheum.090108 ◽

2009 ◽

Vol 36 (9) ◽

pp. 1917-1923 ◽

Cited By ~ 11

Author(s):

KOICHI YANABA ◽

EIJI MUROI ◽

AYUMI YOSHIZAKI ◽

TOSHIHIDE HARA ◽

FUMIHIDE OGAWA ◽

...

Keyword(s):

Longitudinal Study ◽

Systemic Sclerosis ◽

Therapeutic Target ◽

Skin Fibrosis ◽

Healthy Controls ◽

Serum Concentrations ◽

Potential Therapeutic Target ◽

Skin Sclerosis ◽

Clinical Associations

Objective.To determine serum concentrations of soluble CXCL16 and its clinical associations in patients with systemic sclerosis (SSc).Methods.Serum CXCL16 levels from 89 patients with SSc were examined by ELISA. In a retrospective longitudinal study, 68 sera from 28 patients with SSc were analyzed (followup 1.3 to 7.3 yrs).Results.Serum CXCL16 levels were elevated in patients with SSc compared with healthy controls (n = 42). Patients with diffuse cutaneous SSc (n = 52) had higher levels of CXCL16 than those with limited cutaneous SSc (n = 37). Serum CXCL16 levels correlated positively with the extent of skin sclerosis. In the longitudinal study, CXCL16 levels generally decreased on a parallel with the improvement in skin sclerosis.Conclusion.CXCL16 levels were increased in patients with SSc, and correlated with the extent of skin sclerosis, suggesting that CXCL16 may have a role in the development of skin fibrosis in SSc. Blockade of CXCL16 interaction might be a potential therapeutic target in patients with SSc.

Download Full-text

Is IL-4 a potential therapeutic target in systemic sclerosis-associated pulmonary fibrosis?

Clinical Immunology ◽

10.1016/j.clim.2011.09.010 ◽

2011 ◽

Vol 141 (3) ◽

pp. 240-241 ◽

Cited By ~ 2

Author(s):

Petros P. Sfikakis

Keyword(s):

Systemic Sclerosis ◽

Pulmonary Fibrosis ◽

Therapeutic Target ◽

Potential Therapeutic Target

Download Full-text

Peroxisome proliferator-activated receptor γ: innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis

Current Opinion in Rheumatology ◽

10.1097/bor.0b013e32833de1a7 ◽

2010 ◽

Vol 22 (6) ◽

pp. 671-676 ◽

Cited By ~ 52

Author(s):

Jun Wei ◽

Swati Bhattacharyya ◽

John Varga

Keyword(s):

Systemic Sclerosis ◽

Therapeutic Target ◽

Peroxisome Proliferator ◽

Potential Therapeutic Target ◽

Peroxisome Proliferator Activated Receptor

Download Full-text

PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins

The Journal of Cell Biology ◽

10.1083/jcb.200511045 ◽

2006 ◽

Vol 174 (1) ◽

pp. 65-76 ◽

Cited By ~ 62

Author(s):

Alexandre Janer ◽

Elodie Martin ◽

Marie-Paule Muriel ◽

Morwena Latouche ◽

Hiroto Fujigasaki ◽

...

Keyword(s):

Ubiquitin Proteasome System ◽

Nuclear Bodies ◽

Nuclear Accumulation ◽

Spinocerebellar Ataxia Type ◽

Aggregate Formation ◽

Potential Therapeutic Target ◽

Promyelocytic Leukemia Protein ◽

Pml Nuclear Bodies ◽

Spinocerebellar Ataxia Type 7 ◽

Ubiquitin Proteasome

The pathogenesis of spinocerebellar ataxia type 7 and other neurodegenerative polyglutamine (polyQ) disorders correlates with the aberrant accumulation of toxic polyQ-expanded proteins in the nucleus. Promyelocytic leukemia protein (PML) nuclear bodies are often present in polyQ aggregates, but their relation to pathogenesis is unclear. We show that expression of PML isoform IV leads to the formation of distinct nuclear bodies enriched in components of the ubiquitin-proteasome system. These bodies recruit soluble mutant ataxin-7 and promote its degradation by proteasome-dependent proteolysis, thus preventing the aggregate formation. Inversely, disruption of the endogenous nuclear bodies with cadmium increases the nuclear accumulation and aggregation of mutant ataxin-7, demonstrating their role in ataxin-7 turnover. Interestingly, β-interferon treatment, which induces the expression of endogenous PML IV, prevents the accumulation of transiently expressed mutant ataxin-7 without affecting the level of the endogenous wild-type protein. Therefore, clastosomes represent a potential therapeutic target for preventing polyQ disorders.

Download Full-text