Chemical Inducers of Targeted Protein Degradation

Raina, Kanak; Crews, Craig M.

doi:10.1074/jbc.r109.078105

Cited by 64 publications

(49 citation statements)

References 29 publications

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“…Cooperative functions of autophagy and ubiquitin proteasome system can serve as an integral part of clearance mechanism and may heal the detrimental cellular loss induced by proteotoxic insults [103][104][105]. One of the key tactics is to find out novel chemical inducers which can specifically promote protein degradation, and this strategy can be also useful to keep low basal levels of over accumulated abnormal proteins [106]. Understanding the detailed physiological functions of protein quality control mechanism and its hidden possible mechanisms in the causation can help in the prevention of neurotoxic load caused by protein misfolding aggregation.…”

Section: Future Prospective and Key Questionsmentioning

confidence: 99%

Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

et al. 2015

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In healthy cell, inappropriate accumulation of poor or damaged proteins is prevented by cellular quality control system. Autophagy and ubiquitin proteasome system (UPS) provides regular cytoprotection against proteotoxicity induced by abnormal or disruptive proteins. E3 ubiquitin ligases are crucial components in this defense mechanism. Mahogunin Ring Finger-1 (MGRN1), an E3 ubiquitin ligase of the Really Interesting New Gene (RING) finger family, plays a pivotal role in many biological and cellular mechanisms. Previous findings indicate that lack of functions of MGRN1 can cause spongiform neurodegeneration, congenital heart defects, abnormal left-right patterning, and mitochondrial dysfunctions in mice brains. However, the detailed molecular pathomechanism of MGRN1 in cellular functions and diseases is not well known. This article comprehensively represents the molecular nature, characterization, and functions of MGRN1; we also summarize possible beneficiary aspects of this novel E3 ubiquitin ligase. Here, we review recent literature on the role of MGRN1 in the neuro-pathobiological mechanisms, with precise focus on the processes of neurodegeneration, and thereby propose new lines of potential targets for therapeutic intervention.

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Section: Future Prospective and Key Questionsmentioning

confidence: 99%

Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

et al. 2015

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“…As an alternative, approaches to eliminate disease-causing abnormal proteins, either by RNAi or by small molecule-induced protein degradation, are evolving as novel strategies for targeting the “undruggable” or “difficult” targets (Burnett et al, 2011; Howell et al, 2004). We have developed an induced protein degradation strategy that utilizes Proteolysis Targeting Chimerae (PROTACs) that recruit targeted proteins to the E3 ubiquitin ligase Von Hippel Lindau (VHL) for ubiquitination and subsequent proteasome-mediated degradation (Buckley and Crews, 2014; Raina and Crews, 2010; Sakamoto et al, 2001; Sakamoto et al, 2003; Schneekloth and Crews, 2005; Schneekloth et al, 2004). This PROTAC technology provides great potential in harnessing the action of a single E3 ligase toward pathologically important proteins which are currently “undruggable” through conventional strategies for drug development.…”

Section: Introductionmentioning

confidence: 99%

Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4

Lü

Qian

Altieri

et al. 2015

Chemistry & Biology

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932

865

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Summary BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt’s Lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest anti-proliferative activity and lack of apoptotic induction. To address these limitations, we designed ARV-825, a heterobifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small molecule BRD4 inhibitors resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small molecule inhibitors.

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“…Protein concentration is dynamically regulated in the cell by modulating the rates of transcription, RNA degradation, translation and/or protein degradation (Babiskin and Smolke, 2011;Jungbluth et al, 2010;Raina and Crews, 2010;Sekar et al, 2016). In metabolic engineering, specific protein levels are typically controlled through transcription (at the promoter level); control mechanisms at other levels, especially at the protein level, have not been well exploited in yeast.…”

Section: Introductionmentioning

confidence: 99%

A squalene synthase protein degradation method for improved sesquiterpene production in Saccharomyces cerevisiae

Peng

Plan

Chrysanthopoulos

et al. 2017

Metabolic Engineering

101

128

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A squalene synthase protein degradation method for improved sesquiterpene production in Saccharomyces cerevisiae, Metabolic Engineering, http://dx.doi.org/10. 1016/j.ymben.2016.12.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractSesquiterpenes are C15 isoprenoids with utility as fragrances, flavours, pharmaceuticals, and potential biofuels. Microbial fermentation is being examined as a competitive approach for bulk production of these compounds. Competition for carbon allocation between synthesis of endogenous sterols and production of the introduced sesquiterpene limits yields. Achieving balance between endogenous sterols and heterologous sesquiterpenes is therefore required to achieve economical yields. In the current study, the yeast Saccharomyces cerevisiae was used to produce the acyclic sesquiterpene alcohol, trans-nerolidol. Nerolidol production was first improved by enhancing the upstream mevalonate pathway for the synthesis of the precursor farnesyl pyrophosphate (FPP). However, excess FPP was partially directed towards squalene by squalene synthase (Erg9p), resulting in squalene accumulation to 1 % biomass; moreover, the specific growth rate declined. In order to redirect carbon away from sterol production and towards the desired heterologous sesquiterpene, a novel protein destabilisation approach was developed for Erg9p. It was shown that Erg9p is located on endoplasmic reticulum and lipid droplets through a C-terminal ER-targeted transmembrane peptide. 2A PEST (rich in Pro, Glu/Asp, Ser, and Thr) sequence-dependent endoplasmic reticulum-associated protein degradation (ERAD) mechanism was established to decrease cellular levels of Erg9p without relying on inducers, repressors or specific repressing conditions. This improved nerolidol titre by 86 % to ~100 mg L -1 . In this strain, squalene levels were similar to the wild-type control strain, and downstream ergosterol levels were slightly decreased relative to the control, indicating redirection of carbon away from sterols and towards sesquiterpene production. There was no negative effect on cell growth under these conditions. Protein degradation is an efficient mechanism to control carbon allocation at flux-competing nodes in metabolic engineering applications. This study demonstrates that an engineered ERAD mechanism can be used to balance flux competition between the endogenous sterol pathway and an introduced bio-product pathways at the FPP node. The approach of protein degradation in general might be more widely applied to improve metabolic engineering outcomes.

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Chemical Inducers of Targeted Protein Degradation

Cited by 64 publications

References 29 publications

Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4

A squalene synthase protein degradation method for improved sesquiterpene production in Saccharomyces cerevisiae

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