4-Phenylbutyrate Stimulates Hsp70 Expression through the Elp2 Component of Elongator and STAT-3 in Cystic Fibrosis Epithelial Cells

Suaud, Laurence; Miller, Katelyn D.; Panichelli, Ashley E.; Randell, Rachel L.; Marando, Catherine M.; Rubenstein, Ronald C.

doi:10.1074/jbc.m111.293282

Cited by 41 publications

(39 citation statements)

References 69 publications

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“…Other HDAC inhibitors have also been shown to rescue mutant ABC proteins. Hutt et al (50) used multiple HDAC inhibitors to rescue ΔF508 CFTR surface expression and function and proposed that inhibiting HDAC7 function may alter chaperone levels including Hsp 70, similar to the proposed action of 4-PBA (33,34,50). Interestingly, Basseville et al (17) recently found that a different suite of HDAC inhibitors rescued Q141K ABCG2 function and expression levels but did not observe any changes in Hsp 70 or Hsp 90 levels.…”

Section: Discussionmentioning

confidence: 99%

“…The histone deacetylase (HDAC) inhibitor 4-phenylbutyrate (4-PBA) rescues trafficking defects in other ABC proteins (33,34) by increasing the HSP70 chaperone protein, thereby protecting misfolded proteins from being targeted to the ERAD pathway. We found that application of 4-PBA increased significantly the expression of the Q141K protein ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules

Woodward

Tukaye

Cui

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

117

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ABCG2 is a secretory efflux uric acid transporter of the kidney proximal tubule and gut that plays a key role in uric acid excretion. Genetic defect in ABCG2 leads to significant increases in serum urate levels (SUA) causing hyperuricemia and gout. A single common variant, Q141K, is responsible for the majority of ABCG2 associated gout risk. The Q141K mutation is a loss of function mutation associated with a severe reduction in protein abundance and transport function. Previously we hypothesized the Q141K mutation leads to instability in the nucleotide‐binding domain and here we present the specific molecular mechanism of the defect and a proof of concept of its correction using small molecules. We found using a ABCG2 structural model and targeted amino acid substitutions that the Q141K mutations leads to a localized disruption in packing that affects abundance and can be partially rescued with a secondary substitution at H155A. However the use of the signature motif suppressor mutation, G188E, provides full rescue of the Q141K abundance by stabilizing the NBD dimer sandwich, a finding consistent with a Q141K defect in NBD dimer formation. Finally we show that a small molecule, VRT‐325, known to bind directly to the NBD of ABC transporters can rescue both abundance and function of Q141K ABCG2.

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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules

Woodward

Tukaye

Cui

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

117

View full text Add to dashboard Cite

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“…For instance, beneficial therapeutic effects of 4-PBA due to its histone deacetylase inhibitor function were demonstrated for motor neuron survival in mice with amyotrophic lateral sclerosis (35) or for treatment of different types of tumors (25). The therapeutic effect of 4-PBA to correct trafficking of mutant CFTR⌬F508 in cystic fibrosis epithelial cells could be attributed to increased expression of some cytosolic molecular chaperones like heat shock protein 70 (HSP70) (37). In consequence, increased UMOD content in supernatant as well as in cell lysate of UMOD-expressing MTC clones in our study might be caused by the histone deacetylase inhibition due to 4-PBA administration increasing UMOD expression in a dose-dependent manner.…”

Section: C93fmentioning

confidence: 99%

No Amelioration of Uromodulin Maturation and Trafficking Defect by Sodium 4-Phenylbutyrate in Vivo

Kemter

Sklenak

Rathkolb

et al. 2014

Journal of Biological Chemistry

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“…For instance, 4‐BPA was shown to be a histone deacetylase (HDAC) inhibitor and an autophagy inducer, to regulate Hsp70 expression and to present antioxidant and anti‐inflammatory properties (Iannitti and Palmieri 2011; Suaud et al. 2011; Roy et al. 2012; Rekha et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

181

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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4-Phenylbutyrate Stimulates Hsp70 Expression through the Elp2 Component of Elongator and STAT-3 in Cystic Fibrosis Epithelial Cells

Cited by 41 publications

References 69 publications

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules

No Amelioration of Uromodulin Maturation and Trafficking Defect by Sodium 4-Phenylbutyrate in Vivo

Role of endoplasmic reticulum stress in drug‐induced toxicity

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