Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins

Wright, Jerry; Zeitlin, Pamela L.; Cebotaru, Liudmila; Guggino, Sandra E.; Guggino, William B.

doi:10.1152/physiolgenomics.00160.2003

Cited by 76 publications

(70 citation statements)

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“…As shown in Figure 2, this was the case. The cell response to 4-PBA is complex and includes changes in gene expression and inhibition of histone acetylation (Chen et al 1997;Wright et al 2004), which can also affect Cx43 expression Asklund et al 2004;Hattori et al 2007;Khan et al 2007). Interestingly, geldanamycin, an agent also shown to alter Cx43 regulation (Carystinos et al 2003;Lidington et al 2000Lidington et al , 2002Rodriguez-Sinovas et al 2006) had no effect on 3(3) cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of rab20 as a Potential Regulator of Connexin43 Trafficking

Sarma

Kaplan

Willemsen

et al. 2008

Cell Communication & Adhesion

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Connexin oligomerization and trafficking are regulated processes. To identify proteins that control connexin43 (Cx43), a screen was designed using HeLa cells expressing a Cx43 construct with di-lysine endoplasmic reticulum (ER)-retention/retrieval motif, Cx43-HKKSL. At moderate levels of expression, Cx43-HKKSL is retained in the ER as monomers; however, Cx43-HKKSL stably overexpressed by HeLa cells localizes to the perinuclear region and oligomerizes. HeLa/Cx43-HKKSL overexpressors were transiently transfected with pooled clones from a human kidney cDNA library and used immunofluorescence microscopy to identify cDNAs that enabled overexpressed Cx43-HKKSL to convert from a perinuclear to ER localization pattern. Using this approach, a small molecular weight GTPase, rab20, was identified as a candidate protein with the ability to regulate Cx43 trafficking. Enhanced green florescent protein (EGFP)-tagged rab20 showed a predominantly perinuclear and ER localization pattern and caused wild-type Cx43 to be retained inside the cell. By contrast, mutant EGFP-rab20T19N, which lacks the ability to bind GTP, had no effect on Cx43. These results suggest Cx43 is transported through an intracellular compartment regulated by rab20 along the secretory pathway.

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Section: Discussionmentioning

confidence: 99%

Identification of rab20 as a Potential Regulator of Connexin43 Trafficking

Sarma

Kaplan

Willemsen

et al. 2008

Cell Communication & Adhesion

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“…Of the five classes of HDAC inhibitors, the butyrates are the most developed for clinical use because they are able to penetrate the blood-brain barrier (Cremer et al, 1977;Collins et al, 1995). Sodium 4-phenylbutyrate (4-PBA), an orally bioavailable short-chain fatty acid originally approved for treatment of urea cycle disorders (Brusilow and Maestri, 1996), is a HDAC inhibitor that activates transcription of a variety of genes involved in the regulation of cell development and proliferation (Wright et al, 2004). The formation of long-term memories is thought to entail lasting changes in gene expression that are necessary for memory consolidation (Bailey et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

Ricobaraza

Cuadrado‐Tejedor

Pérez-Mediavilla

et al. 2009

Neuropsychopharmacol

369

265

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Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering b-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3b (GSK3b). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

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“…Understanding the molecular basis for this difference, as well as the ability of monomeric Cx43 to be transported from the ER to the Golgi apparatus has proven difficult, because little is known about chaperones that regulate connexin folding. In particular, it seemed likely that one or more chaperones would be required to stabilize Cx43 as monomers in the ER and the early secretory pathway.One clue to a putative Cx43 chaperone came from previous studies using 4-phenylbutyrate (4-PBA), a histone deacetylase inhibitor that influences the expression and function of several proteins, including heat shock proteins and connexins (Rubenstein and Zeitlin, 2000;Berthoud et al, 2003;Asklund et al, 2004;Wright et al, 2004;Khan et al, 2007). Importantly, 4-PBA improves the trafficking of several mutant transmembrane proteins, including the ⌬F508 mutant of cystic fibrosis transmembrane regulator (CFTR) (Rubenstein et al, 1997).…”

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confidence: 99%

ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum

Das

Smith

Sarma

et al. 2009

MBoC

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Connexin43 (Cx43) is a gap junction protein that forms multimeric channels that enable intercellular communication through the direct transfer of signals and metabolites. Although most multimeric protein complexes form in the endoplasmic reticulum (ER), Cx43 seems to exit from the ER as monomers and subsequently oligomerizes in the Golgi complex. This suggests that one or more protein chaperones inhibit premature Cx43 oligomerization in the ER. Here, we provide evidence that an ER-localized, 29-kDa thioredoxin-family protein (ERp29) regulates Cx43 trafficking and function. Interfering with ERp29 function destabilized monomeric Cx43 oligomerization in the ER, caused increased Cx43 accumulation in the Golgi apparatus, reduced transport of Cx43 to the plasma membrane, and inhibited gap junctional communication. ERp29 also formed a specific complex with monomeric Cx43. Together, this supports a new role for ERp29 as a chaperone that helps stabilize monomeric Cx43 to enable oligomerization to occur in the Golgi apparatus. INTRODUCTIONConnexins form gap junction channels that mediate intercellular communication by allowing the direct transfer of ions and small aqueous molecules between neighboring cells or by serving as hemichannels at the plasma membrane (Harris, 2001;Goodenough and Paul, 2003;Saez et al., 2003;Laird, 2006). There are Ͼ20 human connexin genes and one of the most ubiquitously expressed is connexin43 (Cx43). Several diseases have been linked to mutations in different connexin genes, including Cx43 (Kelsell et al., 2001;Laird, 2008). Many of these mutant connexins are not efficiently processed and lack the ability to form functional gap junction channels. Determining how mutant connexins are mistargeted requires a more complete understanding of how normal connexins are processed by the cell.A gap junction hemichannel consists of six connexins, which oligomerize before delivery to the plasma membrane (Martin and Evans, 2004;Segretain and Falk, 2004;Koval, 2006). Unlike most multimeric membrane channels, Cx43 is unusual in that it does not oligomerize in the endoplasmic reticulum (ER) (Musil and Goodenough, 1993), which is more commonly a prerequisite to further transport along the secretory pathway (Ellgaard and Helenius, 2003;Anelli and Sitia, 2008). Instead, Cx43 is transported out of the ER as an apparent monomer that then oligomerizes in the Golgi complex (Musil and Goodenough, 1993;Koval et al., 1997). Although other connexins, such as Cx46 (Koval et al., 1997), also oligomerize in the Golgi apparatus, this is not a universal pathway for connexin oligomerization because other gap junction proteins, such as Cx32, preferentially oligomerize in the ER (Martin and Evans, 2004;Koval, 2006). Understanding the molecular basis for this difference, as well as the ability of monomeric Cx43 to be transported from the ER to the Golgi apparatus has proven difficult, because little is known about chaperones that regulate connexin folding. In particular, it seemed likely that one or more chaperones would be requir...

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Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins

Abstract: expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins.

Cited by 76 publications

References 50 publications

Identification of rab20 as a Potential Regulator of Connexin43 Trafficking

Identification of rab20 as a Potential Regulator of Connexin43 Trafficking

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum

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