Human lung expresses unique gamma-glutamyl transpeptidase transcripts.

Wetmore, Lois A.; Gérard, Craig; Drazen, Jeffrey M.

doi:10.1073/pnas.90.16.7461

Cited by 24 publications

(27 citation statements)

References 27 publications

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“…the stability of the fully "mature" ⌬F508 CFTR protein. While using high concentrations of osmolytes may not be clinically desirable, GSNO, a substrate for GGT, an enzyme also expressed in the lung (62), is one potential therapeutic candidate. In this regard, a study of nine CF patients receiving one dose of aerosolized GSNO showed that the compound was safely tolerated (63).…”

Section: Fig 4 Gsno Promotes the Maturation And Function Of ⌬F508mentioning

confidence: 99%

Mammalian Osmolytes and S-Nitrosoglutathione Promote ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein Maturation and Function

Howard

Fischer²,

Roux

et al. 2003

Journal of Biological Chemistry

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In cystic fibrosis, the absence of functional CFTR results in thick mucous secretions in the lung and intestines, as well as pancreatic deficiency. Although expressed at high levels in the kidney, mutations in CFTR result in little or no apparent kidney dysfunction. In an effort to understand this phenomenon, we analyzed ⌬F508 CFTR maturation and function in kidney cells under conditions that are common to the kidney, namely osmotic stress. Kidney cells were grown in culture and adapted to 250 mM NaCl and 250 mM urea. High performance liquid chromatography analysis of lysates from kidney cells adapted to these conditions identified an increase in the cellular osmolytes glycerophosphorylcholine, myo-inositol, sorbitol, and taurine. In contrast to isoosmotic conditions, hyperosmotic stress led to the proper folding and processing of ⌬F508 CFTR. Furthermore, three of the cellular osmolytes, when added individually to cells, proved effective in promoting the proper folding and processing of the ⌬F508 CFTR protein in both epithelial and fibroblast cells. Whole-cell patch clamping of osmolyte-treated cells showed that ⌬F508 CFTR had trafficked to the plasma membrane and was activated by forskolin. Encouraged by these findings, we looked at other features common to the kidney that may impact ⌬F508 maturation and function. Interestingly, a small molecule, S-nitrosoglutathione, which is a substrate for gamma glutamyltranspeptidase, an abundant enzyme in the kidney, likewise promoted ⌬F508 CFTR maturation and function. S-Nitrosoglutathione-corrected ⌬F508 CFTR exhibited a shorter half-life as compared with wild type CFTR. These results demonstrate the feasibility of a small molecule approach as a therapeutic treatment in promoting ⌬F508 CFTR maturation and function and suggest that an additional treatment may be required to stabilize ⌬F508 CFTR protein once present at the plasma membrane. Finally, our observations may help to explain why ⌬F508 homozygous patients do not present with kidney dysfunction.

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Section: Fig 4 Gsno Promotes the Maturation And Function Of ⌬F508mentioning

confidence: 99%

Mammalian Osmolytes and S-Nitrosoglutathione Promote ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein Maturation and Function

Howard

Fischer²,

Roux

et al. 2003

Journal of Biological Chemistry

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“…2). As compared to the truncated group II wt mRNAs described by Wetmore et al [9], type III mRNAs exhibit the sequences corresponding to the region named C and the two bases of the 3' end of the region named B [9]. Further, three point mutations distinguish type III mRNA from group II wt mRNAs.…”

Section: Partial Cloning Of Ggt Type III Mrnamentioning

confidence: 93%

“…3). Because of the presence of the unspliced intron and point mutations, this polypeptide has about 80% homology with the amino acid sequence deduced from wild-type truncated mRNA peptide [9].…”

Section: Partial Cloning Of Ggt Type III Mrnamentioning

confidence: 99%

“…Human GGT mRNAs expressed in placenta [6], pancreas [7], fetal liver [8], lung [9] and HepG2 hepatoma [10] have been described previously and show a unique ORF. This ORF encodes for a single polypeptide precursor which upon cleavage during the post-translational process gives rise to the two non-identical subunits of the mature enzymes (large subunit 55-60 kDa, small subunit 21-30 kDa) [11].…”

Section: Introductionmentioning

confidence: 99%

“…Wetmore et al [9] have characterized another type I mRNA expressed in human lung which is truncated in the sequences encoding the large subunit. The sequences encoding the small subunit are identical to type I mRNA.…”

Section: Introductionmentioning

confidence: 99%

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Cloning and expression of a novel type (III) of human γ‐glutamyltransferase truncated mRNA

et al. 1996

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We report the characterization of a novel human 7-glutamyltransferase mRNA type. This type III mRNA differs from type I and type II mRNAs previously described by several point mutations and the presence of an unspliced 81 bp intron in the open reading frame. Further, type III mRNAs are truncated ones and are tissue and pathology specifically expressed. In fact, type III mRNAs are present in human placenta, sigmoid, lung and in 50% of acute lymphoblastic leukemia blood cells but they are never found in healthy lymphocytes.

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