Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Palmitoyl protein thioesterase 1 (PPT1) removes palmitate from specific cysteine residues in peptides and proteins. We have previously shown that a palmitoylated myelin glycoprotein. Po octapeptide (IRYCWLRR) can be specifically depalmitoylated by PPT1 in vitro (Cho and Dawson [1998] J. Neurochem. 171 ;323-329). To characterize further the substrate specificity of PPT1, we prepared various palmitoylated oligopeptides, based on palmitoylated sequences from different proteins. A truncated tetrapeptide from Po (RY[palmitoyl]-CW) was as good a substrate as the octapeptide Po, with optimal activity at pH 4.0. In contrast, other peptide substrates showed marked differences. Thus, the deacylation of GAP-43 (MLCCMRR), rhodopsin (VTTLCCGKN), and Galpha subunit (MGCLGNSK) peptides was more efficient at neutral pH (7.4) than at acidic pH (4.0), with the greatest efficiency toward the Galpha peptide (five- to sixfold higher than other substrates). Infantile neuronal ceroid lipofuscinosis (INCL) is caused by PPT1 deficiency, and the absence of enzymatic activity was confirmed with GAP-43 peptide as well as the Po peptide. LA-N-5 human neuroblastoma cells overexpressing PPT1 showed increased depalmitoylation of all the peptide substrates, indicating that these peptides are deacylated by PPT1. An amide derivative of a palmitoylated K-Ras peptide (AcG-palmitoyl diamino propionate-VKIKK) acted as an enzyme pseudosubstrate and inhibited PPT1 enzyme activity in a dose-dependent manner. The peptide itself (AcGCVKIKK) did not affect PPT activity. In summary, PPT1 is able to hydrolyze a range of cysteinyl peptide sequences found in both neuron-specific and ubiquitous (e.g., Galpha) proteins. The inhibitor of PPT1 activity should facilitate the development of a model for INCL and help explain the neuronal death in this disease.
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PMID:In vitro depalmitoylation of neurospecific peptides: implication for infantile neuronal ceroid lipofuscinosis. 1065 83

Infantile neuronal ceroid lipofuscinosis (INCL) is a childhood neurodegenerative disease caused by the selective death of cortical neurons and retinal degeneration, as the result of a palmitoyl protein thioesterase 1 (PPT1) deficiency. Recently, we showed that overexpression of PPT1 protects LA-N-5 human neuroblastoma cells against apoptotic death (Cho and Dawson [2000a] J. Neurochem. 74:1478-1488) and we now show that inhibition of PPT1 increases the susceptibility of these cells to apoptotic cell death. Transient transfection of LA-N-5 neuroblastoma cells with PPT1-FLAG resulted in a strong expression of PPT-FLAG-tagged protein as evidenced by Western blot analysis and immunofluorescence. Co-transfection of a reverse-oriented (antisense) PPT1 (AS-PPT1) decreased the expression of PPT-FLAG to almost zero, reduced PPT1 enzyme activity (as measured by an in vitro assay) and increased the susceptibility to apoptosis induced by C(2) ceramide. Similarly, inhibition of PPT1 with a synthetic inhibitor (AcG-palmitoyl diaminoproprionate-VKIKK) (DAP1) (100 microM) increased the susceptibility of the cells to apoptosis induced by either C(2)-ceramide or etoposide, a common chemotherapeutic agent used in the treatment of neuroblastoma. Cells stably overexpressing PPT1 were resistant to apoptosis induced by DAP1 suggesting that the inhibitor has a specific action and confirming that low levels of protein palmitoylation block the death pathway. Drugs that raise the level of protein palmitoylation are pro-apoptotic and PPT1 inhibition may enhance the killing efficacy of chemotherapeutic agents used to kill neuroblastoma-derived cells.
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PMID:Antisense palmitoyl protein thioesterase 1 (PPT1) treatment inhibits PPT1 activity and increases cell death in LA-N-5 neuroblastoma cells. 1102 Feb 16

Infantile neuronal ceroid lipofuscinosis (INCL) is a childhood neurodegenerative disease caused by the selective death of cortical and retinal neurons as the result of an inherited palmitoyl-protein thioesterase 1 (PPT1) deficiency. Neuronal death is common to many lysosomal storage diseases but it occurs very early in INCL and we show here that inhibition of PPT1 increases the susceptibility of these cells to apoptotic cell death. Thus transient transfection of LA-N-5 neuroblastoma cells with a reverse-oriented (antisense) PPT1 (AS-PPT1) reduced PPT1 enzyme activity (as measured by an in vitro assay) and increased the susceptibility to apoptosis induced by C2 ceramide. Similarly, inhibition of PPT1 with a synthetic inhibitor (AcG-palmitoyl diaminoproprionate-VKIKK) (DAP1) (100 microM) increased the susceptibility of the cells to apoptosis induced by either C2-ceramide or etoposide and Adriamycin (doxorubicin), common chemotherapeutic agents used in the treatment of solid tumours. In contrast, overexpression of PPT1 led to increased resistance to cell death induced by these drugs.
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PMID:Role of palmitoyl-protein thioesterase in cell death: implications for infantile neuronal ceroid lipofuscinosis. 1158 8