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Signalling steps in apoptosis by ether lipids (1999)

Smets, L. A. ; Van Rooij, H. ; Salomons, G. S.

Springer

Apoptosis 4 (1999), S. 419-427

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ISSN: 1573-675X

Keywords: Anti-oxidant defence ; apoptosis ; ether lipids ; glutathione ; ionising radiation ; stress.

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Medicine

Notes: Abstract We have investigated the mechanisms of induction of apoptosis by the antineoplastic ether lipid ET-18-OCH3 (ALP) in sensitive S49wt mouse lymphoma cells and ALP-resistant S49ar variants, both with wild-type p53, and in related L1210 cells with mutated p53. Ether lipid-resistant S49ar cells were cross-resistant to extracellular stress factors (cold shock, heat shock, H2O2, dimethylsulfoxide) and to radiation-induced apoptosis but not to physiological apoptotic signals (dexamethasone, growth factor deprivation, thapsigargin, C2-ceramide) and expressed similar levels of the apoptosis-regulating proteins Bcl-2, Bcl-X, Bax, Bad and Bak as did the parent S49wt cells. The uptake of [3H]-ALP was strongly reduced in the stress-resistant cells but this was not associated with significant differences in membrane cholesterol:phospholipid content nor in membrane microviscosity. In S49ar cells the activity of the antioxidant enzyme glutathione peroxidase (GSH-Px) was increased 4-fold and depletion of glutathione with the drug L-buthionine-S-R-sulfoximine (L-BSO) lowered the resistance of S49ar cells to ALP, stress factors and ionising radiation. The results indicate that ether lipids induce apoptosis by imposing a special form of physico-chemical stress, mediated by reactive oxygen species but independent of p53 status. The capacity of glutathione-dependent anti-oxidant defence appeared an important and shared determinant of the sensitivity to ether lipids, several types of extracellular stress and ionising radiation.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1009644208512

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Small aminothiol compounds improve the function of Arg to Cys variant proteins: effect on the human cystathionine {beta}-synthase p.R336C (2015)

Mendes, M. I. S., Smith, D. E. C., Vicente, J. B., Tavares De Almeida, I., Ben-Omran, T., Salomons, G. S., Rivera, I. A., Leandro, P., Blom, H. J.

Oxford University Press

In: Human Molecular Genetics

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Publication Date: 2015-12-01

Description: The key regulatory point of L-methionine (Met) and L-homocysteine (Hcy) degradation is catalyzed by cystathionine beta-synthase (CBS). CBS deficiency is caused by mutations in CBS gene, often resulting in protein misfolding. The prevalence of CBS deficiency in Qatar is 1/1800, ~200-fold higher than the worldwide prevalence of 1/344 000. Almost all patients bear the CBS p.R336C variant. More than 20 years ago, it was shown in vitro that two unrelated protein variants with a substitution of an arginine (Arg) residue by cysteine (Cys) could be rescued by cysteamine (mercaptoethylamine), likely via formation of a disulfide between Cys and cysteamine, functionally mimicking the wild-type (WT) Arg side-chain. Based on these findings, we aimed to study whether cysteamine was able to improve the function of p.R336C CBS variant. Additionally, we tested the effect of mercaptoethylguanidine (MEG), a compound with a guanidino and a thiol function that may resemble Arg structure better than cysteamine. Three purified recombinant CBS proteins (p.R336C, p.R336H and WT) were pre-incubated with cysteamine, MEG or Cys (as negative control), and CBS activity and stability were measured. Pre-incubation with cysteamine and MEG increased the enzymatic activity of the p.R336C protein, which was absent upon pre-incubation with Cys. The WT and the p.R336H variant enzyme activity presented no increase with any of the tested compounds. Our results show that cysteamine and MEG are able to specifically improve the function of the CBS p.R336C variant, suggesting that any Arg-to-Cys substitution accessible to these small molecules may be converted back to a moiety resembling Arg.

Print ISSN: 0964-6906

Electronic ISSN: 1460-2083

Topics: Biology , Medicine