Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sphingosine, a sphingolipid breakdown product, has been proposed as an apoptosis-inducing agent. In this study, we examined the effect of sphingosine in bcl-2-overexpressing cells compared with cells that do not express the bcl-2 gene. The human erythroleukemic cell line TF1, which lacks bcl-2 expression, was easily induced to undergo apoptotic cell death by a variety of stimuli, including depletion of granulocyte-macrophage colony-stimulating factor (GM-CSF) or exposure to methylmethane sulfonate (MMS) (100 microg/mL), ultraviolet light (15 J/m2), X-ray irradiation (20 Gy), or sphingosine, a sphingolipid breakdown product (5 microM). In contrast, bcl-2 transfectants of TF1 (TF1-bcl2), which we established, were resistant to most of these treatments but remained sensitive to sphingosine. Neither C2- nor C6-ceramide (short-chain ceramide) induced apoptosis in TF1-mock and TF1-bcl2 cells. Sphingosine-induced apoptosis could not be inhibited by fumonisin B1, which can prevent conversion of sphingosine to ceramide, suggesting that sphingosine itself, not ceramide, possesses apoptosis-inducing capability. Western blotting, which revealed a 21-kDa bax protein in untreated cells, revealed the presence of an additional 18-kDa protein in GM-CSF-depleted and MMS- or sphingosine-treated TF1-mock cells. In TF1-bcl2 cells, this protein was not detected after GM-CSF depletion or MMS treatment, but was observed after sphingosine treatment. Immunoprecipitation with anti-bcl2 antibody, followed by immunoblotting with anti-bax antibody, showed that both the 21-kDa bax protein and the 18-kDa protein heterodimerized with bcl-2 protein. These results suggest that sphingosine is a unique reagent for apoptosis and that it can overcome bcl-2 gene expression. Furthermore, induction of 18-kDa bax-related protein may play an important role in apoptosis. Sphingosine, but not ceramide, may prove applicable as a reagent for future cytotoxic drugs used to treat intractable tumors overexpressing bcl-2.
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PMID:Analysis of bax protein in sphingosine-induced apoptosis in the human leukemic cell line TF1 and its bcl-2 transfectants. 980 50

Nicotine-induced cell survival is associated with chemoresistance of human lung cancer cells, but our understanding of the intracellular mechanism(s) is fragmentary. Bax is a major proapoptotic member of the Bcl2 family and a molecule required for apoptotic cell death. Growth factor (i.e. granulocyte-macrophage colony-stimulating factor)-induced phosphorylation of Bax has been reported to negatively regulate its proapoptotic function. Because Bax is ubiquitously expressed in both small cell lung cancer and non-small cell lung cancer cells, nicotine may mimic growth factor(s) to regulate the activity of Bax. We found that nicotine potently induces Bax phosphorylation at Ser-184, which results in abrogation of the proapoptotic activity of Bax and increased cell survival. AKT, a known physiological Bax kinase, is activated by nicotine, co-localizes with Bax in the cytoplasm, and can directly phosphorylate Bax in vitro. Treatment of cells with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or specific depletion of AKT expression by RNA interference can block both nicotine-induced Bax phosphorylation and cell survival. Importantly, nicotine-induced Bax phosphorylation potently blocks stress-induced translocation of Bax from cytosol to mitochondria, impairs Bax insertion into mitochondrial membranes, and reduces the half-life of Bax protein (i.e. from 9-12 h to <6 h). Because knockdown of Bax expression by gene silencing results in prolonged cell survival following treatment with cisplatin in the absence or presence of nicotine, Bax may be an essential component in the nicotine survival signaling pathway. Thus, nicotine-induced survival and chemoresistance of human lung cancer cells may occur in a novel mechanism involving activation of PI3K/AKT that directly phosphorylates and inactivates the proapoptotic function of Bax.
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PMID:Nicotine inactivation of the proapoptotic function of Bax through phosphorylation. 1564 28