Involvement of Ceramide in the Mechanism of Cr(VI)-induced Apoptosis of CHO Cells

Muranaka, Shikibu; Kanno, Tomoko; Fujita, Hirofumi; Kobuchi, Hirotsugu; Akiyama, Jitsuo; Yasuda, Tatsuji; Utsumi, Kozo

doi:10.1080/10715760410001694035

Cited by 13 publications

(6 citation statements)

References 51 publications

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“…Interestingly, the ability of Cr(VI) to downregulate Akt activity has been previously reported, albeit with much higher concentrations (50 µM) of Cr(VI). 41 The mechanism of Cr(VI)-induced Akt downregulation is currently under investigation in our laboratory. Importantly, we did not observe any effect of SOV on ERK activation in the present study (data not shown).…”

Section: Discussionmentioning

confidence: 99%

AKT1 mediates bypass of the G1/S checkpoint after genotoxic stress in normal human cells

Lal¹,

Bae²,

Camilli³

et al. 2009

Cell Cycle

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Certain forms of hexavalent chromium [Cr(VI)] are human carcinogens. Our recent work has shown that a broad range protein tyrosine phosphatase (PTP) inhibitor, sodium orthovanadate (SOV), abrogated both Cr(VI)-induced growth arrest and clonogenic lethality. Notably, SOV enhanced Cr(VI) mutation frequency, ostensibly through forced survival of genetically damaged cells. In the present study, co-treatment with this PTP inhibitor bypassed the Cr(VI)-induced G1/S checkpoint arrest in diploid human lung fibroblasts (HLF). Moreover, the PTP inhibitor abrogated the Cr(VI)-induced decrease in the expression of key effectors of the G1/S checkpoint [Cyclin D1, phospho Ser 807/811 Rb (pRB), p27]. Cr(VI)-induced G1 arrest was associated with the cytoplasmic appearance of pRb and the nuclear localization of p27, both of which were reversed by the PTP inhibitor. The PTP inhibitor’s reversal of G1/S checkpoint effector localization after Cr exposure was found to be Akt1-dependent, as this was abrogated by transfection with either akt1 siRNA or an Akt1-kinase dead plasmid. Furthermore, Akt1 activation alone was sufficient to induce G1/S checkpoint bypass and to prevent Cr(VI)-induced changes in pRb and p27 localization. In conclusion, this work establishes Akt1 activation to be both sufficient to bypass the Cr(VI)-induced G1/S checkpoint, as well as necessary for the observed PTP inhibitor effects on key mediators of the G1/S transition. The potential for Akt to bypass G1/S checkpoint arrest in the face of genotoxic damage could increase genomic instability, which is a hallmark of neoplastic progression.

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Section: Discussionmentioning

confidence: 99%

AKT1 mediates bypass of the G1/S checkpoint after genotoxic stress in normal human cells

Lal¹,

Bae²,

Camilli³

et al. 2009

Cell Cycle

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“…Desipramine was found to induce rapid intracellular degradation of mature aSMase when added to cultured human skin fibroblasts in the micromolar range, concomitantly abolishing the enzymatic activity. Desipramine was shown to prevent the increase in Cer levels and to inhibit apoptosis of various cell lines after treatment with apoptosis-stimulating compounds (such as macrophage colony-stimulating factor deprivation in bone marrowderived macrophages [87]; histon deacetylase inhibitor/ perifosine-treatment of human leukemia cells [88]; and Cr(VI)-induced activation of apoptosis in CHO cells [89]). Imipramine is another tricyclic antidepressant drug (Fig.…”

Section: (A) Acidic Sphingomyelinase Inhibitorsmentioning

confidence: 99%

Ceramide Involvement in Apoptosis and Apoptotic Diseases

Thevissen¹,

François²,

Winderickx³

et al. 2006

MRMC

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Apoptosis is implicated in a number of diseases, including neurodegenerative diseases and AIDS. More and more, evidence is accumulating pointing to the critical role of ceramides in the induction of apoptosis. The present review summarizes (i) the molecular basis and regulation of the apoptotic machinery, (ii) the molecular role of ceramides in the induction or execution of apoptotic pathways, and (iii) evidence linking ceramide generation to various apoptotic diseases. Additionally, this review discusses putative therapeutic approaches inhibiting ceramide production in apoptotic diseases.

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“…Glucocerebroside-induced apoptosis may be mediated by glucocerebroside itself or by altered levels of other compounds in its metabolic pathway, such as ceramide, which has a well characterized proapoptotic effect (Muranaka et al, 2004). Binding of glycolipids to CD1d is mediated by anchoring of their lipid tail to the hydrophobic pockets of the CD1d antigen-binding groove.…”

Section: Discussionmentioning

confidence: 99%

Glucocerebroside Ameliorates the Metabolic Syndrome in OB/OB Mice

Margalit

Shalev²,

Pappo³

et al. 2006

J Pharmacol Exp Ther

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Glucocerebroside (GC) is a naturally occurring glycolipid that may alter natural killer T (NKT) cell function. To determine the effect of GC on the metabolic derangements and immune profile in leptin-deficient mice, Ob/Ob mice were treated by daily injections of GC for 8 weeks and followed for various metabolic and immunological parameters. Marked amelioration of the metabolic alterations characteristic of leptin-deficient mice was observed in GC-treated animals compared with controls. A significant decrease in liver size and hepatic fat content were observed in GC-treated mice. Near-normalization of glucose tolerance and decreased serum triglyceride levels were observed. Fluorescence-activated cell sorting analysis of peripheral and intrahepatic lymphocytes revealed a 1.6-fold increase of the peripheral/intrahepatic NKT lymphocyte ratio. A 33% decrease of serum interferon-␥ level and a 2.6-fold increase of serum interleukin 10 level were noted in GC-treated mice. Immune modulation by GC may have a role in the treatment of nonalcoholic steatohepatitis and other immune-mediated disorders.

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Involvement of Ceramide in the Mechanism of Cr(VI)-induced Apoptosis of CHO Cells

Cited by 13 publications

References 51 publications

AKT1 mediates bypass of the G1/S checkpoint after genotoxic stress in normal human cells

AKT1 mediates bypass of the G1/S checkpoint after genotoxic stress in normal human cells

Ceramide Involvement in Apoptosis and Apoptotic Diseases

Glucocerebroside Ameliorates the Metabolic Syndrome in OB/OB Mice

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