| 1. |
- Abdissa, Negera, et al.
(författare)
-
Cytotoxic Quinones from the roots of Aloe dawei
- 2014
-
Ingår i: Molecules. - : MDPI AG. - 1420-3049 .- 1431-5157. ; 19:3, s. 3264-3273
-
Tidskriftsartikel (refereegranskat)abstract
- Seven naphthoquinones and nine anthraquinones were isolated from the roots of Aloe dawei by chromatographic separation. The purified metabolites were identified by NMR and MS analyses. Out of the sixteen quinones, 6-hydroxy-3,5-dimethoxy-2-methyl-1,4-naphthoquinone is a new compound. Two of the isolates, 5,8-dihydroxy-3-methoxy-2-methylnaphthalene-1,4-dione and 1-hydroxy-8-methoxy-3-methylanthraquinone showed high cytotoxic activity (IC50 1.15 and 4.85 µM) on MCF-7 breast cancer cells, whereas the others showed moderate to low cytotoxic activity against MDA-MB-231 (ER Negative) and MCF-7 (ER Positive) cancer cells.
|
|
| 2. |
- Alao, John Patrick, 1973, et al.
(författare)
-
Caffeine as a tool for investigating the integration of Cdc25 phosphorylation, activity and ubiquitin-dependent degradation in Schizosaccharomyces pombe.
- 2020
-
Ingår i: Cell Division. - : Springer Science and Business Media LLC. - 1747-1028. ; 15
-
Forskningsöversikt (refereegranskat)abstract
- The evolutionarily conserved Cdc25 phosphatase is an essential protein that removes inhibitory phosphorylation moieties on the mitotic regulator Cdc2. Together with the Wee1 kinase, a negative regulator of Cdc2 activity, Cdc25 is thus a central regulator of cell cycle progression in Schizosaccharomyces pombe. The expression and activity of Cdc25 is dependent on the activity of the Target of Rapamycin Complex 1 (TORC1). TORC1 inhibition leads to the activation of Cdc25 and repression of Wee1, leading to advanced entry into mitosis. Withdrawal of nitrogen leads to rapid Cdc25 degradation via the ubiquitin- dependent degradation pathway by the Pub1 E3- ligase. Caffeine is believed to mediate the override of DNA damage checkpoint signalling, by inhibiting the activity of the ataxia telangiectasia mutated (ATM)/Rad3 homologues. This model remains controversial, as TORC1 appears to be the preferred target of caffeine in vivo. Recent studies suggest that caffeine induces DNA damage checkpoint override by inducing the nuclear accumulation of Cdc25 in S. pombe. Caffeine may thus modulate Cdc25 activity and stability via inhibition of TORC1. A clearer understanding of the mechanisms by which caffeine stabilises Cdc25, may provide novel insights into how TORC1 and DNA damage signalling is integrated.
|
|
| 3. |
- Alao, John Patrick, 1973
(författare)
-
Caffeine, cyclin D1 and cell proliferation
- 2012
-
Ingår i: Tea in Health and Disease Prevention. - : Academic Press. - 9780123849373 ; , s. 1159-1169
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Although well characterized as an inhibitor of DNA damage-induced checkpoint signaling, caffeine has also been reported to delay G1-S-phase cell cycle progression in various cell lines. This activity is known to result from the inhibitory effect of caffeine on cyclin-dependent kinase 4/6 activity and occurs independently of p53. Ataxia telangiectasia mutated, a proposed target of caffeine, is required for insulin-induced protein kinase B/Akt phosphorylation and thus indirectly enhances cyclin-dependent kinase 4/6 activity by promoting cyclin D1 synthesis and stability. Caffeine and a selective ataxia telangiectasia mutated inhibitor (KU55933) have been shown to suppress Akt phosphorylation following exposure to insulin. Furthermore, both caffeine and KU55933 have been shown to suppress cyclin D1 expression. These studies suggest that caffeine suppresses G1-S-phase progression by indirectly inhibiting cyclin D1 synthesis and cyclin dependent kinase 4/6 activity. The precise in vivo target(s) of caffeine has not, however, been clearly defined.
|
|
| 4. |
- Alao, John Patrick, 1973, et al.
(författare)
-
Caffeine stabilises fission yeast Wee1 in a Rad24-dependent manner but attenuates Its expression in response to DNA damage.
- 2020
-
Ingår i: Microorganisms. - : MDPI AG. - 2076-2607. ; 8:10
-
Tidskriftsartikel (refereegranskat)abstract
- The widely consumed neuroactive compound caffeine has generated much interest due to its ability to override the DNA damage and replication checkpoints. Previously Rad3 and its homologues was thought to be the target of caffeine's inhibitory activity. Later findings indicate that the Target of Rapamycin Complex 1 (TORC1) is the preferred target of caffeine. Effective Cdc2 inhibition requires both the activation of the Wee1 kinase and inhibition of the Cdc25 phosphatase. The TORC1, DNA damage, and environmental stress response pathways all converge on Cdc25 and Wee1. We previously demonstrated that caffeine overrides DNA damage checkpoints by modulating Cdc25 stability. The effect of caffeine on cell cycle progression resembles that of TORC1 inhibition. Furthermore, caffeine activates the Sty1 regulated environmental stress response. Caffeine may thus modulate multiple signalling pathways that regulate Cdc25 and Wee1 levels, localisation and activity. Here we show that the activity of caffeine stabilises both Cdc25 and Wee1. The stabilising effect of caffeine and genotoxic agents on Wee1 was dependent on the Rad24 chaperone. Interestingly, caffeine inhibited the accumulation of Wee1 in response to DNA damage. Caffeine may modulate cell cycle progression through increased Cdc25 activity and Wee1 repression following DNA damage via TORC1 inhibition, as TORC1 inhibition increased DNA damage sensitivity.
|
|
| 5. |
- Alao, John Patrick, 1973, et al.
(författare)
-
Caffeine stabilizes Cdc25 independently of Rad3 in Schizosaccharomyces pombe contributing to checkpoint override
- 2014
-
Ingår i: Molecular Microbiology. - : Wiley. - 0950-382X .- 1365-2958. ; 92:4, s. 777-796
-
Tidskriftsartikel (refereegranskat)abstract
- Cdc25 is required for Cdc2 dephosphorylation and is thus essential for cell cycle progression. Checkpoint activation requires dual inhibition of Cdc25 and Cdc2 in a Rad3-dependent manner. Caffeine is believed to override activation of the replication and DNA damage checkpoints by inhibiting Rad3-related proteins in both Schizosaccharomyces pombe and mammalian cells. In this study, we have investigated the impact of caffeine on Cdc25 stability, cell cycle progression and checkpoint override. Caffeine induced Cdc25 accumulation in S.pombe independently of Rad3. Caffeine delayed cell cycle progression under normal conditions but advanced mitosis in cells treated with replication inhibitors and DNA-damaging agents. In the absence of Cdc25, caffeine inhibited cell cycle progression even in the presence of hydroxyurea or phleomycin. Caffeine induces Cdc25 accumulation in S.pombe by suppressing its degradation independently of Rad3. The induction of Cdc25 accumulation was not associated with accelerated progression through mitosis, but rather with delayed progression through cytokinesis. Caffeine-induced Cdc25 accumulation appears to underlie its ability to override cell cycle checkpoints. The impact of Cdc25 accumulation on cell cycle progression is attenuated by Srk1 and Mad2. Together our findings suggest that caffeine overrides checkpoint enforcement by inducing the inappropriate nuclear localization of Cdc25.
|
|
| 6. |
- Alao, John Patrick, 1973
(författare)
-
G1 Phase cyclins in cancer development and progression
- 2009
-
Ingår i: Checkpoint controls and targets in cancer therapy. Cancer drug discovery and development. (Zahid H. Siddik, editor). - New York : Humana Press. - 9781607611776 ; , s. 123-153
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Cyclin D1 and cyclin E are rate limiting for progression through G1 and entry into S phase during the cell cycle. Cyclin D1 plays a crucial role in linking favourable environmental conditions with cell cycle progression. Cyclin D1 indirectly induces cyclin E expression and activation which is required for entry into S phase. The deregulated expression of either cyclin would thus greatly impact on a cell’s ability to effectively regulate cell cycle progression. It perhaps not surprising therefore, that both cyclin D1 and cyclin E play important roles in the development and progression of cancer. This chapter explores the roles of these cyclins in cancer. For clarity, the major focus will be on the well characterized roles of cyclin D1 and cyclin E and thus to a lesser extent on other G1 cyclins such as cyclins D2 and D3. This chapter summarizes the evidence linking cyclin D1 and cyclin E to cancer development and progression. The cellular pathways that underlie the deregulated expression of the G1 cyclins in cancer, as well as their oncogenic roles are also discussed. Lastly, this chapter explores the potential of these cyclins to serve as therapeutic targets in cancer therapy.
|
|
| 7. |
- Alao, John Patrick, 1973, et al.
(författare)
-
Hyperosmosis enhances radiation and hydroxyurea resistance of S. pombe checkpoint mutants through the spindle checkpoint and delayed cytokinesis
- 2010
-
Ingår i: Molecular Microbiology. - : Wiley. - 0950-382X. ; 77:1, s. 143-157
-
Tidskriftsartikel (refereegranskat)abstract
- The DNA damage and stress response pathways interact to regulate cellular responses to genotoxins and environmental stresses. How these pathways interact in Schizosaccharomyces pombe is not well understood. We demonstrate that osmotic stress suppresses the DNA damage sensitivity of checkpoint mutants, and that this occurs through three distinct cell cycle delays. A delay in G2/M is dependent on Srk1. Progression through mitosis is halted by a Mad2-dependent spindle checkpoint. Finally, cytokinesis is impaired by modulating Cdc25 expression. These three delays, imposed by osmotic stress, together compensate for the loss of checkpoint signalling.
|
|
| 8. |
- Alao, John Patrick, 1973, et al.
(författare)
-
Inhibition of type I histone deacetylase increases resistance of checkpoint-deficient cells to genotoxic agents through mitotic delay
- 2009
-
Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 8, s. 2606-2615
-
Tidskriftsartikel (refereegranskat)abstract
- Histone deacetylase (HDAC) inhibitors potently inhibit tumor growth and are currently being evaluated for their efficacy as chemosensitizers and radiosensitizers. This efficacy is likely to be limited by the fact that HDACinhibitors also induce cell cycle arrest. Deletion of the class I HDACRpd3 has been shown to specifically suppress the sensitivity of Saccharomyces cerevisiae DNA damage checkpoint mutants to UV and hydroxyurea. We show that in the fission yeast Schizosaccharomyces pombe, inhibition of the homologous class I HDACspe cifically suppresses the DNA damage sensitivity of checkpoint mutants. Importantly, the prototype HDACinhibitor Trichostatin A also suppressed the sensitivity of DNA damage checkpoint but not of DNA repair mutants to UV and HU. TSA suppressed DNA damage activity independently of the mitogen-activated protein kinase–dependent and spindle checkpoint pathways. We show that TSA delays progression into mitosis and propose that this is the main mechanism for suppression of the DNA damage sensitivity of S. pombe checkpoint mutants, partially compensating for the loss of the G2 checkpoint pathway. Our studies also show that the ability of HDACinhibitors to suppress DNA damage sensitivity is not species specific. Class I HDACs are the major target of HDAC inhibitors and cancer cells are often defective in checkpoint activation. Effective use of these agents as chemosensitizers and radiosensitizers may require specific treatment schedules that circumvent their inhibition of cell cycle progression.
|
|
| 9. |
- Alao, John Patrick, 1973, et al.
(författare)
-
Rad3 and Sty1 function in S. pombe: an integrated response to DNA damage and environmental stress?
- 2008
-
Ingår i: Molecular Microbiology. - : Wiley. - 0950-382X. ; 68, s. 246-254
-
Forskningsöversikt (refereegranskat)abstract
- In Schizosaccharomyces pombe, the Ataxia Telangiectasia-mutated (Atm)/Atm and Rad 3 Related (Atr) homologue Rad3 is an essential regulator of the response to DNA damage and stalled replication forks. Rad3 activates the downstream kinases Chk1 and Cds1. These kinases in turn inhibit cell cycle progression by mediating Cdc2 phosphorylation. Studies in both yeast and mammalian cells suggest additional roles for Rad3 in regulating cellular responses to environmental stress. In S. pombe, cellular responses to various environmental stresses are regulated primarily through the stress-activated MAP kinase p38 homologue Sty1. An important function of Sty1 is to drive cells rapidly through mitosis by facilitating the accumulation of Cdc25. Interestingly, Sty1 is activated simultaneously with Rad3 following exposure to UV radiation or ionizing radiation (IR). Similarly, exposure to environmental stresses induces the expression of rad3+, cds1+ and other checkpoint regulator genes. It is currently unclear how the pathways regulated by Sty1 and Rad3 and their opposing effects on mitosis are integrated. Recent studies suggest that Sty1 and Rad3 function together to regulate the expression of several stress response genes following exposure to IR. In this review, we discuss current knowledge on the interaction of Rad3/Atm and Sty1/p38 in regulating cellular responses to environmental stress and DNA damage.
|
|
| 10. |
|
|
