ENDOPLASMIC RETICULUM–NUKLEI SIGNALING ENZYME-1 KNOCKDOWN MODULATES EFFECT OF HYPOXIA AND ISCHEMIA ON THE EXPRESSION OF CIRCADIAN GENES IN GLIOMA CELLS
DOI: http://dx.doi.org/10.30970/sbi.0502.151
Abstract
The main molecular components of circadian clock system are proteins which play a significant role in the control of both metabolism and malignant tumor growth. Endoplasmic reticulum stress as well as hypoxia and ischemia are important factors for tumor neovascularization and growth. We have studied the expression of circadian genes in the glioma cell line U87 under knockdown of endoplasmic reticulum–nuclei-1 (ERN1) sensing and signaling enzyme. It was shown that blockade of ERN1 leads to increase in the expression levels of PER1, PER3 and CLOCK mRNA; but the CRY1, PER2, BMAL1, BMAL2 and DEC2 mRNA levels are decreased. Moreover, the expression levels of most of the studied genes are increased under glucose or glutamine deprivation conditions both in control and ERN1-deficient glioma cells; however knockdown of ERN1 modifies the effect of these ischemic conditions. Hypoxia has different effects on the expression levels of circadian genes and these effects are dependent on ERN1 function. Hypoxia induces the expression of PER1, BMAL1 and DEC2 and decreased – PER3, CLOCK, CRY1 and BMAL2 mRNA in control glioma cells, while in genetically modified cells it induces the expression of BMAL1 mRNA only. Thus, the expression of circadian genes is dependent on ERN1 signaling enzyme function in normal, hypoxic and ischaemic conditions.
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1. Gonze D., Goldbeter A. Circadian rhythms and molecular noise. Chaos, 2006; 16(2): 026110 (1-11). | |
| |
2. Hastings M.H., Maywood E.S., Reddy A.B. Two decades of circadian time. Journal of Neuroendocrinology, 2008; 20(6): 812-819. | |
| |
3. Kovac J., Husse J., Oster H. A time to fast, a time to feast: the crosstalk between metabolism and the circadian clock. Molecules and Cells, 2009; 28(2): 75-80. | |
| |
4. Pfeffer M., Muller C.M., Mordel J. et al. The mammalian molecular clockwork controls rhythmic expression of its own input pathway components. Journal of Neuroscience, 2009; 29(19): 6114- 6123. | |
| |
5. Карбовський Л.Л., Мінченко Д.О., Гармаш Я.А., Мінченко О.Г. Молекулярні механізми функціонування циркадіального годинника. Український біохімічний журнал, 2010; 83(3): 5-25. | |
| |
6. Rudic R.D., McNamara P., Curtis A.M. et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biology, 2004; 2(11): E377. | |
| |
7. Moenner M., Pluquet O., Bouchecareilh M., Chevet E. Integrated endoplasmic reticulum stress responses in cancer. Cancer Research, 2007; 67(22): 10631-10634. | |
| |
8. Drogat B., Auguste P., Nguyen D.T. et al. IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. Cancer Research, 2007; 67: 6700-6707. | |
| |
9. Auf G., Jabouille A., Guérit S. et al. A shift from an angiogenic to invasive phenotype induced in malignant glioma by inhibition of the unfolded protein response sensor IRE1. Proceedings of the National Academy of Sciences of the U.S.A., 2010; 107(35): 15553-15558. | |
| |
10. Bi M., Naczki C., Koritzinsky M. et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO Journal, 2005; 24(19): 3470-3481. | |
| |
11. Blais J.D., Filipenko V., Bi M. et al. Transcription factor 4 is translationally regulated by hypoxic stress. Molecular and Cellular Biology, 2004; 24: 7469-7482. | |
| |
12. Fels D.R., Koumenis C. The PERK/eIF2a/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biology & Therapy, 2006; 5(7): 723-728. | |
| |
13. Luo D., He Y., Zhang H., Yu L. et al. AIP1 is critical in transducing IRE1-mediated endoplasmic reticulums response. The Journal of Biological Chemistry, 2010; 285(18): 11905 -11912. | |
| |
14. Korennykh A.V., Egea P.F., Korostelev A.A. et al. The unfolded protein response signals through high-order assembly of Ire1. Nature, 2009; 457(7230): 687-693. | |
| |
15. Aragón T., van Anken E., Pincus D. et al. Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature, 2009; 457(7230): 736-740. | |
| |
16. Acosta-Alvear D., Zhou Y., Blais A. et al. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Molecular Cell, 2007; 27: 53-66. | |
| |
17. Hollien J., Lin J.H., Li H. et al. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. Journal of Cell Biology, 2009; 186(3): 323-331. | |
| |
18. Greenman C., Stephans P., Smith R. et al. Patterns of somatic mutation in human genomes. Nature, 2007; 446: 153-158. | |
| |
19. Hunt T., Sassone-Corsi P. Riding tandem: Circadian clocks and the cell cycle. Cell, 2007; 129: 461-464. | |
| |
20. Hua H., Wang Y., Wan C. et al. Circadian gene mPer2 overexpression induces cancer cell apoptosis. Cancer Science, 2006; 97: 589-596. | |
| |
21. Cao Q., Gery S., Dashti A. et al. A role for the clock gene per1 in prostate cancer. Cancer Research, 2009; 69(19): 7619-7625. | |
| |
22. Taniguchi H., Fernandez A.F., Setien F. et al. Epigenetic inactivation of the circadian clock gene BMAL1 in hematologic malignancies. Cancer Research, 2009; 69(21): 8447-8454. | |
| |
23. Chen S. T., Choo K. B., Hou M. F. et al. Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis, 2005; 26(7): 1241-1246. | |
| |
24. Climent J., Perez-Losada J., Quigley D.A. et al. Deletion of the PER3 gene on chromosome 1p36 in recurrent ER-positive breast cancer. Journal of Clinical Oncology, 2010; 28(23): 3770-3778. | |
| |
25. Ramsey K.M., Marcheva B., Kohsaka A., Bass J. The clockwork of metabolism. Annual Review of Nutrition, 2007; 27: 219-240. | |
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