Tag Archives: ERN1
Endoplasmic reticulum stress, its sensor and signalling systems and the role in regulation of gene expression at malignant tumor growth and hypoxia
O. H. Minchenko, A. P. Kharkova, T. V. Bakalets, I. V. Kryvdiuk
Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: ominchenko@yahoo.com
Hypoxia is one of the inductors of the expression of a large group of genes, which control glycolysis and proliferation processes in low oxygen conditions or as a result of low oxygen consumption. Moreover, hypoxia is one of the factors which induce the endoplasmic reticulum stress which, like hypoxia, is an obligatory component of malignant tumor growth and is connected with cytoplasm and nuclei through three sensor and signalling systems: PERK, ATF6 та ERN1. The suppression of ERN1, the main sensing and signalling enzyme of endoplasmic reticulum stress, leads to a decrease of tumor growth and changes the character of hypoxic regulation of many genes responsible for the control of proliferation and glycolysis. ERN1 sensing and signalling system controls the expression of a large set of genes, which are dependent on endoplasmic reticulum stress as well as hypoxia. Moreover, this signalling pathway is an important factor of malignant tumor growth.
Expression of phosphoribosyl pyrophosphate synthetase genes in U87 glioma cells with ERN1 knockdown: effect of hypoxia and endoplasmic reticulum stress
O. H. Minchenko, I. A. Garmash, O. V. Kovalevska,
D. O. Tsymbal, D. O. Minchenko
Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: ominchenko@yahoo.com
Activation of pentose phosphate pathway is an important factor of enhanced cell proliferation and tumor growth. Phosphoribosyl pyrophosphate synthetase (PRPS) is a key enzyme of this pathway and plays a central role in the synthesis of purines and pyrimidines. Hypoxia as well as ERN1 (from endoplasmic reticulum to nuclei-1) mediated endoplasmic reticulum stress response-signalling pathway is linked to the proliferation because the blockade of ERN1 suppresses tumor growth, including glioma. We studied the expression of different PRPS genes in glioma cells with ERN1 knockdown under hypoxic condition. It was shown that hypoxia decreases the expression of PRPS1 and PRPS2 genes in both types of glioma cells, being more pronounced in cells without ERN1 function, but PRPSAP1 and PRPSAP2 gene expressions are suppressed by hypoxia only in glioma cells with blockade of ERN1. Moreover, the blockade of endoribonuclease activity of ERN1 does not affect the expression of PRPS1 and PRPS2 as well as PPRS-associated protein genes in U87 glioma cells. At the same time, the induction of endoplasmic reticulum stress by tunicamycin in glioma cells with suppressed activity of ERN1 endoribonuclease decreases the expression level of PRPS1 and PRPS2 genes only. Results of this investigation clearly demonstrated that the expression of different genes encoding subunits of PRPS enzyme is affected by hypoxia in U87 glioma cells, but the effect of hypoxia is modified by suppression of endoplasmic reticulum stress signaling enzyme ERN1.
ERN1 knockdown modifies the hypoxic regulation of TP53, MDM2, USP7 and PERP gene expressions in U87 glioma cells
S. V. Danilovskyi1, D. O. Minchenko1,2, О. S. Moliavko1,
O. V. Kovalevska1, L. L. Karbovskyi1, O. H. Minchenko1
1Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, Kyiv;
e-mail: ominchenko@yahoo.com;
2Bogomolets National Medical University, Kyiv, Ukraine
Endoplasmic reticulum stress and hypoxia are necessary components of malignant tumors growth and suppression of ERN1 (from endoplasmic reticulum to nuclei-1) signalling pathway, which is linked to the apoptosis and cell death processes, significantly decreases proliferative processes. Glioma cells with ERN1 knockdown were used in order to investigate the effect of ERN1 blockade on the expression of TP53, MDM2, PERP, and USP7 genes and its hypoxic regulation. We have studied the expression of TP53 (tumor protein 53), MDM2 (TP53 E3 ubiquitin protein ligase homolog), PERP (TP53 apoptosis effector), and USP7 (ubiquitin specific peptidase 7) genes, which are related to cell proliferation and apoptosis, in glioma cells with ERN1 knockdown under hypoxic condition. It was shown that blockade of ERN1 gene function in U87 glioma cells intensified the expression of TP53 and USP7 genes, but decreased the expression of MDM2 and PERP genes. Thus, an enhanced expression of TP53 gene in ERN1 knockdown glioma cells correlates with the decreased level of ubiquitin ligase MDM2 and increased expression level of USP7 which deubiquitinates TP53 and MDM2 and induces TP53-dependent cell growth repression and apoptosis. At the same time, the expression levels of TP53, MDM2, and USP7 genes do not change significantly in glioma cells with suppression of endoribonuclease activity only, but PERP gene expression is strongly increased. Moreover, the expression of TP53 and UPS7 genes is decreased in hypoxic conditions in control glioma cells only; however, MDM2 and PERP gene expressions are increased in both cell types, being more significant in ERN1 knockdown cells. Thus, the expression of genes encoding TP53 and related to TP53 factors depends upon the endoplasmic reticulum stress signaling as well as on hypoxia, and correlates with suppression of glioma growth under ERN1 knockdown.