Inhibition of ERN1 modifies the hypoxic regulation of the expression of TP53-related genes in U87 glioma cells

• Authors: Dmytro O. Minchenko , Serhii V. Danilovskyi , Iryna V. Kryvdiuk , Taia V. Bakalets , Nadia M. Lypova , Leonid L. Karbovskyi , Oleksandr H. Minchenko
• Languages of publication: EN

Abstracts

EN

Inhibition of ERN1 (endoplasmic reticulum to nuclei 1), the major signalling pathway of endoplasmic reticulum stress, significantly decreases tumor growth. We have studied the expression of tumor protein 53 (TP53)- related genes such as TOPORS (topoisomerase I binding, arginine/serine-rich, E3 ubiquitin protein ligase), TP53BP1 (TP53 binding protein 1), TP53BP2, SESN1 (sestrin 1), NME6 (non-metastatic cells 6), and ZMAT3 (zinc finger, Matrin-type 3) in glioma cells expressing dominantnegative ERN1 under baseline and hypoxic conditions. We demonstrated that inhibition of ERN1 function in U87 glioma cells resulted in increased expression of RYBP, TP53BP2, and SESN1 genes, but decreased expression of TP53BP1, TOPORS, NME6, and ZMAT3 genes. Moreover, inhibition of ERN1 affected hypoxia-mediated changes in expression of TP53-related genes and their magnitude. Indeed, hypoxia has no effect on expression of TP53BP1 and SESN1 in control cells, while resulted in increased expression of these genes in cells with inhibited ERN1 function. Magnitude of hypoxia-mediated changes in expression levels of RYBP and TP53BP2 was gene specific and more robust in the case of TP53BP2. Hypoxiamediated decrease in expression levels of TOPORS was more prominent if ERN1 was inhibited. Present study demonstrates that fine-tuning of the expression of TP53- associated genes depends upon endoplasmic reticulum stress signaling under normal and hypoxic conditions. Inhibition of ERN1 branch of endoplasmic reticulum stress response correlates with deregulation of p53 signaling and slower tumor growth.

Keywords

EN

endoplasmic reticulum stress; IRE1; ERN1; RYBP; TP53BP1; TP53BP2; TOPORS; SESN1; ZMAT3; NME6; hypoxia

• Publisher: De Gruyter Open
• Journal: Endoplasmic Reticulum Stress in Diseases
• Year: 2014
• Volume: 1
• Issue: 1

Dates

published

1 - 1 - 2014

accepted

22 - 1 - 2014

online

24 - 2 - 2014

received

8 - 11 - 2013

Contributors

author

Dmytro O. Minchenko

• Department of Molecular Biology, Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, 9 Leontovycha St., 01601, Kyiv, Ukraine
• Departments of Pediatrics, Bogomolets National Medical University, 13 Shevchenka Bvld., 01601, Kyiv, Ukraine

author

Serhii V. Danilovskyi

• Department of Molecular Biology, Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, 9 Leontovycha St., 01601, Kyiv, Ukraine

author

Iryna V. Kryvdiuk

• Department of Molecular Biology, Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, 9 Leontovycha St., 01601, Kyiv, Ukraine

author

Taia V. Bakalets

• Department of Molecular Biology, Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, 9 Leontovycha St., 01601, Kyiv, Ukraine

author

Nadia M. Lypova

• Department of Molecular Biology, Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, 9 Leontovycha St., 01601, Kyiv, Ukraine

author

Leonid L. Karbovskyi

• Department of Molecular Biology, Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, 9 Leontovycha St., 01601, Kyiv, Ukraine

author

Oleksandr H. Minchenko

• Department of Molecular Biology, Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, 9 Leontovycha St., 01601, Kyiv, Ukraine

References

• [1] Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol 2012;197: 857-67.[PubMed][Crossref]
• [2] Moenner M, Pluquet O, Bouchecareilh M, Chevet E. Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 2007; 67: 10631-4.[PubMed][Crossref][WoS]
• [3] Schroder M. Endoplasmic reticulum stress responses. Cell Mol Life Sci 2008 65: 862-94.[Crossref][PubMed]
• [4] Auf G, Jabouille A, Guerit S, et al. Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. Proc Natl Acad Sci USA 2010; 107: 15553-8.[Crossref]
• [5] Drogat B, Auguste P, Nguyen DT, 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 Res 2007; 67: 6700-7.[Crossref]
• [6] Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem 2005; 74: 739-89.[Crossref][PubMed]
• [7] Zhang K, Kaufman RJ. The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 2006; 66 (Suppl 1): S102-9.[Crossref]
• [8] Hollien J, Lin JH, Li H, et al. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 2009; 186: 323-31.[Crossref]
• [9] Golubovskaya VM, Cance WG. Targeting the p53 pathway. Surg Oncol Clin N Am 2013; 22: 747-64.[Crossref]
• [10] Dent P. Non-canonical p53 signaling to promote invasion. Cancer Biol Ther 2013; 14: 879-80.[Crossref]
• [11] Lee SK, Kim YS. Phosphorylation of eIF2α attenuates statininduced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria. Int J Oncol 2013; 42: 810-6.[WoS]
• [12] Chen D, Zhang J, Li M, et al. RYBP stabilizes p53 by modulating MDM2. EMBO Rep 2009; 10: 166-72.[WoS][Crossref]
• [13] Novak RL, Phillips AC. Adenoviral-mediated Rybp expression promotes tumor cell-specific apoptosis. Cancer Gene Ther 2008; 15: 713-22.[PubMed][Crossref]
• [14] Moudry P, Lukas C, Macurek L, et al. Nucleoporin NUP153 guards genome integrity by promoting nuclear import of 53BP1. Cell Death Differ 2012; 19: 798-807.[WoS][Crossref]
• [15] Hong S, Li X, Zhao Y, Yang Q, Kong B. TP53BP1 suppresses tumor growth and promotes susceptibility to apoptosis of ovarian cancer cells through modulation of the Akt pathway. Oncol Rep 2012; 27: 1251-7.[WoS]
• [16] Wang Y, Godin-Heymann N, Dan Wang X, et al. ASPP1 and ASPP2 bind active RAS, potentiate RAS signalling and enhance p53 activity in cancer cells. Cell Death Differ 2013; 20: 525-34.[WoS][Crossref]
• [17] Grotsky DA, Gonzalez-Suarez I, Novell A, et al. BRCA1 loss activates cathepsin L-mediated degradation of 53BP1 in breast cancer cells. J Cell Biol 2013; 200: 187-202.[Crossref][WoS]
• [18] Yang X, Li H, Deng A, Liu X. Plk1 phosphorylation of Topors is involved in its degradation. Mol Biol Rep 2010; 37: 3023-8.[Crossref][WoS]
• [19] Li S, Shi G, Yuan H, et al. Abnormal expression pattern of the ASPP family of proteins in human non-small cell lung cancer and regulatory functions on apoptosis through p53 by iASPP. Oncol Rep 2012; 28: 133-140.[WoS]
• [20] Noon AT, Goodarzi AA. 53BP1-mediated DNA double strand break repair: insert bad pun here. DNA Repair (Amst) 2011; 10:1071-6.[Crossref]
• [21] Li X, Xu B, Moran MS, et al. 53BP1 functions as a tumor suppressor in breast cancer via the inhibition of NF-κB through miR-146a. Carcinogenesis 2012; 33: 2593-600.[WoS]
• [22] Yang X, Li H, Zhou Z, et al. Plk1-mediated phosphorylation of Topors regulates p53 stability. J Biol Chem 2009; 284: 18588-92.
• [23] Serao NV, Delfino KR, Southey BR, Beever JE, Rodriguez-Zas SL. Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival. BMC Med Genomics 2011; 4: 49.[Crossref][WoS][PubMed]
• [24] Wang CH, Ma N, Lin YT, et al. A shRNA functional screen reveals Nme6 and Nme7 are crucial for embryonic stem cell renewal. Stem Cells 2012; 30: 2199-211.[Crossref]
• [25] Desvignes T, Pontarotti P, Fauvel C, Bobe J. Nme protein family evolutionary history, a vertebrate perspective. BMC Evol Biol 2009; 9: 256.[PubMed][WoS][Crossref]
• [26] Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 2008; 134: 451-60.[WoS][Crossref]
• [27] Kim BC, Lee HC, Lee JJ, et al. Wig1 prevents cellular senescence by regulating p21 mRNA decay through control of RISC recruitment. EMBO J 2012; 31: 4289-303.[WoS][Crossref]
• [28] Vilborg A, Bersani C, Wickstrom M, et al. Wig-1, a novel regulator of N-Myc mRNA and N-Myc-driven tumor growth. Cell Death Dis 2012; 3: E298.[WoS][Crossref]
• [29] Vilborg A, Bersani C, Wickstrom M, et al. Wig-1, a novel regulator of N-Myc mRNA and N-Myc-driven tumor growth. Cell Death Dis 2012; 3: e298.[WoS][Crossref]
• [30] Minchenko DО, Kubajchuk КІ, Ratushna OO, Komisarenko SV, Minchenko OH. The effect of hypoxia and ischemic condition on the expression of VEGF genes in glioma U87 cells is dependent from ERN1 knockdown. Adv Biol Chem 2012; 2: 198-206.[Crossref]
• [31] Mills KD. Tumor suppression: Putting p53 in context. Cell Cycle 2013; 12: 1-2.[WoS]
• [32] Shahbazi J, Lock R, Liu T. Tumor Protein 53-Induced Nuclear Protein 1 Enhances p53 Function and Represses Tumorigenesis. Front Genet 2013; 4: 80.
• [33] Thomas SE, Malzer E, Ordonez A, et al. p53 and translation attenuation regulate distinct cell cycle checkpoints during ER stress. J Biol Chem 2013; 288: 7606-17.[WoS]
• [34] Velasco-Miguel S, Buckbinder L, Jean P, et al. PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. Oncogene 1999; 18: 127-37.[Crossref]
• [35] Perina D, Bosnar MH, Mikoč A, Muller WE, Cetković H. Characterization of Nme6-like gene/protein from marine sponge Suberites domuncula. Naunyn Schmiedebergs Arch Pharmacol 2011; 384: 451-60.[WoS]
• [36] Apostolidis PA, Lindsey S, Miller WM, Papoutsakis ET. Proposed megakaryocytic regulon of p53: the genes engaged to control cell cycle and apoptosis during megakaryocytic differentiation. Physiol Genomics 2012; 44: 638-50.[Crossref][WoS]
• [37] Weger S, Hammer E, Heilbronn R. Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS Lett 2005; 579: 5007-12.
• [38] Shinbo Y, Taira T, Niki T, Iguchi-Ariga SM, Ariga H. DJ-1 restores p53 transcription activity inhibited by Topors/p53BP3. Int J Oncol 2005; 26: 641-8.
• [39] Lenihan CR, Taylor CT. The impact of hypoxia on cell death pathways. Biochem Soc Trans 2013; 41: 657-63.[PubMed][Crossref][WoS]
• [40] Malhotra JD, Kaufman RJ. ER stress and its functional link to mitochondria: role in cell survival and death. Cold Spring Harb Perspect Biol 2011; 3: a004424.
• [41] Mimeault M, Batra SK. Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J Cell Mol Med 2013; 17: 30-54. [WoS][Crossref][PubMed]

Identifiers

DOI

10.2478/ersc-2014-0001