TRIM22 promotes the proliferation of glioblastoma cells by activating MAPK signaling and accelerating the degradation of Raf-1
0
조회
0
다운로드
0
인용
0
참고문헌
초록
The tripartite motif (TRIM) 22 and mitogen-activated protein kinase (MAPK) signaling pathways play critical roles in the growth of glioblastoma (GBM). However, the molecular mechanism underlying the relationship between TRIM22 and MAPK signaling remains unclear. Here, we found that TRIM22 binds to exon 2 of the sphingosine kinase 2 (SPHK2) gene. An ERK1/2-driven luciferase reporter construct identified TRIM22 as a potential activator of MAPK signaling. Knockout and overexpression of TRIM22 regulate the inhibition and activation of MAPK signaling through the RING-finger domain. TRIM22 binds to Raf-1, a negative regulator of MAPK signaling, and accelerates its degradation by inducing K48-linked ubiquitination, which is related to the CC and SPRY domains of TRIM22 and the C1D domain of Raf-1. In vitro and in vivo, an SPHK2 inhibitor (K145), an ERK1/2 inhibitor (selumetinib), and the nonphosphorylated mutant Raf-1S338A inhibited GBM growth. In addition, deletion of the RING domain and the nuclear localization sequence of TRIM22 significantly inhibited TRIM22-induced proliferation of GBM cells in vivo and in vitro. In conclusion, our study showed that TRIM22 regulates SPHK2 transcription and activates MAPK signaling through posttranslational modification of two critical regulators of MAPK signaling in GBM cells.
Abstract
The tripartite motif (TRIM) 22 and mitogen-activated protein kinase (MAPK) signaling pathways play critical roles in the growth of glioblastoma (GBM). However, the molecular mechanism underlying the relationship between TRIM22 and MAPK signaling remains unclear. Here, we found that TRIM22 binds to exon 2 of the sphingosine kinase 2 (SPHK2) gene. An ERK1/2-driven luciferase reporter construct identified TRIM22 as a potential activator of MAPK signaling. Knockout and overexpression of TRIM22 regulate the inhibition and activation of MAPK signaling through the RING-finger domain. TRIM22 binds to Raf-1, a negative regulator of MAPK signaling, and accelerates its degradation by inducing K48-linked ubiquitination, which is related to the CC and SPRY domains of TRIM22 and the C1D domain of Raf-1. In vitro and in vivo, an SPHK2 inhibitor (K145), an ERK1/2 inhibitor (selumetinib), and the nonphosphorylated mutant Raf-1S338A inhibited GBM growth. In addition, deletion of the RING domain and the nuclear localization sequence of TRIM22 significantly inhibited TRIM22-induced proliferation of GBM cells in vivo and in vitro. In conclusion, our study showed that TRIM22 regulates SPHK2 transcription and activates MAPK signaling through posttranslational modification of two critical regulators of MAPK signaling in GBM cells.
참고문헌 (36)
- Baccarini, M., "Second nature : biological functions of the Raf-1"kinase"", FEBS Lett, 579, pp.0~3277 (2005)
- |2 mitogen-activated protein kinase pathway as a master regulator of the G1-to S-phase transition, "Oncogene", 2007, 3227~
- Roux, P. P., "ERK and p38 MAPK-activated protein kinases : a family of protein kinases with diverse biological functions", Microbiol. Mol. Biol. Rev, 68, pp.320~344 (2004)
- Daniel, P., "Sensitivity of GBM cells to cAMP agonistmediated apoptosis correlates with CD44 expression and agonist resistance with MAPK signaling", Cell Death Dis, 7, pp.e2494~ (2016)
- Chen, X., "Activation of JNK and p38 MAPK mediated by ZDHHC17 drives glioblastoma multiforme development and malignant progression", Theranostics, 10, pp.998~1015 (2020)
- Xu, Y., "RND2 attenuates apoptosis and autophagy in glioblastoma cells by targeting the p38 MAPK signalling pathway", J. Exp. Clin. Cancer Res, 39, pp.174~ (2020)
- Vitucci, M., "Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis", Neuro. Oncol, 15, pp.1317~1329 (2013)
- Shi, D., "Ubiquitin becomes ubiquitous in cancer : emerging roles of ubiquitin ligases and deubiquitinases in tumorigenesis and as therapeutic targets", Cancer Biol. Ther, 10, pp.737~747 (2010)
- Hatakeyama, S., "TRIM proteins and cancer", Nat. Rev. Cancer, 11, pp.792~804 (2011)
- Akutsu, M., "Ubiquitin chain diversity at a glance", J. Cell Sci, 129, pp.875~880 (2016)
- Swatek, K. N., "Ubiquitin modifications", Cell Res, 26, pp.399~422 (2016)
- Bigenzahn, J., "LZTR1 is a regulator of RAS ubiquitination and signaling", Science, 362, pp.1171~1177 (2018)
- Sato, T., "The TRIM-FLMN protein TRIM45 directly interacts with RACK1 and negatively regulates PKCmediated signaling pathway", Oncogene, 34, pp.1280~1291 (2015)
- Yin, H., "GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK", Erk-TRIM2 signaling axis, 2017, pp.51, 1191~1198
- Duan, Z., "Identification of TRIM22 as a RING finger E3ubiquitin ligase", Biochem. Biophys. Res. Commun, 374, pp.502~506 (2008)
- Bo, G., "Tripartite motif-containing 22 inhibits the activity of hepatitis B virus core promoter, which is dependent on nuclear-located RING domain", Hepatology, 50, pp.424~433 (2010)
- Zhang, F., "Sphingosine kinase 2 inhibitor ABC294640 suppresses neuronal excitability and inhibits multiple endogenously and exogenously expressed voltage-gated ion channels in cultured cells", Channels(Austin), 14, pp.216~230 (2020)
- Dymond, A., "Effects of cytochrome P450(CYP3A4 and CYP2C19)inhibition and induction on the exposure of selumetinib, a MEK1", 2 inhibitor, in healthy subjects : results from two clinical trials, 2017, pp.73, 175~184
- Fei, X., "Eupatilin inhibits glioma proliferation, migration, and invasion by arresting cell cycle at G1", S phase and disrupting the cytoskeletal structure, 2019, pp.11, 4781~4796
- Fei, X., "The role of Toll-like receptor 4 in apoptosis of brain tissue after induction of intracerebral hemorrhage", J. Neuroinflammation, 16, pp.234~ (2019)
- Ji, J., "TRIM22 activates NF-κB signaling in glioblastoma by accelerating the degradation of IκBα", Cell Death Differ, 28, pp.367~381 (2021)
- Chong, H., "Positive and negative regulation of Raf kinase activity and function by phosphorylation", EMBO J, 20, pp.3716~3727 (2001)
- Avruch, J., "Raf meets Ras : completing the framework of a signal transduction pathway", Trends Biochem. Sci, 19, pp.279~283 (1994)
- Rubinfeld, H., "The ERK cascade : a prototype of MAPK signaling", Mol. Biotechnol, 31, pp.151~174 (2005)
- Murphy, L. O., "MAPK signal specificity : the right place at the right time", Trends Biochem. Sci, 31, pp.268~275 (2006)
- Roberts, P., "Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer", Oncogene, 26, pp.3291~3310 (2007)
- LeBlanc, F., "Sphingosine kinase-2 is overexpressed in large granular lymphocyte leukemia and promotes survival through Mcl-1", Br. J. Haematol, 190, pp.405~417 (2020)
- Zhang, R., "Hypoxic preconditioning protects cardiomyocytes against hypoxia", reoxygenation-induced cell apoptosis via sphingosine kinase 2 and FAK, Exp. Mol. Pathol, pp.2016, 100[DOI]
- -thiazolidine-2, 4-dione(K145)as a selective sphingosine kinase-2 inhibitor and anticancer agent, "PLoS ONE", 2013, e56471~
- Dymond, A., "Pharmacokinetics and pharmacogenetics of the MEK1", 2 inhibitor, selumetinib, in Asian and Western healthy subjects : a pooled analysis, 2017, pp.73, 717~726
- "MEK1/2 inhibition is effective in subsets of pediatric low-grade glioma" (2019)[URL]
- Zhu, Q., "BRCA1 tumour suppression occurs via heterochromatin-mediated silencing", Nature, 477, pp.179~184 (2011)
- Minsky, N., "Monoubiquitinated H2B is associated with the transcribed region of highly expressed genes in human cells", Nat. Cell Biol, 10, pp.483~488 (2008)
- Shema, E., "The histone H2B-specific ubiquitin ligase RNF20", hBRE1 acts as a putative tumor suppressor through selective regulation of gene expression, 2008, pp.22, 2664~2676
- Badie, B., "Combined radiation and p53 gene therapy of malignant glioma cells", Cancer Gene Ther, 6, pp.155~162 (1999)
- Uzzaman, M., "In vivo gene delivery by embryonic-stemcell-derived astrocytes for malignant gliomas", Neuro. Oncol, 11, pp.102~108 (2009)