Geranylgeranyltransferase I Promotes Human Glioma Cell Growth Through Rac1 Membrane Association and Activation

Overview

Journal J Mol Neurosci

Specialties Molecular Biology
Neurology

Date 2012 Oct 18

PMID 23073905

Citations 8

Authors

Xiuping Zhou

JinMing Qian

Lei Hua

Qiong Shi

Zhi Liu

Yinfu Xu

Ben Sang

Jianbing Mo

Rutong Yu

Affiliations

Soon will be listed here.

Abstract

Geranylgeranyltransferase I (GGTase-I) is responsible for the posttranslational lipidation of several signaling proteins such as RhoA, Rac1, and Cdc42, which contribute to tumor development and metastasis. However, the role of GGTase-I in the progression of human glioma is largely unknown. Here, we provide the evidence that Rac1 mediates the effects of GGTase-I on the proliferation and apoptosis in human glioma cells. We found that GGTase-I was abundantly expressed in human primary glioma tissues. Inhibition or downregulation of GGTase-I markedly decreased the proliferation of glioma cells and induced their apoptosis, while overexpression of GGTase-I promoted cell growth in vitro. Inactivation of GGTase-I eliminated geranylgeranylation of RhoA and Rac1, prevented them from targeting to the plasma membrane, and inhibited Rac1 activity. Furthermore, overexpressing wild type or constitutively active Rac1 stimulated glioma cell growth, similar to the effect of GGTase-I overexpression. Importantly, overexpressing dominant-negative Rac1 or Rac1 with the prenylation site deleted or mutated abrogated GGTase-I-induced proliferation in glioma cells. These results confirm the view that geranylgeranylation is essential to the activity and localization of Rho family proteins and suggest that Rac1 is required for GGTase-I-mediated glioma growth.

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References

Hirata E, Yukinaga H, Kamioka Y, Arakawa Y, Miyamoto S, Okada T . In vivo fluorescence resonance energy transfer imaging reveals differential activation of Rho-family GTPases in glioblastoma cell invasion. J Cell Sci. 2012; 125(Pt 4):858-68. DOI: 10.1242/jcs.089995. View

Sequeira L, Dubyk C, Riesenberger T, Cooper C, van Golen K . Rho GTPases in PC-3 prostate cancer cell morphology, invasion and tumor cell diapedesis. Clin Exp Metastasis. 2008; 25(5):569-79. DOI: 10.1007/s10585-008-9173-3. View

Liu M, Sjogren A, Karlsson C, Ibrahim M, Andersson K, Olofsson F . Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer. Proc Natl Acad Sci U S A. 2010; 107(14):6471-6. PMC: 2852017. DOI: 10.1073/pnas.0908396107. View

Sjogren A, Andersson K, Khan O, Olofsson F, Karlsson C, Bergo M . Inactivating GGTase-I reduces disease phenotypes in a mouse model of K-RAS-induced myeloproliferative disease. Leukemia. 2010; 25(1):186-9. DOI: 10.1038/leu.2010.242. View

Taylor J, Reid T, Terry K, Casey P, Beese L . Structure of mammalian protein geranylgeranyltransferase type-I. EMBO J. 2003; 22(22):5963-74. PMC: 275430. DOI: 10.1093/emboj/cdg571. View

Nakabayashi H, Shimizu K . HA1077, a Rho kinase inhibitor, suppresses glioma-induced angiogenesis by targeting the Rho-ROCK and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signal pathways. Cancer Sci. 2010; 102(2):393-9. DOI: 10.1111/j.1349-7006.2010.01794.x. View

Fukuda A, Hikita A, Wakeyama H, Akiyama T, Oda H, Nakamura K . Regulation of osteoclast apoptosis and motility by small GTPase binding protein Rac1. J Bone Miner Res. 2005; 20(12):2245-53. DOI: 10.1359/JBMR.050816. View

Moomaw J, Casey P . Mammalian protein geranylgeranyltransferase. Subunit composition and metal requirements. J Biol Chem. 1992; 267(24):17438-43. View

Sun J, Ohkanda J, Coppola D, Yin H, Kothare M, Busciglio B . Geranylgeranyltransferase I inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice. Cancer Res. 2003; 63(24):8922-9. View

10.

Kazi A, Carie A, Blaskovich M, Bucher C, Thai V, Moulder S . Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol Cell Biol. 2009; 29(8):2254-63. PMC: 2663293. DOI: 10.1128/MCB.01029-08. View

11.

Zhang F, Casey P . Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996; 65:241-69. DOI: 10.1146/annurev.bi.65.070196.001325. View

12.

Hoshino D, Koshikawa N, Seiki M . A p27(kip1)-binding protein, p27RF-Rho, promotes cancer metastasis via activation of RhoA and RhoC. J Biol Chem. 2010; 286(4):3139-48. PMC: 3024806. DOI: 10.1074/jbc.M110.159715. View

13.

Zhao Y, Lam D, Yang J, Lin J, Tham C, Ng W . Targeted suicide gene therapy for glioma using human embryonic stem cell-derived neural stem cells genetically modified by baculoviral vectors. Gene Ther. 2011; 19(2):189-200. DOI: 10.1038/gt.2011.82. View

14.

Lane K, Beese L . Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. J Lipid Res. 2006; 47(4):681-99. DOI: 10.1194/jlr.R600002-JLR200. View

15.

Michaelson D, Silletti J, Murphy G, DEustachio P, Rush M, Philips M . Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J Cell Biol. 2001; 152(1):111-26. PMC: 2193662. DOI: 10.1083/jcb.152.1.111. View

16.

Yokoyama K, Goodwin G, Ghomashchi F, Glomset J, Gelb M . A protein geranylgeranyltransferase from bovine brain: implications for protein prenylation specificity. Proc Natl Acad Sci U S A. 1991; 88(12):5302-6. PMC: 51860. DOI: 10.1073/pnas.88.12.5302. View

17.

Joly A, POPJAK G, Edwards P . In vitro identification of a soluble protein:geranylgeranyl transferase from rat tissues. J Biol Chem. 1991; 266(21):13495-8. View

18.

Elias M, Klimes V . Rho GTPases: deciphering the evolutionary history of a complex protein family. Methods Mol Biol. 2011; 827:13-34. DOI: 10.1007/978-1-61779-442-1_2. View

19.

Wong K, Mohammadi S, Isberg R . Disruption of RhoGDI and RhoA regulation by a Rac1 specificity switch mutant. J Biol Chem. 2006; 281(52):40379-88. DOI: 10.1074/jbc.M605387200. View

20.

Zhou X, Luo Z . Regulation of protein prenyltransferase in central neurons. Commun Integr Biol. 2009; 2(2):138-40. PMC: 2686367. DOI: 10.4161/cib.7819. View