Abstract
RhoB is a small GTPase that regulates actin organization and vesicle transport. It is required for signalling apoptosis in transformed cells that are exposed to farnesyltransferase inhibitors, DNA-damaging agents or taxol. Genetic analysis in mice indicates that RhoB is dispensable for normal cell physiology, but that it has a suppressor or negative modifier function in stress-associated processes, including cancer.
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References
Van Aelst, L. & D'Souza-Schorey, C. Rho GTPases and signaling networks. Genes Dev. 11, 2295–2322 (1997).
Ridley, A. J. Rho proteins: linking signaling with membrane trafficking. Traffic 2, 303–310 (2001).
Wu, W. J., Erickson, J. W., Lin, R. & Cerione, R. A. The β-subunit of the coatomer complex binds Cdc42 to mediate transformation. Nature 405, 800–804 (2000).
Adamson, P., Paterson, H. F. & Hall, A. Intracellular localization of the p21rho proteins. J. Cell Biol. 119, 617–627 (1992).
Lebowitz, P. F., Davide, J. P. & Prendergast, G. C. Evidence that farnesyltransferase inhibitors suppress Ras transformation by interfering with Rho activity. Mol. Cell. Biol. 15, 6613–6622 (1995).
Zalcman, G. et al. Regulation of Ras-related RhoB protein expression during the cell cycle. Oncogene 10, 1935–1945 (1995).
Lebowitz, P. & Prendergast, G. C. Functional interaction between RhoB and the transcription factor DB1. Cell Adhes Commun 6, 277–287 (1998).
Michaelson, D. et al. Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J. Cell Biol. 152, 111–126 (2001).
Mellor, J., Flynn, P., Nobes, C. D., Hall, A. & Parker, P. J. Prk1 is targeted to endosomes by the small GTPase, RhoB. J. Biol. Chem. 273, 4811–4814 (1998).
Gampel, A., Parker, P. J. & Mellor, H. Regulation of epidermal growth factor receptor traffic by the small GTPase RhoB. Curr. Biol. 9, 955–958 (1999).
Jahner, D. & Hunter, T. The ras-related gene RhoB is an immediate-early gene inducible by v-Fps, epidermal growth factor, and platelet-derived growth factor in rat fibroblasts. Mol. Cell. Biol. 11, 3682–3690 (1991).
Fritz, G., Kaina, B. & Aktories, K. The ras-related small GTP-binding protein RhoB is immediate-early inducible by DNA damaging treatments. J. Biol. Chem. 270, 25172–25177 (1995).
Engel, M. E., Datta, P. K. & Moses, H. L. RhoB is stabilized by transforming growth factor-β and antagonizes transcriptional activation. J. Biol. Chem. 273, 9921–9926 (1998).
Trapp, T. et al. GTPase RhoB: an early predictor of neuronal death after transient focal ischemia in mice. Mol. Cell. Neurosci. 17, 883–894 (2001).
Lebowitz, P., Casey, P. J., Prendergast, G. C. & Thissen, J. Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB. J. Biol. Chem. 272, 15591–15594 (1997).
Prendergast, G. C. et al. Critical role of Rho in cell transformation by oncogenic Ras. Oncogene 10, 2289–2296 (1995).
Du, W., Lebowitz, P. & Prendergast, G. C. Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB. Mol. Cell. Biol. 19, 1831–1840 (1999).
Du, W. & Prendergast, G. C. Geranylgeranylated RhoB mediates inhibition of human tumor cell growth by farnesyltransferase inhibitors. Cancer Res. 59, 5492–5496 (1999).
Chen, Z. et al. Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice. J. Biol. Chem. 275, 17974–17978 (2000).
Liu, A.-X., Rane, N., Liu, J.-P. & Prendergast, G. C. RhoB is dispensable for mouse development, but it modifies susceptibility to tumor formation as well as cell adhesion and growth factor signaling in transformed cells. Mol. Cell. Biol. 21, 6906–6912 (2001).
Khosravi-Far, R., Solski, P. A., Clark, G. J., Kinch, M. S. & Der, C. J. Activation of Rac1, RhoA, and mitogen-activated protein kinase are required for Ras transformation. Mol. Cell. Biol. 15, 6443–6453 (1995).
van Golen, K. L., Wu, Z.-F., Qiao, X. T., Bao, L. W. & Marajver, S. D. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res. 60, 5832–5838 (2000).
Lebowitz, P. F. & Prendergast, G. C. Non-Ras targets for farnesyltransferase inhibitors: focus on Rho. Oncogene 17, 1439–1447 (1998).
Prendergast, G. C. Farnesyltransferase inhibitors: antineoplastic mechanism and clinical prospects. Curr. Opin. Cell Biol. 12, 166–173 (2000).
Cox, A. D. & Der, C. J. Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim. Biophys. Acta 1333, F51–F71 (1997).
Prendergast, G. C. & Du, W. Targeting farnesyltransferase: is Ras relevant? Drug Resist. Updat 2, 81–84 (1999).
Rowinsky, E. K., Windle, J. J. & Von Hoff, D. D. Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J. Clin. Oncol. 17, 3631–3652 (1999).
Sebti, S. M. & Hamilton, A. D. Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies. Oncogene 19, 6584–6593 (2000).
Prendergast, G. C. & Oliff, A. Farnesyltransferase inhibitors: antineoplastic properties, mechanisms of action, and clinical prospects. Semin. Cancer Biol. 10, 443–452 (2000).
Adjei, A. A. Blocking oncogenic Ras signaling for cancer therapy. J. Natl Cancer Inst. 93, 1062–1074 (2001).
Prendergast, G. C. et al. Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton. Mol. Cell. Biol. 14, 4193–4202 (1994).
Liu, A.-X., Du, W., Liu, J.-P., Jessell, T. M. & Prendergast, G. C. RhoB alteration is required for the apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Mol. Cell. Biol. 20, 6105–6113 (2000).
Kohl, N. E. et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nature Med. 1, 792–797 (1995).
Fritz, G. & Kaina, B. RhoB encoding a UV-inducible ras-related small GTP-binding protein is regulated by GTPases of the rho family and independent of JNK, ERK, and p38 MAP kinase. J. Biol. Chem. 272, 30637–30644 (1997).
Liu, A.-X., Cerniglia, G. J., Bernhard, E. J. & Prendergast, G. C. RhoB is required for the apoptotic response of neoplastically transformed cells to DNA damage. Proc. Natl Acad. Sci. USA 98, 6192–6197 (2001).
Lowe, S. W., Ruley, H. E., Jacks, T. & Housman, D. E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74, 957–967 (1993).
Bernhard, E. J. et al. The farnesyltransferase inhibitor FTI-277 radiosensitizes Hras-transformed rat embryo fibroblasts. Cancer Res. 56, 1727–1730 (1996).
Bernhard, E. J. et al. Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of Ras oncogenes. Cancer Res. 58, 1754–1761 (1998).
Fritz, G. & Kaina, B. Ras-related GTPase RhoB forces alkylation-induced apoptotic cell death. Biochem. Biophys. Res. Comm. 268, 784–789 (2000).
Mendrysa, S. M. & Perry, M. E. The p53 tumor suppressor protein does regulate expression of its own inhibitor, MDM2, except under conditions of stress. Mol. Cell. Biol. 20, 2023–2030 (2000).
Liu, J. P. & Jessell, T. M. A role for RhoB in the delamination of neural crest cells from the dorsal neural tube. Development 125, 5055–5067 (1998).
Flynn, P., Mellor, H., Casamassima, A. & Parker, P. J. Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase. J. Biol. Chem. 275, 11064–11070 (2000).
Balendran, A. et al. PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Curr. Biol. 9, 393–404 (1999).
Jiang, K. et al. The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol. Cell. Biol. 20, 139–148 (2000).
Liu, A.-X. & Prendergast, G. C. Geranylgeranylated RhoB is sufficient to mediate tissue-specific suppression of Akt kinase activity by farnesyltransferase inhibitors. FEBS Lett. 481, 205–208 (2000).
Du, W., Liu, A. & Prendergast, G. C. Activation of the PI3K–AKT pathway masks the proapoptotic effect of farnesyltransferase inhibitors. Cancer Res. 59, 4808–4812 (1999).
Fritz, G. & Kaina, B. Ras-related GTPase RhoB represses NF-κB signaling. J. Biol. Chem. 276, 3115–3122 (2001).
Montaner, S., Perona, R., Saniger, L. & Lacal, J. C. Multiple signalling pathways lead to the activation of the nuclear factor-αB by the Rho family of GTPases. J. Biol. Chem. 273, 12779–12785 (1998).
Perona, R. et al. Activation of the nuclear factor-κB by Rho, Cdc42, and Rac-1 proteins. Genes Dev. 11, 463–475 (1997).
Gnad, R., Kaina, B. & Fritz, G. Rho GTPases are involved in the regulation of NF-κB by genotoxic stress. Exp. Cell Res. 264, 244–249 (2001).
Kato, T. et al. Localization of a mammalian homolog of diaphanous, mDia1, to the mitotic spindle in HeLa cells. J. Cell Sci. 114, 775–784 (2001).
Miquel, K. et al. GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells. Cancer Res. 57, 1846–1850 (1997).
Song, S. Y., Meszoely, I. M., Coffey, R. J., Pietenpol, J. A. & Leach, S. D. KRas-independent effects of the farnesyl transferase inhibitor L-744,832 on cyclin B1/cdc2 kinase activity, G2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cells. Neoplasia 2, 261–272 (2000).
Ashar, H. R. et al. The farnesyl transferase inhibitor SCH 66336 induces a G2 → M or G1 pause in sensitive human tumor cell lines. Exp. Cell Res. 262, 17–27 (2001).
Crespo, N. C., Ohkanda, J., Yen, T. J., Hamilton, A. D. & Sebti, S. M. The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells. J. Biol. Chem. 276, 16161–16167 (2001).
Gachet, Y., Tournier, S., Millar, J. B. A. & Hyams, J. S. A MAP kinase-dependent actin checkpoint ensures proper spindle orientation in fission yeast. Nature 412, 352–354 (2001).
Fritz, G. & Kaina, B. Transcriptional activation of the small GTPase gene RhoB by genotoxic stress is regulated via a CCAAT element. Nucleic Acids Res. 29, 792–798 (2001).
Prendergast, G. C. Mode of action of farnesyltransferase inhibitors. Lancet Oncology 1, 73 (2000).
Clark, E. A., Golub, T. R., Lander, E. S. & Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).
Ise, K. et al. Targeted deletion of the Hras gene decreases tumor formation in mouse skin carcinogenesis. Oncogene 19, 2951–2956 (2000).
Suwa, H. et al. Overexpression of the RhoC gene correlates with progression of ductal adenocarcinoma of the pancreas. Br. J. Cancer 77, 147–152 (1998).
van Golen, K. L. et al. A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin. Cancer Res. 5, 2511–2519 (1999).
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DATABASES
Glossary
- AKT
-
Also known as protein kinase B. This is a serine/threonine protein kinase activated by the phosphatidylinositol-3-OH kinase pathway that activates survival responses.
- ANAPHASE-PROMOTING COMPLEX
-
(APC). This complex triggers chromosome separation at the end of metaphase in mitosis. It is inactivated by checkpoint pathways that are triggered by damage to the mitotic spindle or by kinetochore problems that cause chromosomes to be released from the spindle.
- MOUSE EMBRYO FIBROBLASTS
-
(MEFs). These cells are widely used to characterize the gross effects of gene deletion because they can be readily cultured from mice, including knockout mice that do not survive to term.
- NF-κB
-
A heterodimeric transcription factor that is regulated by a variety of extracellular stimuli, including many that regulate cell survival.
- TAXOL
-
A chemotherapeutic agent that kills cancer cells in mitosis by stabilizing microtubules.
- TRANSFORMATION
-
The processes through which normal cells acquire malignant character.
- XENOGRAFT ASSAY
-
A tumour-formation assay in which heterologous tumour cells are grown in an immunologically compromised mouse, or other animal, often under the skin.
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Prendergast, G. Actin' up: RhoB in cancer and apoptosis. Nat Rev Cancer 1, 162–168 (2001). https://doi.org/10.1038/35101096
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DOI: https://doi.org/10.1038/35101096
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