Abstract
Tuberous sclerosis (TS) is an autosomal dominant disease associated with the formation of usually benign tumors or hamartomas. The disease is connected with upregulation of mammalian target of rapamycin, central regulator of protein translation, which is usually regarded to be activated by Akt kinase. Here, we show for the first time that in all four brain lesions and one angiomyolipoma from TS patients both extracellular signal-regulated kinase (Erk) and p90 ribosomal S6 kinase 1 activation as well as Erk-dependent phosphorylation of p70 ribosomal S6 kinase 1 are markedly elevated whereas Akt, participating in the classical pathway of mammalian target of rapamycin activation is not always activated. Erk activation is also present in TS-derived cell lines. Importantly, Erk inhibition leads to the decrease of proliferation potential of such lines. These results show that Erk is specifically implicated in the pathogenesis of hamartomas.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Dan H. C., Sun M., Yang L., et al. (2002) Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J. Biol. Chem. 277, 35,364–35,370.
Dong J. and Pan D. (2004) Tsc2 is not a critical target of Akt during normal Drosophila development. Genes Dev. 18, 2479–2484.
Gera J. F., Mellinghoff I. K., Shi Y., et al. (2004) AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J. Biol. Chem. 279, 2737–2746.
Govindarajan B., Mizesko M. C., Miller M. S., et al. (2003) Tuberous sclerosis-associated neoplasms express activated p42/44 mitogen-activated protein (MAP) kinase, and inhibition of MAP kinase signaling results in decreased in vivo tumor growth. Clin. Cancer Res. 9, 3469–3475.
Han S., Santos T. M., Puga A., et al. (2004) Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions. Cancer Res. 64, 812–816.
Hartmann W., Koch A., Brune H., et al. (2005) Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells. Am. J. Pathol. 166, 1153–1162.
Henske E. P., Wessner L. L., Golden J., et al. (1997) Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am. J. Pathol. 151, 1639–1647.
Inoki K., Li Y., Zhu T., Wu J., and Guan K. L. (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657.
Jansen F. E., Notenboom R. G., Nellist M., et al. (2004) Differential localization of hamartin and tuberin and increased S6 phosphorylation in a tuber. Neurology 63, 1293–1295.
Johannessen C. M., Reczek E. E., James M. F., Brems H., Legius E., and Cichowski K. (2005) The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl. Acad. Sci. USA 102, 8573–8578.
Jozwiak J. (2006) Hamartin and tuberin: working together for tumour suppression. Int. J. Cancer 118, 1–5.
Jozwiak J. and Jozwiak S. (2005) Giant cells: contradiction to two-hit model of tuber formation? Cell Mol. Neurobiol. 25, 795–805.
Jozwiak S., Schwartz R. A., Janniger C. K., and Bielicka-Cymerman J. (2000) Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J. Child Neurol. 15, 652–659.
Jozwiak S., Dabora S., Kasprzyk-Obara J., Domanska-Pakiela D., and Grajkowska W. (2001) [Tests for loss of heterozygosity in tuberous sclerosis]. Przegl. Lek. 58(Suppl 1), 12–15.
Kinkl N., Sahel J., and Hicks D. (2001) Alternate FGF2-ERK1/2 signaling pathways in retinal photoreceptor and glial cells in vitro. J. Biol. Chem. 276, 43,871–43,878.
Kinzler K. W. and Vogelstein B. (1996) Lessons from hereditary colorectal cancer. Cell 87, 159–170.
Kitamura T., Ogawa W., Sakaue H., et al. (1998) Requirement for activation of the serine-threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but not of glucose transport. Mol. Cell Biol. 18, 3708–3717.
Knowles M. A., Habuchi T., Kennedy W., and Cuthbert-Heavens D. (2003) Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. Cancer Res. 63, 7652–7656.
Lehman J. A., Calvo V., and Gomez-Cambronero J. (2003) Mechanism of ribosomal p70S6 kinase activation by granulocyte macrophage colony-stimulating factor in neutrophils: cooperation of a MEK-related, THR421/SER424 kinase and a rapamycin-sensitive, m-TOR-related THR389 kinase. J. Biol. Chem. 278, 28,130–28,138.
Liu X., Powlas J., Shi Y., et al. (2004) Rapamycin inhibits Akt-mediated oncogenic transformation and tumor growth. Anticancer Res. 24, 2697–2704.
Long X., Lin Y., Ortiz-Vega S., Yonezawa K., and Avruch J. (2005) Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702–713.
Ma L., Chen Z., Erdjument-Bromage H., Tempst P., and Pandolfi P. P. (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193.
McCoy M. S., Bargmann C. I., and Weinberg R. A. (1984) Human colon carcinoma Ki-ras2 oncogene and its corresponding proto-oncogene. Mol. Cell Biol. 4, 1577–1582.
Meikle L., McMullen J. R., Sherwood M. C., et al. (2005) A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes. Hum. Mol. Genet. 14, 429–435.
Mizuguchi M. and Takashima S. (2001) Neuropathology of tuberous sclerosis. Brain Dev. 23, 508–515.
Mizuguchi M., Ikeda K., and Takashima S. (2000) Simultaneous loss of hamartin and tuberin from the cerebrum, kidney and heart with tuberous sclerosis. Acta Neuropathol. (Berl.) 99, 503–510.
Nellist M., Burgers P. C., van den Ouweland A. M., Halley D. J., and Luider T. M. (2005) Phosphorylation and binding partner analysis of the TSC1-TSC2 complex. Biochem. Biophys. Res. Commun. 333, 818–826.
Onda H., Lueck A., Marks P. W., Warren H. B., and Kwiatkowski D. J. (1999) Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J. Clin. Invest. 104, 687–695.
Potter C. J., Pedraza L. G., and Xu T. (2002) Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4, 658–665.
Roux P. P., Ballif B. A., Anjum R., Gygi S. P., and Blenis J. (2004) Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. USA 101, 13,489–13,494.
Tabuchi S., Takigawa H., Oka A., Mizuguchi M., Horie Y., and Watanabe T. (2003) Subependymal giant cell astrocytoma with positive tuberin expression—case report. Neurol. Med. Chir (Tokyo) 43, 616–618.
Takahashi D. K., Dinday M. T., Barbara N. M., and Baraban S. C. (2004) Abnormal cortical cells and astrocytomas in the Eker rat model of tuberous sclerosis complex. Epilepsia 45, 1525–1530.
Wlodarski P., Kasprzycka M., Liu X., et al. (2005) Activation of mammalian target of rapamycin in transformed B lymphocytes is nutrient dependent but independent of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, insulin growth factor-I, and serum. Cancer Res. 65, 7800–7808.
Zhang Y., Gao X., Saucedo L. J., Ru B., Edgar B. A., and Pan D. (2003) Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 5, 578–581.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jozwiak, J., Grajkowska, W., Kotulska, K. et al. Brain tumor formation in tuberous sclerosis depends on erk activation. Neuromol Med 9, 117–127 (2007). https://doi.org/10.1007/BF02685886
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02685886