DF/HCC Program Affiliation

Neuro-Oncology

Research Abstract

Each year in the United States, 17000 new cases of primary brain tumors are diagnosed, of which the large majority are comprised of the gliomas. Progress in our understanding of the pathogenesis of gliomas has been slow in part because of the lack of clear markers of tumor initiation and progression. Although astrocytes or their precursors are thought to be the cell of origin in the most common gliomas that include the glioblastoma tumors, we are just beginning to characterize the mechanisms that regulate the proliferation and differentiation of astrocytes and their precursors in the developing central nervous system. In studies employing an in vitro cell culture system that recapitulates aspects of the development of the mammalian cerebral cortex, we found that CNTF-related cytokines impose a glial fate on cerebral cortical precursor cells by inducing their differentiation into astrocytes and inhibiting their differentiation into neurons. We also found that although CNTF activates both the JAK-STAT and Ras-MAPK signaling pathways in the precursor cells, the JAK-STAT signaling pathway selectively promotes astrocyte differentiation whereas the Ras-MAPK signaling pathway suppresses gliogenesis. It will be important to use studies of gliogenesis during normal development as a guide to determine if aberrancies in the mechanisms that regulate gliogenesis contribute to the pathogenesis of brain gliomas.

Publications

• Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y.The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases.Cell 2007 Mar 23;128(6):1077-88.
  17320160
• Kim AH, Bonni A.Thinking within the D box: initial identification of Cdh1-APC substrates in the nervous system.Mol Cell Neurosci 2007 Mar;34(3):281-7.
  17223572
• Lehtinen MK, Bonni A.Modeling oxidative stress in the central nervous system.Curr Mol Med 2006 Dec;6(8):871-81.
  17168738
• Cai B, Chang S, Becker EB, Bonni A, Xia Z.p38 MAP kinase mediates apoptosis through phosphorylation of Bimel at Ser65.J Biol Chem 2006 Jul 3.
  16818494
• Lasorella A, Stegmüller J, Guardavaccaro D, Liu G, Carro MS, Rothschild G, de la Torre-Ubieta L, Pagano M, Bonni A, Iavarone A.Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth.Nature 2006 Jul 27;442(7101):471-
  16810178
• Stegmüller J, Konishi Y, Huynh MA, Yuan Z, Dibacco S, Bonni A.Cell-intrinsic regulation of axonal morphogenesis by the Cdh1-APC target SnoN.Neuron 2006 May 4;50(3):389-400.
  16675394
• Becker EB, Bonni A.Pin1 mediates neural-specific activation of the mitochondrial apoptotic machinery.Neuron 2006 Mar 2;49(5):655-62.
  16504941
• Shalizi A, Gaudillière B, Yuan Z, Stegmüller J, Shirogane T, Ge Q, Tan Y, Schulman B, Harper JW, Bonni A.A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation.Science 2006 Feb 17;311(5763):1012-7.
  16484498
• Shalizi AK, Bonni A.Brawn for Brains: The Role of MEF2 Proteins in the Developing Nervous System.Curr Top Dev Biol 2005;69:239-66.
  16243602
• Stegmüller J, Bonni A.Moving past proliferation: new roles for Cdh1-APC in postmitotic neurons.Trends Neurosci 2005 Nov;28(11):596-601.
  16168498
• Berndtsson M, Konishi Y, Bonni A, Hägg M, Shoshan M, Linder S, Havelka AM.Phosphorylation of BAD at Ser-128 during mitosis and paclitaxel-induced apoptosis.FEBS Lett 2005 Jun 6;579(14):3090-4.
  15907327
• Benedito AB, Lehtinen M, Massol R, Lopes UG, Kirchhausen T, Rao A, Bonni A.The transcription factor NFAT3 mediates neuronal survival.J Biol Chem 2005 Jan 28;280(4):2818-25.
  15537643
• Mao Z, Bonni A, Xia F, Nadal-Vicens M, Greenberg ME.Neuronal activity-dependent cell survival mediated by transcription factor MEF2.Science 1999 Oct 22;286(5440):785-90.
  10531066
• Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME.Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway.Science 1997 Oct 17;278(5337):477-83.
  9334309
• Yuan Z, Becker EB, Merlo P, Yamada T, DiBacco S, Konishi Y, Schaefer EM, Bonni A.Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons.Science 2008 Mar 21;319(5870):1665-8.
  18356527
• Stegmuller J, Huynh MA, Yuan Z, Konishi Y, Bonni A.TGFbeta-Smad2 signaling regulates the Cdh1-APC/SnoN pathway of axonal morphogenesis.J Neurosci 2008 Feb 20;28(8):1961-9.
  18287512
• de la Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ, Levy DE, Depinho RA, Bonni A.Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway.Genes Dev 2008 Feb 15;22(4):449-62.
  18258752
• de la Torre-Ubieta L, Bonni A.Combinatorial assembly of neurons: from chromatin to dendrites.Trends Cell Biol 2008 Feb;18(2):48-51.
  18222691
• Shalizi A, Bilimoria PM, Stegmuller J, Gaudilliere B, Yang Y, Shuai K, Bonni A.PIASx is a MEF2 SUMO E3 ligase that promotes postsynaptic dendritic morphogenesis.J Neurosci 2007 Sep 12;27(37):10037-46.
  17855618
• Becker EB, Bonni A.Pin1 in neuronal apoptosis.Cell Cycle 2007 Jun 1;6(11):1332-5.
  17568190
• Ramos B, Gaudilliere B, Bonni A, Gill G.Transcription factor Sp4 regulates dendritic patterning during cerebellar maturation.Proc Natl Acad Sci U S A 2007 Jun 5;104(23):9882-7.
  17535924
• Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villén J, Becker EB, DiBacco S, de la Iglesia N, Gygi S, Blackwell TK, Bonni A.A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span.Cell 2006 Jun 2;125(5):987-1001.
  16751106
• Reginato MJ, Mills KR, Becker EB, Lynch DK, Bonni A, Muthuswamy SK, Brugge JS.Bim regulation of lumen formation in cultured mammary epithelial acini is targeted by oncogenes.Mol Cell Biol 2005 Jun;25(11):4591-601.
  15899862
• Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME.Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms.Science 1999 Nov 12;286(5443):1358-62.
  10558990
• Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME.Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.Cell 1999 Mar 19;96(6):857-68.
  10102273
• Bonni A, Greenberg ME.Neurotrophin regulation of gene expression.Can J Neurol Sci 1997 Nov;24(4):272-83.
  9398973
• Frank DA, Robertson MJ, Bonni A, Ritz J, Greenberg ME.Interleukin 2 signaling involves the phosphorylation of Stat proteins.Proc Natl Acad Sci U S A 1995 Aug 15;92(17):7779-83.
  7544001
• Bonni A, Ginty DD, Dudek H, Greenberg ME.Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals.Mol Cell Neurosci 1995 Apr;6(2):168-83.
  7551568
• Thompson MA, Ginty DD, Bonni A, Greenberg ME.L-type voltage-sensitive Ca2+ channel activation regulates c-fos transcription at multiple levels.J Biol Chem 1995 Mar 3;270(9):4224-35.
  7876182
• Misra RP, Bonni A, Miranti CK, Rivera VM, Sheng M, Greenberg ME.L-type voltage-sensitive calcium channel activation stimulates gene expression by a serum response factor-dependent pathway.J Biol Chem 1994 Oct 14;269(41):25483-93.
  7929249
• Ginty DD, Bonni A, Greenberg ME.Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB.Cell 1994 Jun 3;77(5):713-25.
  8205620
• Bonni A, Frank DA, Schindler C, Greenberg ME.Characterization of a pathway for ciliary neurotrophic factor signaling to the nucleus.Science 1993 Dec 3;262(5139):1575-9.
  7504325