Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells
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Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells. / Hartmann, Wolfgang; Koch, Arend; Brune, Hendrik; Waha, Anke; Schüller, Ulrich; Dani, Indra; Denkhaus, Dorota; Langmann, Wilhelma; Bode, Udo; Wiestler, Otmar D; Schilling, Karl; Pietsch, Torsten.
in: AM J PATHOL, Jahrgang 166, Nr. 4, 04.2005, S. 1153-62.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells
AU - Hartmann, Wolfgang
AU - Koch, Arend
AU - Brune, Hendrik
AU - Waha, Anke
AU - Schüller, Ulrich
AU - Dani, Indra
AU - Denkhaus, Dorota
AU - Langmann, Wilhelma
AU - Bode, Udo
AU - Wiestler, Otmar D
AU - Schilling, Karl
AU - Pietsch, Torsten
PY - 2005/4
Y1 - 2005/4
N2 - Medulloblastomas (MBs), the most frequent malignant brain tumors of childhood, presumably originate from cerebellar neural precursor cells. An essential fetal mitogen involved in the pathogenesis of different embryonal tumors is insulin-like growth factor II (IGF-II). We screened human MB biopsies of the classic (CMB) and desmoplastic (DMB) variants for IGF2 transcripts of the four IGF2 promoters. We found IGF2 transcription from the imprinted promoter P3 to be significantly increased in the desmoplastic variant compared to the classic subgroup. This was not a result of loss of imprinting of IGF2 in desmoplastic tumors. We next examined the interaction of IGF-II and Sonic hedgehog (Shh), which serves as a critical mitogen for cerebellar granule cell precursors (GCPs) in the external granule cell layer from which DMBs are believed to originate. Mutations of genes encoding components of the Shh-Patched signaling pathway occur in approximately 50% of DMBs. To analyze the effects of IGF-II on Hedgehog signaling, we cultured murine GCP and human MB cells in the presence of Shh and Igf-II. In GCPs, a synergistic effect of Shh and Igf-II on proliferation and gli1 and cyclin D1 mRNA expression was found. Igf-II, but not Shh, induced phosphorylation of Akt and its downstream target Gsk-3beta. In six of nine human MB cell lines IGF-II displayed a growth-promoting effect that was mediated mainly through the IGF-I receptor. Together, our data point to an important role of IGF-II for the proliferation control of both cerebellar neural precursors and MB cells.
AB - Medulloblastomas (MBs), the most frequent malignant brain tumors of childhood, presumably originate from cerebellar neural precursor cells. An essential fetal mitogen involved in the pathogenesis of different embryonal tumors is insulin-like growth factor II (IGF-II). We screened human MB biopsies of the classic (CMB) and desmoplastic (DMB) variants for IGF2 transcripts of the four IGF2 promoters. We found IGF2 transcription from the imprinted promoter P3 to be significantly increased in the desmoplastic variant compared to the classic subgroup. This was not a result of loss of imprinting of IGF2 in desmoplastic tumors. We next examined the interaction of IGF-II and Sonic hedgehog (Shh), which serves as a critical mitogen for cerebellar granule cell precursors (GCPs) in the external granule cell layer from which DMBs are believed to originate. Mutations of genes encoding components of the Shh-Patched signaling pathway occur in approximately 50% of DMBs. To analyze the effects of IGF-II on Hedgehog signaling, we cultured murine GCP and human MB cells in the presence of Shh and Igf-II. In GCPs, a synergistic effect of Shh and Igf-II on proliferation and gli1 and cyclin D1 mRNA expression was found. Igf-II, but not Shh, induced phosphorylation of Akt and its downstream target Gsk-3beta. In six of nine human MB cell lines IGF-II displayed a growth-promoting effect that was mediated mainly through the IGF-I receptor. Together, our data point to an important role of IGF-II for the proliferation control of both cerebellar neural precursors and MB cells.
KW - Animals
KW - Blotting, Western
KW - Brain
KW - Cell Proliferation
KW - Cells, Cultured
KW - Cerebellar Neoplasms
KW - DNA Primers
KW - Fetus
KW - Hedgehog Proteins
KW - Humans
KW - Medulloblastoma
KW - Mice
KW - Neurons
KW - Promoter Regions, Genetic
KW - RNA, Messenger
KW - Receptor, Insulin
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Somatomedins
KW - Stem Cells
KW - Trans-Activators
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/S0002-9440(10)62335-8
DO - 10.1016/S0002-9440(10)62335-8
M3 - SCORING: Journal article
C2 - 15793295
VL - 166
SP - 1153
EP - 1162
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 4
ER -