Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas.
Insulin-like growth factor I receptor (IGF-IR) has been implicated in the normal and malignant growth of many cell types including cells from the central nervous system. In the cerebellar cortex IGF-IR mRNA is found in granular cells and IGF-I stimulation is mitogenic and protects cells from low-potassium-induced apoptosis. Since primitive neuroectodermal tumors/medulloblastomas (PNETs/medulloblastomas) are suspected to originate from the external cerebellar granular layer, it is reasonable to postulate that IGF-IR and/or its signaling molecules may contribute to the transformation of these poorly differentiated cells. To study activation of the IGF-IR system in medulloblastomas, we have utilized an antibody (anti-pY1316) that specifically recognizes the phosphorylated (active) form of the IGF-IR. Medulloblastoma biopsy specimens were positive when examined immunohistochemically with anti-Y1316 antibody. Further analysis of the IGF-IR system was performed in three human (Daoy, TE-671, D283 Med) and four mouse (BsB8, BsB13, Bs-1b, Bs-1c) medulloblastoma cell lines. All the murine cell lines examined express IGF-IR and PI3-kinase at relatively normal levels, and grossly overexpress IRS-1, when compared with normal mouse cerebellum. Within 15 min following IGF-I stimulation both mouse and human cell lines phosphorylate the beta subunit of the IGF-IR, IRS-1, Akt, and MAP kinases. They respond with cell proliferation when stimulated solely with IGF-I and are strongly inhibited when challenged with a dominant negative mutant of the IGF-IR (486/STOP), or with antisense oligonucleotides against the IGF-IR mRNA.
Wang
J Y
JY
Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, 1900 North 12th Street, Biology Life Science Building, Room 238 Philadelphia, Pennsylvania, PA 19122, USA.
Del Valle
L
L
Gordon
J
J
Rubini
M
M
Romano
G
G
Croul
S
S
Peruzzi
F
F
Khalili
K
K
Reiss
K
K
D000818:Animals; D002455:Cell Division; D002528:Cerebellar Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1